Scientific Abuse in Migraine/Headache Research Related to Aspartame

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Summary of Aspartame and Migraine/Headache Issue

Headaches comprise 28.7% of the aspartame toxicity reactions reported to the U.S. Food and Drug Administration Adverse Reaction Monitoring System (DHHS 1997). In a survey of 551 aspartame toxicity cases, 45% (249) reported headaches or migraines from aspartame use (Roberts 1988). In a survey of 190 patients seen at the Montefiore Headache Unit in New York, Lipton (1989) found that 8.2% of the patients reported aspartame as a definite headache precipitant. Johns (1986) reported a case of aspartame causing migraine in a young woman. Migraines decreased and ceased upon elimination of aspartame. Rechallenge with aspartame in liquid led to a reoccurance of migraines. Watts (1991) reported headache, shaking chills, lethargy, confusion, and myagia from aspartame use. Blumenthal (1997) reported three cases of headaches in women chewing aspartame-containing gum.

Headaches reported refer to migraines, cluster headaches, and other headaches. In addition, aspartame-caused headaches are often part of many symptoms linked to aspartame use:

    "A 68-y-old female respondent developed nausea, vomiting and diarrhea after using 15 mL (one tablespoon) of a popular aspartame-flavored powdered laxative twice daily for several months. There was concomitant decreased vision and pain in both eyes, impaired hearing, marked sensitivity to noise in both ears, severe headaches, dizziness and unsteadiness (at times requiring assistance while walking), intense drowsiness, tremors, depression and itching. Her symptoms dissappeared several weeks after she stopped using this and other aspartame products, and had not recurred when she completed the questionnaire." (Roberts 1988)

    "A 39-year-old white female complained of depression, memory loss, lethargy, irritability, dizziness, and headaches. The complainant's first use of aspartame-containing products was in March 1983, when she began using approximately 8 packs on Equal per day. During the symptomatic interval, the complaintant added other aspartmae-containing products to he diet, including Diet Coke and Kool Aid. The symptoms started in mid-April and increased in number and intensity in subsequent months. the first symptom to occur was lethargy. Over the ensuing months, irritability, dizziness, depression, and memory loss occurred. She states that when she stopped using aspartmae-containing products in mid-September following a news report, the symptoms improved within 1 day and ceased within 1 week. The complainant subsequently re challenged herself approximately 2 months later with Equal, consuming 4 packets per day for approximately 3 days. She stated that she became dizzy on the third day and that the episode was "very frightening." After these symptoms appeared she stated that she stopped consuming Equal, and approximately 24 hours later the symptoms subsided." (CDC 1984)

Koehler (1988) conducted a double-blind study of patients who had a medical diagnosis of migraines, who were not on medications (other than analgesics) and who suspected that aspartame had a negative effect on their migraine headaches. Following a baseline period where the subjects tracked their headaches and their diets, the subjects were given 300 mg of aspartame or placebo, 4 times daily, for four weeks. The placebo group had no increase in headaches over the baseline levels. Approximately half of the subjects who took aspartame had a large increase in headaches.

The most likely causes for migraines/headaches from aspartame use is the combination of the excitotoxin, aspartic acid, and the formaldehyde metabolites of aspartame as discussed in the Methanol/Formaldehyde document in this section. Ingestion of aspartame leads to a significant and sudden influx of free-form excitotoxic amino acid (Stegink 1987) and methanol (Davoli 1986). The methanol metabolizes into the highly toxic formaldehyde once in the body (DHHS 1993, Liesivuori 1991). Since the aspartic acid is in free form, it is absorbed very quickly, rather than the very slow influx of aspartic acid from the break down of proteins during the digestion of food (Stegink 1987). As will be discussed in the aspartic acid section, the amount of aspartic acid absorbed suddenly is many times the baseline level of plasma aspartic acid.

In 1990, it was hypothesized that migraines and spreading depression were caused by excess excitatory amino acids in the Central Nervous System (CNS) (Welch 1990). These researchers showed a high level of the excitotoxic amino acid, glutamate in the platelets during headaches and during migraines with aura. Brain magnesium (Mg++) was reduced approximately 19% in the brains during a migraine attack (based on NMR spectroscopy measurements). D'Andrea (1991) found increased levels of platelet aspartate and glutamate during migraines with aura. Castillo (1995) found increased levels of plasma glutamate and glutamate in the cerebrospinal fluid (CSF) in patients with headache during the acute phase of cerebrovascular ischemic disease. Cananzi (1995) found increased levels of glutamate in platelets (but not plasma) in patients experiencing migraines with aura. In a study of migraine and children, D'Eufemia (1997) found that aspartate was significantly increased in the erythrocytes (red blood cells) of children suffering from migraine (both with and without aura). The plasma glutamate and aspartate levels were reduced as compared to controls. The excitotoxins were increased in the erythrocytes and decreased in the plasma during migraine in children. The authors conclude:

    "These results seem to suggest the presence of a higher activity of the erythrocytes' glutamate/aspartate transport system that could reflect a similar alteration at the neuronal/glial cell level in the CNS. Our study suggests an imbalance of the excitatory amino acid turnover in the pathogenesis of migraine in children."

As pointed out in the
Methanol/Formaldehyde document in this section, the formaldehyde/formic acid metabolite of aspartame will likely increase the excitotoxic effects of the free-form aspartic acid absorbed from aspartame.

Meaningless Industry Research

In 1987, Schiffman (1987) published a double-blind, cross-over study of 40 subjects claiming to have headaches from aspartame ingestion. No increase in headaches were seen in the aspartame group. The authors conclude:

    "In this population, aspartame is no more likely to produce headache than placebo."

