For More Information GO TO Aspartame (NutraSweet) Toxicity Home Page: http://www.holisticmed.com/aspartame/ 8. Phenylalanine The article states: "...the presence of phenylalanine, however, is a potential concern for persons suffering from phenylketornuia (PKU)--a rare genetic disease in which phenylalanine is improperly metabolized. .... But remember that PKU is extremely rare, and that phenylalanine is an important nutrient for the vast majority of people." It is unfortunate that Dr. Leibovitz glosses over such a crucial issue of phenylalanine intake. Everyone in the research community is well-aware of the fact that phenylalanine is an important amino acid and that it is commonly found in many foods. The issue revolves around the intake of a free amino acid that is very quickly absorbed without the presence of other amino acids that commonly make up protein. Never in the history of man has phenylalanine been ingested in free form without the presence of other amino acids on a long-term basis. 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. Phenylalanine Absorption ------------------------ When phenylalanine is taken as part of aspartame, particularly in liquid form, the phenylalanine is absorbed very quickly and can spike the plasma phenylalanine to extremely high levels. The plasma level of the amino acid phenylalanine can rise more than as seven (7) times its average baseline (fasting) value after aspartame ingestion (in liquids such as carbonated beverages) (Stegink 1987a, Matalon 1988). The spike in the plasma phenylalanine level lasts about 2 hours (average). Even lower levels of aspartame cause spikes in the plasma phenylalanine levels (Caballero 1986, Burns 1991). Plasma phenylalanine levels gradually rise after a meal but the levels do not rise nearly as high (Stegink 1987b). Lactating women ingesting fresh aspartame in orange juice were found to have increased phenylalanine levels in their milk (Stegink 1979c). Plasma Phenylalanine/Large Neutral Amino Acids (LNAA) Ratio When a high protein meal is eaten, a number of amino acids gradually enter the bloodstream. Other Large Neutral Amino Acids (LNAAs) in addition to phenylalanine enter the bloodstream after the proteins from the foods are broken down. The other LNAAs are: valine leucine isoleucine tryptophan tyrosine histidine methionine These amino acids tend to be more abundant in foods than phenylalanine. When a protein food is eaten the plasma level of all the LNAAs (including phenylalanine) rises gradually. However, since the other LNAAs are more abundant than phenylalanine, the Phenylalanine/(Other LNAA) ratio goes down (Fernstrom 1979, Maher 1984). In other words the plasma phenylalanine level gradually rises, but to a much less extent than the plasma level of the other LNAAs. Aspartame is the only "food" that contains phenylalanine and no other large neutral amino acids (LNAAs). Therefore, not only can the plasma phenylalanine level spike to high levels after aspartame ingestion, but the plasma phenylalanine/LNAA ratio also increases to very high levels after aspartame ingestion. In other words the phenylalanine level rises, and the other LNAA levels do not rise at all. Several studies have shown that ingestion of aspartame can spike the plasma phenylalanine levels and increase the phenylalanine/LNAA ratio tremendously (Stegink 1987a, Caballero 1986, Stegink 1989, Stegink 1990, Stegink 1979c). Ingestion of an aspartame-containing product along with a glucose or starch-containing product can increase the plasma phenylalanine/LNAA ratio much more than simply ingesting aspartame alone. Martin-Du Pan (1982) showed that doses of glucose as little as 6 grams can cause a drop in plasma LNAA levels by an average of 10%. Twenty-five (25) grams of glucose led to a 30% drop in plasma LNAA levels. Since these reductions in LNAA levels were caused by large decreases in the levels of most large neutral amino acids except phenylalanine which only had a small decrease, the plasma phenylalanine/LNAA ratio will be increased by administration of glucose or starch. Yokogoshi (1984) found this to be the case in studies on rats. Wolf-Novak (1990) confirmed this effect in humans. This large spike in plasma phenylalanine levels and the large increase in the phenylalanine/LNAA ratio after aspartame ingestion is one major difference between protein metabolism and aspartame metabolism. In fact, phenylalanine ingested as part of liquid aspartame-containing products produces a much more severe biochemical change then when phenylalanine is ingested in capsules or slow-dissolving tablets -- much like one would find it in a dietary supplement (Stegink 1987a, Burns 1990). In addition, many free amino acid supplements contain other LNAAs such that the plasma phenylalanine/LNAA ratio would not change significantly. NutraSweet researchers often try to argue that the peak level of the phenylalanine/LNAA ratio is not important, but only the "Area Under the Curve" (AUC) which is a combination of the level and the time the Phenylalanine/LNAA is above the baseline (i.e., fasting) level (Burns 1990). In this way, they try to claim that ingestion of phenylalanine in liquids which tends to spike the phenylalanine quickly and for a short period of time at high levels is the same as taking phenylalanine in capsules which spikes the plasma phenylalanine to a much less extent but for a longer time. One has to leave their brain at the door in order to buy into this argument. First of all, the whole argument falls apart when one realizes that they are using averages of all of the subjects for each time period to calculate the AUCs. Comparing each individual's AUC for liquid aspartame ingestion and capsule aspartame ingestion would show a much larger difference for most people than inappropriately using averages for each time period. Second, even using average measurements for each time period, Stegink (1987a) showed a much greater AUC for liquid aspartame ingestion as opposed to capsule ingestion. Third, capsule ingestion of aspartame, while still different than ingesting a high-protein meal because there are not other LNAAs present, comes closer to what the body is used to as far as the more gradual rise in plasma phenylalanine levels. The human body has never experienced such a sudden and large influx of phenylalanine without other LNAAs present every day for a lifetime. Finally, by using capsules, NutraSweet researchers are testing a different product with a much lower spike on plasma phenylalanine and phenylalanine/LNAA levels. The metabolism is quite different in when ingested in liquid as opposed to capsules. NutraSweet researchers are guessing that this hugh difference doesn't matter. Considering all of the serious health problems being linked to aspartame ingestion, I do not think it is appropriate to base aspartame testing on the wild guesses and wishful thinking of NutraSweet researchers. If they insist upon studying aspartame in capsules, then aspartame should only be sold in freshly prepared capsules. Burns (1991) claims that ingestion of aspartame or sucrose produce similar Phenylalanine/LNAA ratios. First, Burns (1991) inappropriately used the groups' average values for each time period. Second, the phenylalanine levels actually goes down when the sucrose is administered. This is an enormous metabolic difference from the large phenylalanine spikes when aspartame is administered. It is possible that the neutral amino acid transport sites at the blood brain barrier which are normally saturated with phenylalanine and other amino acids become less saturated when sucrose is administered and do not have a similar change in brain chemistry as occurs with aspartame. (See Brain Uptake of Phenylalanine below for details.) Third, the change in the Phenylalanine/LNAA ratio is relatively small when sucrose is given, but extended over a longer period of time than when aspartame is given. Therefore, Burns (1991) had to use the Area Under the Curve (AUC) nonsense to try to prove that the changes are the same with both sucrose and aspartame. Even using this argument, there was a greater increase the phenylalanine/LNAA ratio when aspartame was administered. It is clear that the biochemical changes that occur when sucrose is administered is quite dissimilar to the changes which occurs when aspartame is administered. Finally, it is unclear whether the ingestion of carbohydrates along with aspartame renders the phenylalanine part of aspartame more dangerous. Carbohydrate ingestion lowers the levels of Large Neutral Amino Acids (LNAAs) and therefore the neutral amino acid trasport cites may become unsaturated causing a smaller change in brain chemistry than would otherwise happen with the phenylalanine alone. Removal of Excess Phenylalanine ------------------------------- Excess phenylalanine is converted in the liver to the amino acid tyrosine by the enzyme phenylalanine hydroxylase. Persons who have a genetic defect know as Phenylketonuria (PKU) have little or no phenylalanine hydroxylase activity and can therefore not convert excess phenylalanine in the blood to tyrosine. Excess