From: Mark Gold [mgold@shelltown.net]
Sent: Sunday, January 12, 2003 11:10 PM
To: fdadockets@oc.fda.gov
Subject: Docket # 02P-0317 Recall Aspartame as a Neurotoxic Drug: File
#3: Aspartame and Seizures

Subject: Docket # 02P-0317

To: FDA Dockets Submittal

From: Mark D. Gold
      Aspartame Toxicity Information Center
      12 East Side Dr., Suite 2-18
      Concord, NH 03301
      603-225-2110

Date: January 12, 2002

Please find below Evidence File #3: Aspartame and Seizures

              Scientific Abuse in Seizure Research
                    Related to Aspartame

          Please print and read completely through this document!

Table of Contents

       Summary of Aspartame-Induced Seizures Issue
       Hopelessly Flawed Double-Blind Studies Funded by
         Monsanto/NutraSweet
       FDA Gift to Monsanto
       Aspartame Industry Pumps Out Its Own Animal Research
       References

Summary of Aspartame-Induced Seizures Issue

As of 1995 more than 7% of the aspartame toxicity reactions reports sent
to the U.S. Food and Drug Administration (FDA) involve seizures and
convulsions (DHHS 1995). The FDA stopped accepting aspartame toxicity
reaction reports in 1995 (Food 1995). In a study looking at 551 aspartame
reactors, Roberts (1988) found that grand mal, petit mal, and absence
seizures occurred in 18% of the cases.

In 1986, Food and Chemical News reported that 80 cases of
aspartame-induced seizures had been reported to Dr. Richard Wurtman at
M.I.T. (Food 1986).  Dr. Wurtman reported three cases in The Lancet
(Wurtman 1985). Walton (1986, 1988) published reports of nine cases of
seizures linked to aspartame use.

Both the U.S. Air Force's magazine "Flying Safety" and the U.S. Navy's
magazine, "Navy Physiology" published articles warning about the many
dangers of aspartame including that the ingestion of aspartame may make
pilots more susceptible to seizures and vertigo (US Air Force 1992)

In an independent double-blind study of aspartame in children with
generalized absence epilepsy, Camfield showed that a single dose of 40
mg/kg of aspartame mixed in liquid exacerbated EEG spike-wave discharge.
The authors stated:

  "Aspartame appears to significantly increase the duration of time that
   children with absence epilepsy have spike wave on their EEG. In this
   study, the children spent 40% more time in spike wave after aspartame
   than after sucrose."

The subjects were not on anti-seizure medication during the study. The
authors called for a longer study to be conducted.

I believe that the aspartame-induced seizures are at least partially
caused by the synergistic effects of formaldehyde and excitotoxins derived
from aspartame metabolism. However, many researchers believe that the
adverse neurological effects of aspartame may be at least partially due to
the phenylalanine derived from aspartame ingestion. Because the
phenylalanine from aspartame is in free-form (unbound to protein), it is
absorbed suddenly and can spike the blood plasma levels of phenylalanine
(Caballero 1986, Matalon 1988, Stegink 1987). This sudden "rush" of
phenylalanine does not happen when ingesting food because protein is
broken down slowly and the phenylalanine is gradually absorbed. Nor does
this phenylalanine "rush" occur when ingesting aspartame in capsules
(Stegink 1987).

Maher (1987) points out that increased levels of phenylalanine along with
an increase ratio of phenylalanine to other Large Neutral Amino Acids
(LNAAs)  can inhibit enzymes needed to synthesize the neurotransmitters
and diminish the production of brain catecholamines and serotonin. The
hypothesis is that this change in brain chemistry will lead to a lowering
of the seizure threshold and persons ingesting aspartame will become more
susceptible to having seizures.

Wurtman (1988) reviews the research to show that a dose of 60 times more
aspartame is needed for rodent studies to simulate the change in
phenylalanine/LNAA ratio change that occurs in humans. Based on these
findings, several research teams have found that aspartame lowers the
seizure threshold in animals (Diomede 1991, Garrattini 1988, Guiso 1988,
Kim 1988, Maher 1987, Pinto 1986, Pinto 1988)

Hopelessly Flawed Double-Blind Studies Funded by
Monsanto/NutraSweet

Shaywitz (1994) concludes that "our findings indicate that, in this group
of vulnerable children, APM [aspartame] does not provoke seizures." Rowen
(1995) concludes that "aspartame, in acute dosage of ~50 mg/kg, is no more
likely than placebo to cause seizures in individuals who reported that
their seizures were provoked by aspartame consumption." Trefz (1994)
reports that doses of 15 mg/kg and 45 mg/kg of aspartame in PKU
heterozygotes does not change EEG spectral parameters. (The Trefz (1994)
study appears to have been published in summary form as Benninger (1991),
Benninger (1993a) and Benninger (1993b) ). Others have cited these studies
as evidence that aspartame does not cause seizures (Lajtha 1994, Butchko
1994).

