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.