phenylalanine in the cases of such genetic defects is converted to phenylpyruvic acid and acetyl-phenylalanine and eliminated through the urine (Caballero 1988). However, in cases of PKU, excess phenylalanine can be quite toxic and such persons, who are identified at birth, are told to limit their phenylalanine intake and warned to not ingest aspartame. Persons are considered to be "hyperphenylalaninemic" if they have only 5% to 15% of normal phenylalanine hydroxylase activity (Matalon 1988). PKU and hyperphenylalaninemia are rare conditions that are identified at birth, making up approximately 0.014% of the population (Guttler 1988). Persons who are the carriers of the PKU gene, "PKU heterozygotes," usually have anywhere from 15% to 40% of normal phenylalanine hydroxylase activity (Matalon 1988) and make up approximately 2% of the population (Caballero 1986). PKU heterozygotes are not identified at birth any many people do not know that they are carriers of the PKU gene. Finally, it has been shown that the elderly population tends to have a delayed plasma phenylalanine clearance (Rudman 1991). This would tend to increase their susceptibility to the long-term negative effects of spiking the phenyalalnine/LNAA ratio. Rodent Phenylalanine Metabolism ------------------------------- It is important to understand that rodents metabolize phenylalanine much faster than humans. The conversion of phenylalanine to tyrosine occurs at a rate more than 12 times faster in rats than in humans (Caballero 1988). It takes 60 times the dose of aspartame in rats to produce a similar phenylalanine to tyrosine ratio (and therefore an equivalent change in the phenylalanine/LNAA ratio) as found when humans are given aspartame (Wurtman 1988). Therefore, a dose of aspartame of 1000 mg/kg given to a rat over its lifetime only approximates a dose of 17 mg/kg in humans as far as the phenylalanine part of aspartame is concerned. NutraSweet researchers have tried to claim that it only takes 2 to 6 times the amount of aspartame in mice and rats to cause an equivalent rise in plasma phenylalanine/LNAA ratio as is found in humans (Hjelle 1992). This experiment was conducted by NutraSweet Company and Hazelton Laboratory employees. The phenylalanine measurements in the rats and mice are so different than found by other researchers that they should be discounted. For example, a dose of 200 mg/kg of aspartame given to the rats was found to increase the plasma phenylalanine from 73.6 nmol/ml to 295.0 nmol/ml -- an increase of 4.0 times higher than the base value. The plasma tyrosine levels were found to increase from 91.6 nmol/ml to 212.0 nmol/ml -- a increase of 2.3 times higher than the base value. Wurtman (1983a) found that giving aspartame to rats at 200 mg/kg increased their plasma phenylalanine by only 1.92 times and increase their plasma tyrosine by 2.57 times. This shows that the tyrosine actually increased more than the phenylalanine. This makes sense since the rats convert phenylalanine to tyrosine much quicker than do humans. Yokogoshi (1984) showed similar results to Wurtman (1983a) after giving rats 200 mg/kg of aspartame. The plasma phenylalanine rose to 1.62 times its base value and the plasma tyrosine rose to 2.42 times its base value. Pinto (1988) tested 200 mg/kg of aspartame on mice. After one hour (half of the time alloted by the Wurtman and Yokogoshi experiments listed above), the plasma phenylalanine level was 1.26 times over its base value and the tyrosine was 1.48 times over its base value. The increases were less in this experiment than in Yokogoshi (1984) and Wurtman (1983a) because the measurements occurred at 1 hour, but the ratio of changes in phenylalanine to the changes in tyrosine are similar in all three experiments. For all three studies (Wurtman 1983a, Yokogoshi 1984, Pinto 1988), the plasma tyrosine rose 1.17 to 1.5 times more than the plasma phenylalanine. This is a relatively consistant result. In the NutraSweet-conducted experiment, the plasma phenylalanine rose 1.74 times more than the plasma tyrosine. This result is ridiculous. Even at the 500 mg/kg dosage there results in changes in plasma phenylalanine and tyrosine do not come close to matching any other researchers (Perego 1988, Pinto 1988). The rest of the discussion by Hjelle (1992) simply amounts to twisting of results from previous studies (which is something only someone intimately familiar with the research would be able to discover) and dredging up inaccurate information provided in previous NutraSweet-sponsored "research." The simple fact is that no one but NutraSweet researchers can seem to get rats to spike plasma phenylalanine and phenylalanine/LNAA levels similar to what happens in humans unless they give approximately 60 times the dosage typically tested in humans, i.e., over 1000 mg/kg. If they give less, the rats have increase tyrosine levels more than phenylalanine levels -- something which never occurs in humans with aspartame ingestion. Hjelle (1992) had the nerve to give the appearance that their results were similar to other studies: "The results at 200 mg/kg were similar to those of Yokogoshi (1984). We also obtained results similar to those of Fernstrom et al. (1983) who demonstrated that serum concentrations of PHE [phenylalanine] and tyrosine peaked in rats within 30-60 min. after an oral of 200 mg/kg of aspartame. The Cmaxs, Tmaxs and AUC for PHE and tyrosine at the 200 and 1,000 mg/kg doses of aspartame were generally the same as those calculated from data reported by Romano et al. (1990) who administered bolus doses of 250 and 1,000 mg/kg of aspartame to rats." I guess that since Hjelle (1992) decided to present such ridiculous phenylalanine and tyrosine measurements, it is not surprising that these researchers would go one step further in the insanity and imply that their results are similar to other studies. The plasma phenylalanine and tyrosine changes in Yogokoshi (1984), Fernstrom (1983), and Romano (1990) are enormously different than the changes shown in Hjelle (1992) as anyone who examines these studies can easily see. In fact, Hjelle (1992) goes on to admit at least one major difference: "However, at 1,000 mg/kg, Romano et al. (1990) reported plasma concentrations of PHE that were approximately one half of the current value and AUCs that were not directly proportional to the aspartame dose." Earlier Hjelle (1992) had said his data was "generally the same" as that of Romano (1990). But here he admits that his study had double the phenylalanine levels when 1,000 mg/kg was administered! Such obviously nonsensical results and such a deceptive presentation in this publication of the "research" performed by NutraSweet and Hazelton Laboratory personnel raises a very serious and important question: "If NutraSweet research cannot even honestly and accurately determine plasma phenylalanine and tyrosine levels in rats, how can we believe any study they have performed or will perform on any of their products"? Brain Uptake of Large Neutral Amino Acids (LNAAs) In humans, large neutral amino acids (LNAAs) compete for entry (at the neutral amino acid carrier sites) into the brain across the Blood Brain Barrier (BBB) (Pardridge 1988a). For example, when plasma phenylalanine levels are low, uptake of the LNAA methionine into the brain has been shown to increase. When plasma phenylalanine levels increase, uptake of the LNAA methionine into the brain has been shown to decrease (Comar 1981). Pardridge (1988a) points out that: "In experimental hyperphenylalaninemia, the impairment of brain protein synthesis can be normalized by the coadministration of other large neurtral amino acids that compete with phenylalanine at the neutral amino acid carrier sites within the brain capillary." A rise in the plasma phenylalanine/LNAA ratio leads to an increased uptake of phenylalanine into the brain and a decreased uptake of other LNAAs into the brain (Pardridge 1983). The neutral amino acid carrier sites are normally saturated with neutral amino acids (Pardridge 1986, Smith 1991, Shulkin 1995). Since the affinity for phenylalanine at the neutral amino acid transport sites is high, an increase in the plasma phenylalanine levels without a corresponding increase in the levels of other large neutral amino acids (LNAAs) could saturate the transports sites with phenylalanine and block the availability of other amino acids (Pardrige 1988a). NutraSweet funded a study by Koeppe (1991) where seven subjects received 34 mg/kg of fresh aspartame in a beverage on one day and a placebo drink on another day. Before each ingestion, a positron emission tomography (PET) was performed using [11C]ACHC as a tracer to estimate neutral amino acid transport across the blood brain barrier at different sites. Forty-five (45) minutes after ingestion of the beverage, another PET was performed to determine any changes in transport of neutral amino acids. The authors conclude: "We observed an 11.5% decrease in the amino acid transport rate constant K1 and a smaller decrease in the tissue distribution volume of ACHC (6%). Under conditions of normal dietary use, aspartame