Other industry researchers have cited this study as evidence that aspartame does not induce headaches (Butchko 1994, Leon 1989, Moser 1994). In addition, Yost (1989) claimed that aspartame is not more likely to cause headache than placebo. Tollefson (1992) of the FDA cited this Schiffman study as evidence that aspartame does not cause headaches. (The Tollefson review was discussed in detail in the
Seizure Research Abuse section).

What these researchers fail to mention is that the Schiffman (1987) research is useless because of major design flaws. It is also particularly troubling that none of the above-mentioned authors cited the Koehler (1988) double-blind study!

Before we discuss the major flaws of the Schiffman study, I will present some background information. The study was partially funded by Monsanto/NutraSweet and conducted at the Searle Center at Duke University. (G.D. Searle is owned by Monsanto.) Susan Schiffman performed her research at the "Searle Center" at Duke University. The Searle Center is under the guidance of William Anlyan, a former G.D. Searle director. Schiffman is a former General Foods and G.D. Searle consultant. The FDA helped design the study protocol. [Gordon 1987, page 500 of US Senate 1987; Shapiro 1987, page 403 of US Senate 1987].)

Schiffman (1987) major flaws:

  1. The aspartame was given for only one day.

  2. The aspartame was given in encapsulated form which would lower the toxicity by eliminating the sudden absorption of the excitotoxic amino acid and methanol (Stegink 1987). The absorption of the excitotoxin is gradual, somewhat closer to what happens when ingesting food. The methanol is absorbed more slowly and that may significantly reduce toxicity as happens when food in the stomach slows methanol absorption (Posner 1975).

  3. There was no baseline frequency of headaches determined before administering aspartame or placebo.

      It is very important to note the main distinction between the Koehler (1988) study and the Schiffman (1987) study. While both studies used capsules which would be expected to significantly reduce aspartame toxicity and both studies used subjects who claimed to have headaches from aspartame, the Koehler (1988) study administered aspartame for four weeks while the Schiffman (1987) study administered the aspartame for only one day!

      When one examines the double-blind studies funded by the aspartame industry, a pattern develops. Industry-supported research on subjects who have reported serious reactions to aspartame is almost always one day long and the aspartame is administered in capsules (e.g., Hertelendy 1993, Rowen 1995, Schiffman 1987). Industry-supported research that lasts several weeks is usually performed on individuals that might be expected to experience adverse reactions after at least several months of aspartame use (e.g., Shaywitz 1994) or on individuals even less susceptible to short-term aspartame toxicity, but where more sensitive neurological tests were conducted (e.g., Spiers 1998). The longer (but still relatively short) industry-supported research (3-6 months) usually uses healthy subjects who would likely only experience serious adverse reactions after many months or several years of aspartame use (e.g., Leon 1989, Trefz 1994). While the length of the study is not the only flaw in these industry-sponsored studies, there appears to be an obvious pattern of exceptionally short studies used on more susceptible subjects. It would appear that the manufacturer funds research with protocol designs virtually guaranteed to find no adverse reactions!

      Other Migraine/Headache Aspartame Research

      In 1994, Van Den Eeden (1994) pubished a double-blind, cross-over study related to aspartame and headaches. The aspartame was given for 7 days at a dose of 30 mg/kg/day (300 mg capsules) in three separate doses at mealtimes. The subjects who were "very certain" that aspartame caused their headaches showed a significant increase in headaches. Subjects who were either not certain or somewhat certain that aspartame caused their headaches showed no increase during the aspartame treatment period.

      In this independent study, we see an increase in headaches. The increase was not as dramatic as in the Koehler (1988) study, but this study was only 1/4 the length. In addition, one of the capsule ingestions during the Koehler study was at bedtime. The capsule administration in both studies significantly slows the influx of methanol, aspartic acid, phenylalanine and other aspartame breakdown products. Ingesting food at the same time as the capsules might be expected to further slow the absorption of these breakdown products. One capsule ingestion period in the Koehler study was possibly on an empty stomach (at bedtime).

      Some may raise the issue that there are more factors to quality double-blind studies than just length and capsule administration. That is true. However, clinical experience has shown that the length of aspartame use is a major factor in the development of toxicity symptoms (CDC 1984, Roberts 1988) and an understanding of the toxicity of aspartame metabolites (methanol/formaldehyde, aspartic acid, etc.) leads one to the conclusion that capsule administration would significantly reduce toxicity (so that it would take a much higher dose and/or longer use to produce symptoms).

      Roberts (1995) made the unusual, but understandable point that Van Den Eeden (1994) should be wary of obtaining aspartame and capsules from the manufacturer (Monsanto/NutraSweet). While this may seem strange, it is important to note that some independent researchers no longer trust aspartame manufacturer involvement in studies. Roberts points out that since 1978, aspartame was hidden in the drink mixes given to controls in experiments studying the adverse effects of the excitotoxin MSG and where the study was funded by the MSG industry (Ebert 1991). Since the aspartame manufacturer had the patent on aspartame, they must have given aspartame to the MSG industry to use in these drink mixes (before it was approved for human use!) and should have known that giving an excitotoxin to the control group in an excitotoxin experiment amounted to scientific fraud. Secondly, Roberts points out that Monsanto/NutraSweet refused to sell aspartame to an independent researcher for a study on aspartame and depression (Walton 1993). Roberts suggests that aspartame should be obtained from independent chemical suppliers and analyzed by corporate-neutral individuals.


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