is thus unlikely to cause changes in brain amino acid uptake that are measurable by PET." Flaws ----- i. The second PET scan was performed at 45 minutes. This is a major flaw. The researchers based their assumption that plasma phenylalanine levels would peak at 45 minutes on an old study by Stegink (1977) which only showed average values for all subjects at each time period. When individual values are shown such as in Stegink (1987a), one can see the following estimations for peak phenylalanine levels after ingestion: Estimated Time of Peak Subject No. Phenylalanine Level (min.) 1 15 2 15 3 45 4 30 5 30 6 15 7 45 8 30 9 60 10 30 Mean 31.5 As can easily be seen, many of the subjects had plasma phenylalanine peaks at a much earlier time than 45 minutes. One subject had a peak at near 60 minutes. The measured mean peak phenylalanine level from Koeppe 1991 was only 56% of that measured in Stegink (1987a). It is safe to assume that the measured mean peak phenylalanine level from Stegink (1987a) was below the actual mean peak level because measurements occurred only every 15 minutes. It is also a fairly safe assumption that the actual mean peak phenylalanine levels from Stegink (1987a) were approximately twice as high as that measured in this study (Koeppe 1991). Therefore, their average values from the PET scan after aspartame ingestion was closer to measuring amino acid transport after ingestion of 17 mg/kg of aspartame as opposed to 34 mg/kg of aspartame. ii. The researchers based their conclusion on the groups' average change in amino acid transport rate at a particular time. This flaw tends to dismiss the possibility that there can be a differences in phenylalanine transport rates from person to person. One can easily see individual differences in phenyalalnine metabolism by looking at the different levels of peak plasma phenyalalnine from Stegink (1987a). There is probably also differences in the changes in neutral amino acid transport rates from person to person at the same plasma phenylalanine level. iii. The authors tend to dismiss an 11.5% change in the amino acid transport rate constant and a 6% change in the ACHC tissue distribution volume at what really amounts to 17 mg/kg of aspartame. However, one of the major points of concern with ingesting large amounts of free phenylalanine without other LNAAs is that it could cause the brain chemistry to change very slowly, almost imperceptibly over a period of months or years. After a single dose, the researchers found a small, but measurable change. Can these researchers find a change in blockages of arteries after a single dose of a high-fat meal. Or can they find significant changes to lung tissue after smoking a single cigarette? In this case they did find a measurable change after a single dose. Drinking significant amounts of aspartame-containing product regularly may very well cause gradual changes in brain chemistry due to the phenylalanine (not to mention the damage from the other parts of aspartame) over many months or years depending upon a person's susceptibility. The large number of serious neurological adverse reactions reported from medium- and long-term use of aspartame tends to add weight to this argument. iv. These researchers seemed to simply cut-and-paste NutraSweet's nonsensical dosage arguments from other "studies." First of all, they claim that they tested a high dose of aspartame or 34 mg/kg. 34 mg/kg is only two- thirds of the FDA Acceptable Daily Intake. Second, due to errors in timing of the PET scan, they were testing a value closer to 17 mg/kg of aspartame. The researchers further claimed that 34 mg/kg amounts to ~5 liters of diet beverage for a 76.3 kg man. However, they base this figure on 500 mg of aspartame per liter. In reality, there is closer to 600 mg in a liter of aspartame (Tsang 1985). Also, not everyone is a 76.3 kg man. A 50 kg woman would have to drink 2.8 liters of aspartame-containing beverage (or a 2-liter bottle plus a few of aspartame-containing products) to reach 34 mg/kg. The equivalent of a "Super Big Gulp" would nearly reach 17 mg/kg of aspartame (the equivalent amount actually measured in this experiment) for a 50 kg woman. Two cans of diet soda would cause a 25 kg child to reach the 17 mg/kg level. If we discuss diet orange soda, the amounts needed to reach 17 mg/kg are much less. Conclusion ---------- Even if a person ingested less aspartame than was ingested in this experiment, we get back to 1) the fact that there are individual susceptibilities and 2) it is the long-term ingestion that is the major concern as far as the phenylalanine goes, not a single ingestion. General Effects From Changes in Phenylalanine/LNAA Ratio It is nearly impossible to measure the very gradual changes that might occur in brain chemistry after months or years of ingesting phenylalanine from aspartame. We do, however, have some clues from animal studies as well as case histories. Yokogoshi (1984) found that aspartame given to rats significantly affected the brain levels of the amino acids tyrosine, valine, isoleucine, tryptophan, leucine, and phenyalalnine. Administration of aspartame and glucose increased these changes even more. Wurtman (1983a) found that the administration of aspartame plus glucose was shown to block the normal rise in brain 5- hydroxyindole (5-HIAA -- a metabolite of the neurotransmitter serotonin) levels that occur after glucose administration. Who knows what the consequences of regularly blocking a normal change in brain chemistry might be. Coulombe (1986) tested doses of 13, 130, and 650 mg/kg of aspartame on mice. He found significant changes in norephinephrine (NE) in hypothalamus, medulla oblongata, and corpus striatum. He also found changes in dopamine (DA) and various catecholamine metabolistes VMA, HVA, and DOPAC in certain sections of the brain. Finally, no changes in 5-HIAA were found. However, unlike Wurtman (1983a), Coulombe (1986) did not co-administer glucose with aspartame. Coulombe concludes: "Such observed alterations in brain neurotransmitter concentrations may be responsible for the reported clinical and behavioral effects associated with ASM [aspartame] ingestion." During (1988) gave doses of 200, 500, and 1000 mg/kg to rats. When 200 mg/kg was given to rats, there was an increase in basal dopamine (DA) of 59%. This was presumably because at such low doses in rats, the plasma tyrosine levels increase much more than the phenylalanine. At a dose which is more appropriate in mimicing what phenylalanine/tyrosine changes that occur in humans after aspartame administration -- 1000 mg/kg -- dopamine release was reduced by 26%. The authors conclude: "No corresponding changes were observed in the concentrations of DOPAC and HVA with any of the treatments, indicating that changes in brain phenylalanine and tyrosine levels may selectively affect production of the dopamine molecules that are preferentially released into synapses." .... Although the changes in dopamine release (the increase by 59% and the decrease by 26%) were small compared with the changes seen after a drug like amphetamine (2 mg/kg increasing release by 1600%), they may still be sufficient to cause behavioral effects, particularly in animals or humans with impaired nigrostriatal neurons." In addition to the consideration of humans with "impaired nigrostriatal neurons" one must consider the effects of a diminished dopamine release day after day for years. Reilly (1989) claims that aspartame does not alter levels of norephinephrine (NE) , serotonin (5-HT), dopamine (DA) in the rat. She administered 500 mg/kg per day to rats via their drinking water. Flaws ----- i. The changes found in DA by Coulumbe (1986) were to a large extent in areas of the brain not looked at in this experiment. ii. The researchers claim that they were using 10 times the FDA Acceptable Daily Intake (ADI) in this experiment. In reality they gave a total of 500 mg/kg of aspartame to the rats throughout the day. Since it takes 60 times the amount of aspartame to be equivalent to human intake, they were really giving the equivalent of 8.3 mg/kg of aspartame per day. This is less than one-fifth the FDA ADI! iii. The experiment lasted for only 30 days. They gave the equivalent of 8.3 mg/kg to rats for 30 days. This is hardly a good way to measure long-term effect. iv. The brain measurements may not have been at a time when obvious changes would be expected. No details were provided on the timing of the tests. Coulumbe (1986) found changes three hours after a single aspartame dose (650 mg/kg or the equivalent of 11 mg/kg in humans). The brain chemistry may have returned to closer to normal since the animals were not given a significant dose within a few hours of sacrifice. Fernstrom (1983) found that a relatively small dose of aspartame given to rats, 200 mg/kg caused changes in brain levels of phenylalanine and tyrosine. It is not surprising that the brain levels of tyrosine increased more than that of phenylalanine because at a dose of only 200 mg/kg the plasma tyrosine rises more than the plasma phenylalanine in a rat. At this dosage, it was no surprise that after a single administration there was no significant change in brain levels of 5-HT, DA, NE, or various metabolites of these neurotransmitters. Phenylalanine and Psychological/Psychiatry Problems --------------------------------------------------- Medium- to long-term use of real-world aspartame-containing products may precipitate or worsen depression and other psychological conditions. Gradual changes in brain chemistry and function caused by the phenylalanine part of aspartame (and possibly other breakdown products) could easily produce a myriad of problems in susceptible individuals. It is believed by some researchers that excessive spiking of plasma phenylalanine levels can affect the levels of serotonin in the brain and possibly lead to neurological problems such as depression (Pardridge 1986). Since neurological problems including depression seem to be occurring in near epidemic proportions, any change that would further lead to brain chemistry imbalances in the population over a long period of time should be of enormous concern. The U.S. Department of Health and Human Services lists the following figures for persons reporting psychological problems caused by aspartame (DHHS 1993b): Health Problem Count - Change in Mood quality or level 558 - Memory Loss 220 - "Other Neurological" [???] 210 - Sleep Problems 186 One has to bear in mind that it would be extremely difficult for many people to link their psychological problems to aspartame use because 1) aspartame-caused changes in brain chemistry often happeneds very slowly over a very long period of time, and 2) aspartame may not be the only causitive factor involved. In his survey of 551 aspartame reactors, Dr. H.J. Roberts found the following psychological health problems caused by aspartame consumption (Roberts 1988): # of people (%) - Severe depression 139 (25%) - "Extreme irritability" 125 (23%) - "Severe anixiety attacks" 105 (19%) - "Marked personality changes" 88 (16%) - Recent "severe insomnia" 76 (14%) - "Severe aggravation of phobias" 41 (7%) Dr. Leibovitz states: "In that study [Walton (1993)], 13 subjects (8 patients and 5 non-patient volunteers) given 300 mg of aspartame showed increased 'number and severity of symptoms for patients with a history of depression.' The main concern about this study is that 5 (out of 8 patients) were on antidepressants (mainly Prozac) at the same time they were given aspartame." What Dr. Leibovitz did not mention was the following two points: a. The study protocol was written to test 40 subjects for 20 days, but the Institutional Review Board stopped the study due to adverse reactions as described by Dr. Walton: The severity of some of the reactions is noteworthy; three study participants spontaneously reported that they felt they had been "poisoned." One of the three to use this term felt that her symptoms were so severe that she had to discontinue the capsules -- after 3 days of her second week [aspartame]. One patient, a 42-year- old PhD psychologist with a history of recurrent major depression, reported pain in his left eye, followed by retinal detachment requiring emergency surgery. On the day of his surgery (day 4 of his second [placebo] week) he discontinued his capsules and symptoms reporting. Although this event occurred during the placebo week, 6 days after the aspartame had been discontinued, another individual -- one of the three to use the term "poisoned" -- experienced a conjunctival hemorrhage for the first time in her life during the aspartame week. These events led the Chairman of the IRB to halt the project. b. There was a clear statistically significant increase in the overall number of adverse reactions in the depressed group of subjects. Table 1 Placebo Aspartame Headache 63% 88% Nervousness 25% 63% Dizziness 13% 25% Trouble remembering 0% 63% Binge eating 13% 13% Lower back pain 25% 25% Nausea 25% 100% Depression 38% 75% Insomnia 38% 50% Temper 0% 25% More energy 0% 25% Fatigue 0% 25% Malaise 0% 38% Weight loss 13% 0% Pain in eye 13% 0% Negative thoughts 0% 13% Bad taste in mouth 0% 13% Swollen lips 0% 13% Facial numbness 0% 13% Conjunctival hemorrhage 0% 13% Weight gain 0% 13% Irritability 0% 25% Less sleep 0% 0% Diarrhea 0% 0% Nightmares 0% 0% More sleep 0% 0% This experiment conducted by Walton (1993) was intended to test vulnerable patients -- those with mood disorders who may or may not be on antidepressants. Given the enormous number of people in the U.S. with mood disorders and who are on antidepressants, it is very important for thorough independent aspartame research to be conducted on this population. Walton's study showed that the subjects with a history of depression had a clear increase in headaches, nervousness, memory loss, nausea, depression, malaise, and a possible increase in a number of other adverse symtpoms. What would years of aspartame do to such patients? The reason why the non-depressed subjects did not show a statistically significant change in adverse reactions may have been due to the fact that capsules were used and that the study lasted only 20 days -- a short time when compared to a lifetime of use. On the positive side: a. This study lasted 20 days, many times longer than most NutraSweet funded studies. b. It was conducted by a researcher not connected to NutraSweet. In fact, NutraSweet refused to sell Dr. Walton the aspartame because they could not control the outcome of the study. On the negative side: a. Capsules were used to administer the aspartame. Much worse reactions would likely have been encountered had aspartame been ingested in real-world products. b. Only 3/5 of the Acceptable Daily Intake (ADI) was given to the subjects. The absolute minimum that should be tested is the current 50 mg/kg/day ADI. c. The control group should have been similar to the test group in mood disorder and percentage of antidepressents taken. It is difficult to understand how Dr. Leibovitz could minimuze the serious reactions that occurred in the group ingesting aspartame. At the very least, these reactions are a cause for great concern. How anyone could so easily recommend aspartame to the general population after reading this study is beyond me. It is necessary to correct some misunderstandings about the effects of phenylalanine on depression. A number of authors have suggested that phenylalanine can be taken to improve cognitive function and to treat depression. See Pearson (1982) for example. It is very important to understand that when phenylalanine supplements are taken, they are usually taken in capsule form and/or with other large neutral amino acids (LNAAs) (at least when taken on a long-term basis). This would, to some extent, offset negative effects. In addition, they are usually not taken recklessly (i.e., in liquid form and without other LNAAs) for a lifetime as is proposed for aspartame. There is some scientific evidence that phenylalanine can help some cases of depression when taken for a relatively short period of time (e.g., a few weeks). After that period, the evidence seems to indicate that the subjects become tolerant of the therapeutic effect. In a non-blinded study testing the efficacy of phenylalanine on depressed patients, Yaryura-Tobias (1974) gave 6 depressed patients 100 mg of d-l-phenylalanine or 100 mg of d-phenylalanine to 9 depressed patients. Earlier experiments had shown that urinary elimination of phenylethylamine (PEA), a metabolite of phenylalanine, is decreased in some cases of depression and therefore, Yaryura-Tobias believed that the administration of the phenylethylamine precursor, phenylalanine might improve cases of depression. The duration of the study was two weeks. Three of the six patients in the first group improved and seven of nine improved in the second group. One patient with depression and psycosis worsened. This study gives clues that short- term phenylalanine administration may improve some cases of depression. It says nothing about administering high doses of phenylalanine in liquid form (without other LNAAs) for a lifetime. Spatz (1975) gave 11 subjects with depression (and a low urinary phenylethylamine output) a daily dose of 100 mg of d- phenylalanine for five days, then 150 mg for five days, and finally 200 mg for five days. Most of the subjects had a significant improvement in their condition. The urinary phenylethylamine output increased after ten days of treatment and fell somewhat in most cases 20 days after treatment completed. This study, while not blinded, seems to show that short-term d-phenylalanine administration may improve some cases of depression. The authors hypothesize that a reduction in brain levels of phenylethylamine (the phenyalalnine metabolite) was one factor in causing the depression. Phenylethylamine has a very mild amphetamine- like effect. Beckmann (1977) administered to 20 depressed subjects 75-200 mg per day of d-l-phenylalanine for 20 days. Eighteen of the 20 patients had been treated in an outpatient setting with antidepressant drugs without any success. At the end of the study, eight patients had a complete recovery and four others had a good response. Out of the remaining eight patients, four had a mild to moderate improvement, and four had no improvement at all. Again, this was not a blinded trial. However, it does provide compelling evidence that short-term administration of phenylalanine may significantly improve some cases of depression. Beckmann (1979) administered 150-200 mg/day of d-l- phenylalanine to 20 depression patients and administered the antidepressant drug, imipramine, to 20 other depressed patients. At the end of 30 days there was a equally significant improvement in several parameters for both the phenylalanine and the imipramine patients. This is another study which provides evidence that the short-term administration of phenylalanine can improve depression in some cases. The authors hypothesized that cause of the improvement in the phenylalanine subjects was either increased brain levels of phenylethylamine or increased production of dopamine in the brain. (Phenylalanine --> Tyrosine --> Dopamine is one pathways for production of dopamine.) (Mann 1980) administered 200-600 mg/day of d-phenylalanine to 11 depressed patients for four weeks. There was a placebo week at the beginning of the trial. There were no significant improvements and two of the subjects had to drop out after becoming suicidal. The results in this experiment are quite different than previous experiments. There is not a clear reason why this result is different. Some of the earlier experiments used a hospital setting rather than an outpatient setting which would tend to change the results significantly. In addition, some of the earlier experiments used d-l-phenylalanine instead of just d-phenylalanine. Birkmayer (1984) administered 250 mg/day of l-phenylalanine and 5-10 mg/day of l-deprenyl to 155 unipolar depressed patients (102 outpatients and 53 inpatients). The dosages were given in the morning for 28 to 96 days. Ninety percent (90%) of the outpatients showed significant improvement and 80.5% of the inpatients showed significant improvement. Six percent (6%) of the outpatients did not improve and 4% had a worsening of their condition. Twelve percent (12%) of the inpatients did not improve and 7.5% dropped out. This non- blinded study provides compelling evidence that l- phenylalanine plus l-deprenyl given to depressed patients for a relatively short period of time can significantly improve depression in many cases. Wood (1985) tested 600 mg/day of l-phenylalanine on nineteen patients with Attention Deficit Disorder (ADD) in a 2-week, double-blind, crossover trial. The results showed significant increases in the patients' mood and overall functioning, but no improvement in the ADD. The therapeutic effects were not observed until after 5-7 days of l- phenylalanine administration. Mild sedation and fatigue were observed in doses over 600 mg. At the end of the two to three month initial testing period, all of the patients became tolerant of the therapeutic effects. Increasing dosage only resulted in increased sleepiness and fatigue. This study, once again, demonstrates that short-term administration of phenylalanine appears to improve mood significantly. However, it was clear that the effect wore off after a short time. This experiment is nothing like administering doses of liquid phenylalanine (from aspartame) without other LNAAs every day for months, years, or an entire lifetime. Sabelli (1986) gave 40 patients with major depression l- phenylalanine in capsules for three or more weeks. The dosage started at 1000 mg (two 500 mg capsules per day) and increased until therapeutic effects or side effects were noticed (up to 14 g/day). The patients were also give 100 mg of decarboxylase cofactor pyridoxine. Some of the patients were kept on lithium. They were allowed to use diazepam or flurazepam for sleep. At the start of the study, the depressed patients had significantly lower blood and urine concentrations of phenylacetic acid (PAA), a metabolite of phenylethylamine (which is a metabolite of phenylalanine) as compared to the 48 control subjects. The phenylalanine supplements increased urinary output and plasma levels of phenylethylamine (PEA) and phenylacetic acid (PAA) in depressed patients. Twenty (20) of the 40 depressed patients had a partial mood elevation, and 11 had a complete recovery. Several patients reported insomnia and increased anxiety and a few transient adverse reactions were reported such as headaches, constipation, and nausea. The results provides more compelling evidence that short-term administration of phenylalanine to depressed patients can improve mood. All of these studies provide some strong evidence of the therapeutic use of phenylalanine in treating depressed patients and elevating mood. Some large, double-blinded trials would be useful as well. However, all of these studies are very short compared to months and years of phenylalanine use from aspartame. In addition, many of the studies used capsules which do not lead to the same type of spike in plasma phenylalanine levels as does liquid administration. The concern that medium- and long-term ingestion of large amounts of phenylalanine, especially in liquid form, and without any other LNAAs, would significantly change brain chemistry leading to health problems is not addressed by these short-term studies on depression. From the independent studies available and the growing number of serious adverse reactions to aspartame, it appears that the long-term effects are being felt in the most susceptible population. The less susceptible population may be in for an unpleasant surprise should they continue this dangerous experiment. It is of interest to researchers that many depressed patients have a blood and urinary deficit of phenylethylamaine (PEA) and phenylacetic acid (PAA). Matalon (1988) showed that subjects ingesting aspartame at the FDA ADI levels had large intermittent spikes in the urinary excretion of PEA. However, some patients with psychiatric disorders have an excess of these phenylalanine metabolites (Boulton 1991). Schizophrenic patients appear to have an excess of phenylethylamine, for example. Such patients might not fare as well with long-term ingestion of real-world aspartame-containing products. Phenylalnine and Seizures ------------------------- Seizures and convulsions make up a total of 7.88% of the total aspartame-related adverse reaction complaints reported to the FDA (DHHS 1993b). Not long after aspartame's approval in beverages in 1983, seizures became such a significant problem that Community Nutrition Institute (CNI) petitioned the FDA to ban aspartame. CNI stated the following regarding the 80 aspartame-related seizures which were reported to the Center for Brain Science and Metabolism at Massachusetts Institute of Technology (MIT) (Food 1986): "These 80 cases meet the FDA's own definition of an imminent hazard to the public health, which requires the FDA to expeditiously remove a product from the market." Some researchers believe that medium- or long-term ingestion of free phenylalanine without other LNAAs lowers the seizure threshhold and precipitates seizures in individuals who would otherwise not have them (Pardridge 1986, Wurtman 1985a). A large body of evidence shows that monoamines -- norepinephrine, dopamine, and serotonin -- can modulate seizure activity and severity (Jobe 1988). It is thought by some researchers (Wurtman 1985a) that phenylalanine may gradually change the level of dopamine, norepinephrine, or serotonin and thus lower the seizure threshold in humans. A number of independent animal studies have shown that aspartame administered to rodents does lower the seizure theshold (Pinto 1986, Maher 1987, Garattini 1988, Kim 1988). The doses used were appeared quite high, i.e., 1000 mg/kg, but remember that one has to divide by 60 to get the equivalent effects of phenylalanine in humans. Still, the effects on animal experiments may be difficult to extrapolate to humans. It is very important to realize that phenylalanine may not be the only factor in the countless seizures linked to aspartame usage. Low-level methanol poisoning, regular ingestion of free aspartic acid in liquids, and regular ingestion of DKP may also play a part in the seizures. There is no consensus on all of the causitive factors, but phenylalanine seems to be one of the likely culprits. Elsas (1988) tested six adult phenylketonuria heterozygotes and one normal volunteer for two weeks in a double-blind, double-crossover study of four 2-week intervals. The amount of phenylalanine given was approximately equivalent to 34 mg/kg of aspartame per day. There was a wide range in the changes in phenylalanine levels. One subject who had a semifasting plasma phneylalanine concentration of 136 uM which rose to 539 uM on phenylalanine supplementation, compained of emotional changes during the phenylalanine supplementation and withdrew from further studies. Another subject had several instances of forgetfulness during the testing phase. Elsas found that there was a slowing of the mean power frequency (MPF) (in the high-frequency alpha- band) of the EEG measurement when the plasma phenylalanine increased, even for small changes in the phenylalanine levels. Walton (1988) presented eight sample case histories of persons suffering seizures from aspartame and stopping those seizures by stopping the intake of aspartame. Walton points out that the reports of seizures from aspartame as well as those of mania (Walton 1986), panic attacks (Wurtman 1983b), and weight gain (Blundell 1986) provide evidence that aspartame may be causing alteration in monoamine metabolism which then causes or contributes to these health problems. In 1992, an independent researcher, Camfield (1992), showed that children with a history of seizures who ingested a single dose of aspartame had abnormal EEG spike waves discharges. This was the first independent scientific test of aspartame and seizures since the Elsas (1988) study showing abnormal EEG measurements. Beyond the hundreds of reported case histories of seizures due to aspartame, it raised additional red flags. Monsanto/NutraSweet was quick to respond with a series of seriously flawed studies intended to "prove" that aspartame does not cause seizures. 1. Shaywitz (1994a) studied 9 children (ages 5-13) who had clinical evidence of seizure disorders for 7 days. He claimed that no seizures were noted nor were there unusual EEG measurements. Selected Flaws -------------- a. Eight out of nine of the subjects were on antiepileptic medication at the time of the study. This definately helped prevent seizures and abnormal EEG readings. b. The aspartame was encapsuled which significantly lessens the plasma spikes of the amino acids. It's difficult to believe that the investigators were not aware of this fact. It also appears that the aspartame was taken near mealtime (breakfast) which would further cut down on the plasma amino acid spike and the methanol toxicity. c. The aspartame was fresh and did not include the numerous breakdown products found in real-world aspartame-containing products. d. The dosage was less than 1/2 the amount that Frey (1976) found that children of that age can ingest when aspartame products are freely available. It was less than 2/3 of the Acceptable Daily Intake (ADI) and less than 1/3 of what they should test (i.e., double the ADI). They base their reasoning on the laughable food survey results discussed earlier in this document. e. A 14-day study is hardly long enough to see seizures develop. Some people are on real-world aspartame products for months or years before they get regular seizures. f. The blood sample was taken when the methanol would have long since been converted to formic acid. The investigator testing the blood samples was none other than Dr. Thomas Tephly. As discussed earlier in this document, urinary formate measures are worthless at low doses, even when those doses can cause health problems. Also, statistically significant changes in blood formate levels are not always present in exposure to low levels of methanol (especially when averages are used for each time period) as discussed earlier. 2. Rowen (1995) used a single dose of aspartame to test 15 adults and 2 children who had a claimed that aspartame caused seizures. He claimed that no clinical seizures were experienced nor were there any statistically significant differences in EEG measurements. Selected Flaws -------------- a. Sixteen of the 17 subjects were on antiepileptic drugs which definately helped to prevent seizures or abnormal EEGs (especially since they hadn't taken aspartame 7 days before the study started and didn't take real-world aspartame on the study). b. This was a one day experiment! Much too short to determine anything. c. The aspartame was encapsuled which significantly lessens the plasma spikes of the amino acids. It's difficult to believe that the investigators were not aware of this fact. Two of the three aspartame doses were administered during meals which would further cut down on the plasma amino acid spike and the methanol toxicity. d. The aspartame was fresh and did not include the numerous breakdown products found in real-world aspartame-containing products. e. The investigators imply that their difficulty finding their goal of 60 subjects suggests that seizures linked to aspartame are rare. This is a ridiculous assumption as there are hundreds of cases registered with the FDA (1993) and countless others reported to independent parties (Stoddard 1995b). There are likely many times more than this that go unreported or undiagnosed. Their inability to find subjects is probably related to 1) inadequate recruitment methods as described by Kulczycki (1995); and 2) people being extremely unwilling to provoke seizures in the interest of "science." It is unlikley that Camfield's small, idependent study (Camfield 1992) showing abnormal spike waves in children who ingest aspartame and the hundreds of reported case histories of aspartame-caused seizures (and probably many more unreported cases) can hold up under the barrage of flawed NutraSweet-funded studies on seizures as shown above. Aspartame ingestion has lead to seizures (including grand mal and petit mal) and convulsions in long-term users. Below is a copy of a case history from the Internet: "In Dec. 1990, I began having strange symptoms. I would awaken in the early morning hours, sometimes with a feeling of anxiety, and smell a strong odor of burning toast. The first time it happened, I went downstairs at 5:00 A.M. in the belief that one of my children was in the kitchen trying to fix breakfast. I was astonished to find no one there. My husband was unable to detect this odor. I had other olfactory hallucinations (simple seizures) for a period of a couple of months. Sometimes it was the odor of toast, sometime burning rubber, even men's cologne. I had one episode of strong deja vu, which is also considered a seizure indicator. I was otherwise in good physical and mental health. In January of 1991, I had a complex partial seizure while driving my car to work. This seizure was evidence by feeling the time was slowed down, that I could only move my foot from the accelerator to the brake by a strong act of will, and involuntary blinking of my eyes. I managed to pull off the road and waited for a while until I felt I could drive. When I got to work, I was told by my colleagues that my speech was slurred. I had trouble completing sentences. The slurring resolved in a couple of days, but the trouble completing sentences persisted for a while. I also experienced post-ictal "fog" for about a week. My memory for normal work and family activities was compromsied, and I had difficulties performing my customary duties. I underwent an EEG that day which showed slowing on one side of the brain. I later had another EEG (sleep- deprived) with the same results. I also had an MRI of my brain, which was normal. Dr. Don Smith, a neurologist in Englewood, Colorado, evaluated me, and asked me to keep track of any seizure activity. He restricted me from driving. After a few more olfactory hallucinations, he decided to put me on medication to control my seizures. He started me on a low dose of Tegretol, which I was instructed to increase over a period of a few weeks until I was at a therapeutic dose. I became ill before the therapeutic dose, with severe sore throat, swollen glands, fatigue and fever. Blood tests revealed that my bone marrow was depressed from the Tegretol. My WBC was 2.0. He told me to stop taking the Tegretol and recover from the illness, and that we would evaluate medication later. I spend the next two weeks in near seclusion waiting for my immune system to recover so I could go out in public without being abnormally vulnerable to disease. Meanwhile, my friend and colleague Kathy Goebel, who was Clinical Coordinator of the Epilepsy Center at Colorado Neurological Institute, told me about an article she had read in a neurological journal. The author stated that aspartame is a neuroexcitotoxin, and that it could lower a person's seizure threshold. At that time, I was using approximately four packets of Equal a day, in tea, coffee and cereal, and also consuming NutraSweet in dessert products such as diet Jello and ice cream. Kathy suggested that I give up all products containing aspartame to see if it had an effect on my seizure activity. I did this immediately. My olfactory hallucinations stopped, and I was greatly relieved. Dr. Smith was skeptical at first and wanted to put me on another seizure medication. I convinced him to wait and see if I had more seizures. I never had another one until recently when I unknowingly ate a popsickle that had NutraSweet in it. I had an olfactory hallucination in the early morning hours. This happened recently, after I moved to Georgia, so Dr. Smith doesn't know about that one. Dr. Smith was convinced that my seizures had, in fact, been caused by aspartame. He testified to this effect during a trial concerning a later automobile accident. The seizures I experienced and the sequelae were terrifying for me. As a Clinical Research Associate at Colorado Neurological Institute, I was very aware of the implications of a diagnosis of epilepsy. I did, in fact, lose my job at CNI, although any connection to my seizure was denied. She was lucky to get off aspartame when she did. For some people, the silent damage becomes more severe and the symptoms get much worse over a long period of time before they notice the connection. Phenylalanine and Behavior -------------------------- In a statement prevented to the U.S. Senate in 1985, research scientist, Dr. Richard Wurtman detailed his concerns about the effects of aspartame on brain chemistry and behavior (Wurtman 1985b): "1. When aspartame is consumed by laboratory rats in doses consonant with those sometimes ingested by people, it changes the chemical composition of the brain: It alters the brain's levels of some amino acids, and thereby affects the production and release of some of the neurotransmitters that the brain uses to carry signals from one nerve cell to another. These changes are enhanced when the aspartame is consumed along with a food that is rich in carbohydrate (as happens, for example, when someone eats a jelly sandwich or cookies or pasta along with diet soda). The changes in neurotransmitter release are likely to affect numerous brain functions (like the control of blood pressure, or the appetite) and aspects of behavior. "2. When normal human volunteers consume aspartame in doses that are high - but with the FDA's estimate of 90th percentile intakes - blood amino acid levels change in ways that almost certainly produce corresponding alterations in the chemical composition of their brains (especially if the aspartame has been ingested along with carbohydrate-rich food). However the particular changes that occur in the human's brain are likely to be different from those occurring in the rat's. (This is because the rat's liver destroys the phenylalanine in aspartame very quickly, while the human's liver destroys the phenylalanine much more slowly. The predominant effect of aspartame on the human's brain is likely to be an increase in its phenylalanine levels; the predominant effect on the rat's brain has been shown to be an increase in its levels of tyrosine, another amino acid that is formed when the liver metabolizes phenylalanine.) Hence, while it seems likely that aspartame, in doses of sufficient size, will affect brain functions and behavior in people, the precise nature of its effects cannot necessarily be predicted using data from experiments on rats. It is necessary also to do functional and behavioral studies on people, - normal people; people with metabolic disorders that impair their ability to emtabolize phenyalalnine; and people with brain disorders that might sensitize them to whatever changes in brain chemistry the aspartame might produce." Dr. Leibovitz states: "More recently, a New England Journal of Medicine article reported that diets high in aspartame (38 mg/kg body weight) were without effect on children's behavior or cognitive function (Wolraich 1994). This dose translates to about 2,800 mg of aspartame -- a hugh amount!" There have been a number of experiments on aspartame and behavior and most of them have been abyssmal. This is in part because the researchers do not understand the science of aspartame well enough to know that it is the long-term effects that tend to be more pronounced and problematic. Wolraich (1994) tested the behavioral effects of three weeks of sucrose (sugar), three weeks of saccharine, and three weeks of aspartame (38 mg/kg) on 23 children (ages 6-10) who reportedly reacted adversely to sugar and 25 normal preschool children (ages 3-5). A dietician prepared the menus adding the sweeteners to the food. All of the diets were free of additives, artificial food coloring, and preservatives. There were no statisitcal difference in the majority of behavioral measurements in any of the groups (aspartame, sucrose, saccharine). Flaws ----- i. Three weeks is hardy enough time to judge the behavioral effects from aspartame, especially if it is the slow changes in brain chemistry that cause those behavioral changes. As Dr. Roberts (1988) discovered, serious adverse reactions to aspartame do not occur immediately, but usually take weeks or months of ingestion. For this reason alone, the aspartame part of the experiment is questionable, at best. It is my opinion that most, "normal" children would tend to be less susceptible than "normal" adults because they likely have not spent as many years slowly damaging their health by eating a poor diet, (i.e., high-fat, high-junkfood) and/or living an unhealthy lifestyle. Therefore, a longer testing period is required for children. The testing period in this experiment was not long enough for most subjects, especially those without a history of regularly ingesting aspartame. ii. Susceptible individuals were not used as test subjects. The fact that 23 of the test subjects reportedly react to sugar has no bearing on their susceptibility to aspartame. It is that susceptibility which would determine the length of time before health problems appear and would also determine the type and severity of those health problems. iii. All of the additives and preservatives were removed from the food and the children were provided with what may have been a more healthy diet other than the junky or dangerous sweeteners. If the sweeteners had any negative behavioral effects, they were likely offset by the significant change in the diet. Food additives, preservatives, and coloring can cause allergic and intolerance reactions and lead to behavioral changes as reported by Crook (1994) and Brenner (1994). This flaw raises significant doubts about the way this study was conducted. Kruesi (1987) tested aspartame in only a single-dose administration (30 mg/kg) before measuring behavioral parameters in non-susceptible children. This study is obviously much too short to determine much of anything. Saravis (1990) tested a single dose of aspartame (34 mg/kg) plus a carbohydrate (polycose) on the learning and behavior of children who were in good health and had not reported food allergies, learning, behavioral, or emotional disorders. Again, this length of experiment might be useful to measure the effects of amphetamines, but certainly not for testing the safety of aspartame. A number of other studies on aspartame and behavior also used extremely short testing periods and often used very low doses (Wolraich 1985, Ferguson 1986, Goldman 1984, Milich 1986, Lieberman 1988). On the other hand, Spiers (1988) found that by administering 50 mg/kg doses (the FDA Acceptable Daily Intake limit) to five subjects and placebos to five controls in a blinded pilot study for 12 days, that two of the aspartame-exposed subjects became irritable and anxious. None of the controls had this reaction. In addition, three of the five aspartame- exposed subjects reported at least two of the following adverse effects: focal pains, autonomic symptoms, nausea, lightheadedness, sleep disruption, frontal headaches, photophobia, and visual disturbances. Finally, there were significant differences between the placebo and aspartame group in the more active tests such as word reading and "Think Fast." This pilot study differed from the other studies in that it recruited subjects who had a history of ingesting at least two to three cans of diet soda per day. The study that Spiers (1988) had intended for more susceptible individuals has apparently never been performed. Eventually, he took part in a another short study on healthy subjects (which will be discussed later) that was presented at an industry conference (Spiers 1993b). A more recent industry study on aspartame and behavior, Shaywitz (1994), will also be discussed in a later section. Phenylalnine and Pregnancy -------------------------- Given the fact that regular ingestion of aspartame can constantly spike the plasma phenylalanine and significantly increase the phenylalanine/LNAA ratio, I find it hard to understand how anyone can support its use during pregnancy. Methanol, aspartic acid, and DKP are also major concerns when discussing the intake of aspartame in pregnancy, but we will limit our discussion here to phenylalanine and pregnancy. The levels of phenylalanine in the brain of a developing fetus will be concentrated many times over that found in the mother's blood plasma. Here are the thoughts of two experts who testified before the U.S. Congress in 1987 (Elsas 1987; Pardridge 1987): Louis J. Elsas, II, M.D., Director, Division of Medical Genetics ---------------------------- "I have no previous contact with this type of hearing. But that is probably appropriate because I am a pediatrician, a Professor of Pediatrics at Emory, and have spent 25 years in the biomedical sciences, trying to prevent mental retardation and birth defects caused by excess phenylalanine ..... "First of all, in the developing fetus -- a situation not considered previously -- the mother is supplying that fetus with nutrients. And if she were dieting, let's say, and increasing her blood phenylalanine uniquely by taking Crystal Lite or Kool Aid, or any of the various diet foods now, to maintain her weight, and increased her blood phenylalanine from its normal 50 to 150 umoles/liter by chronic ingestion at 35 milligrames of aspartame per kilo per day -- which everyone agrees could be reached -- the placenta will concentrate her blood phenylalanine two-fold. So the fetal blood circulation to her baby in utero, is now 300 umole per liter of phenylalanine. The fetal brain then, as Dr. Pardridge will tell you, will increase further that concentration into the brain cells of that baby two- to four-fold. Those are neurotoxic levels in tissue culture and in many other circumstances. "This situation has not been studied in man. We have no research efforts in place to actively survey a cohort group, to find out whether chronic aspartame ingestion is adversely affecting our newborn population, either by producing microencephaly, mental retardation, or other birth defects that are associated with rises in blood phenylalanine. So that is one very worrisome area." His recommendations were as follows: "1) Immediate quantitative labeling of all aspartame-containing foods, so the consumer will know how much phenylalanine he/she is ingesting. 2) Declare an immediate moratorium on addition of aspartame to more foods and remove it from all low-protein beverages, foods,and children's medications. 3) Provide funds not controlled by industry to: a) Allow active surveillance for potential side-effects of aspartame on newborns whose mothers dieted with NutraSweet (Aspartame)-containing foods. b) Allow active evaluation of other users whose complaints cannot be adequately studied at present. c) Clarify the dose relationship and mechanisms by which L-phenylalanine affects human brain function. William M. Pardridge, M.D. Professor of Medicine --------------------- "I am a Professor of Medicine at the University of California, a practicing endocrinologist, and I have been doing neuroscience research on the blood- brain barrier transport of phenylalanine and other substances since 1970 ..... "...the third question that must now be addressed is, are there any untoward effects on the human brain that are associated with a four-fold increase in phenylalanine, bearing in mind that this molecule is a know neurotoxin? And three studies come to mind. One study shows that when blood phenylalanine in pregnant mothers is increased five-fold [to ~250 umole/l], there is a 10-point drop inthe I.Q. of the baby born of that mother. "A second study shows that if you measure choice reaction time, a test of higher cognitive function in humans, that when their blood phenylalanine is increased six-fold, there is a 10 percent shift in your ability to make a key decision before a video screen. "And a more recent study by Dr. Elsas has shown that there are quantitative changes in the human electroencephalogram when the blood phenylalanine is raised three-fold [to ~150-200 umole/l] -- something that clearly will happen in children who consume near 5 servings per 50-pound body weight." Levy (1994) found that plasma phenylalanine levels of around 400 umol/L in patients with mild hyperphenylalaninaemia were associated with a slightly lower birth measurements and offspring IQ than lower plasma phenylalanine measurements. However, Levy (1994) did not found any additional fetal loss, congenital heart disease or severe non-cardiac anomalies when compared to the control group. (Of course, these subjects were not ingesting methanol, aspartic acid, or DKP.) Smith (1995) pointed out that for every 100 umol/L rise in plasma phenylalanine levels, there is a clinically important change. Levy (1995) concurred that there is not a threshold level at 400 umol/L plasma phenylalanine. Given the lack of historical use of aspartame (unlike foods) and the lack of scientific information showing that constantly spiking the levels of plasma phenylalanine levels is okay for expectant mothers and developing fetuses, I would strongly recommend pregnant women stay away from aspartame. In addition, it is not clear what damage might occur from regular exposure to methanol, high levels of aspartic acid, and DKP. Phenylalnine and Other Conditions --------------------------------- a. Parkinson's Disease Levodopa, a hypotensive agent used in treating Parkinson's Disease patients has a significantly reduced effect when co- administered with phenylalanine (Irwin 1992). Levodopa is an LNAA which has to compete for entry into the brain with other LNAAs such as phenylalanine. The dosage of phenylalanine in this experiment appears to be 100 mg/kg which is fairly high. Still, the changes caused by the short treatment of phenylalanine were large. Regular dosing of Parkinson's Disease patients with phenylalanine from aspartame is not a good idea. The adverse reaction reports I have received seem to indicate that aspartame increases Parkinson's tremors, significantly in many cases. An industry study (funded by ILSI), Karstaedt (1993) which claimed to show no negative effects from the ingestion of aspartame on Parkinson's Disease patients was just a single dose study of fresh, encapsulated aspartame. Based on this single dose, the authors (unbelievably) recommended that aspartame need not be restricted in Parkinson's patients. ILSI seems to fund some of the most useless aspartame experiments I have ever seen. b. Melanoma A number of studies have found that phenylalanine-restricted diets limits the growth of melanoma in animals (Demopoulos 1966a, Jensen 1974) and in humans (Lorincz 1965, Demopoulos 1966b, Edmund 1974). However, a result which conflicts with previous human studies was found by Lawson (1985). Lawson (1985) restricted dietary phenylalanine levels to 8 mg/kg for 60 days in four advanced cancer (melanoma) patients. He did not find a positive effect. Since then, however, further animal studies have shown that limiting phenylalanine and tyrosine supresses the metastasis of melanoma (Elstad 1990). Since the ingestion of aspartame increases the plasma phenylalanine to very high levels in many cases, it would seem absurd to not recommend against the use of aspartame in melanoma patients. In addition, one wonders whether constantly spiking the plasma phenylalanine levels would, in some cases, cause the initial cancerous melanoma cells to metastasize more quickly such that melanoma might develop in cases where the immune system would normally have prevented it. Since 1983, not long after the approval of aspartame, there has been a significant and steady rise in in the age- adjusted incidence of melanoma in all susceptible age groups in the United States (Devesa 1995, Elder 1995). The melanoma incidence rates in whites (the most susceptible population group) rose from the 1973-1977 years to the 1983-1987 years 91% in Detroit, 63% in Utah, 55% in Iowa, 54% in New Mexico, 44% in Connecticut, 43% in Hawaii, 42% in San Francisco, 32% in Seattle, and 25% in Atlanta (Elder 1995). Conclusion ---------- There has yet to be any quality, medium- or long-term tests (i.e., more than 3 months) on the negative effects of aspartame. The large majority of tests have been supported by NutraSweet or ILSI and appear to be deliberately designed to avoid finding negative effects. At least a couple of independent investigators have agreed that some people at NutraSweet and at least some (if not all) of their funded researchers have no interest in investigating aspartame's toxicity (Wurtman 1987, page 341 of US Senate 1987, Kulczycki 1995, Samuels 1995a). A good beginning to a quality experiment on the phenylalanine aspects of aspartame would have the following points: - Conducted independently of NutraSweet researchers. In other words, no input or involvment of their researchers. - At least six months long, but preferably one or two years. - Start with tests on the most vulnerable such as those with behavioral problems, schizophrenia, psychosis, severe depression, etc. Negative effects in this population will likely show up sooner. - Use real-world aspartame products after creating a taste mask that in no way interferes with any of the aspartame metabolites. NutraSweet and their researchers should have no part in creating this taste mask and extensive biochemical tests should confirm no significant changes in the metabolism of aspartame when the taste mask is used. - The FDA Acceptable Daily Intake (ADI) level of aspartame should be use. - No other changes in diet such as removing additives and preservatives. - Biochemical measurements should be made on phenylalanine levels as well as other metabolites. Measurements of plasma, erythrocytes, and cerebrospinal fluid (CSF) for amino acids, amino acid metabolites, methanol, and methanol metabolites should be made. In other words, it is important to not just look at the plasma; CSF amino acid level changes seems to occur in some chronic illnesses and may be very important. Measurements should occur at the proper times as determined by independent pilot studies. This type of quality, common sense testing is absolutely essential before a potentially dangerous product such as aspartame is pushed on millions of people, especially considering all of the extremely serious chronic health problems that appear to be caused by its use.