These results appear very convincing, but these industry-sponsored studies
are so flawed so as to be nearly worthless. Below are a selection of major
problems with these studies.

Rowen (1995) Flaws

- 16 of the 18 subjects were taking anti-seizure medication during the
  study.

- The aspartame was given in capsules so that instead of spiking the
  plasma phenylalanine level and significantly changing the
  phenylalanine/LNAA ratio the phenylalanine was absorbed very slowly
  -- more like what happens when ingesting food (Stegink 1987). These
  researchers discussed in detail the issue of plasma phenylalanine and
  LNAA levels. It was particularly absurd is that they gave the aspartame
  in capsules even though they cited industry research (Burns 1990)
  which proves capsule administration of aspartame eliminates the spike
  in plasma phenylalanine levels! Simply stated, the researchers were
  pretending to test the hypothesis that phenyalalnine/LNAA ratio
  changes would cause seizures, but they knowingly administered
  aspartame in a way that eliminated the possibility of a large change in
  plasma phenylalanine levels and phenylalanine/LNAA ratios.

  Capsule administration of aspartame slows the absorption of methanol
  and may reduce its toxicity somewhat similar to the way ingestion of
  food with methanol may slightly reduce its toxicity (Posner 1975).
  Capsule administration of aspartame also eliminates the quick
  absorption of the excitotoxin, aspartic acid (Stegink 1987). When
  aspartic acid is absorbed quickly, it can be excitotoxic (Blaylock 1994,
  Olney 1980) especially in conjunction with formaldehyde derived from
  methanol as discussed in the Methanol article.

- The study consisted of only single dose of aspartame ingestion!

This results of this study only apply to people who ingest a single dose
of encapsulated aspartame while taking anti-seizure medication. Not only
is this study worthless, but key information was not put in the abstract,
namely, the fact that the subject were on anti-seizure medication and that
the aspartame was given in capsules.

Shaywitz (1994) Flaws

- Nine out of 10 children were taking anti-seizure medication during the
  study.

- Again the aspartame was given in capsules at a dose of 34 mg/kg per
  day. This makes the experiment worthless since they were testing the
  hypothesis of changes in plasma phenylalanine to LNAA ratios as
  described above. It also reduces the toxicity of other aspartame
  breakdown products as described above.

- The experiment lasted only two weeks. The Rowen (1995) study used
  individuals who had experienced aspartame-induced seizures and it was
  only one day long (with other flaws described above). This short study
  used epileptic children who had not reported aspartame-induced
  seizures. A cynic might wonder if the researchers were able to make
  this study slightly longer than the Rowen (1995) study because the
  subjects had not reported aspartame-induced seizures.

Trefz (1994) Flaws

- Like the other studies, aspartame was given in slow-dissolving capsules
  despite the fact that the researchers were claiming to test the effects
  of the spike in phenylalanine levels and the change in phenylalanine
  to LNAA ratios.

- The aspartame was given with meals which would further slow the
  absorption of aspartame breakdown products.

-  This study was longer than the others, ~ 3 months. However, an
   analysis of seizure cases by the U.S. Centers for Disease Control (CDC
   1984) shows that most seizures linked to aspartame do not begin to
   appear until after 3 or more months of real-world (i.e.,
   non-encapsulated) aspartame.

What did industry scientists know or should have known?

 1. These researchers must have known that administering the aspartame in
    capsules would mean that they were not testing the phenylalanine and
    LNAA changes as they claimed.

 2. The researchers should have known that given encapsulated aspartame
    would reduced the toxicity of the methanol and the excitotoxic amino
    acid.

 3. These researchers must have known that allowing the subjects to take
    anti-seizure medication during the study would drastically reduce the
    liklihood of seizures.

FDA Gift to Monsanto

In 1992, the FDA published an analysis of reports of seizures associated
with consumption of aspartame (Tollefson 1992). The report concludes:

 "In most cases, information obtained from the complaintants' medical
  records as well as data on consumption patterns, temporal relationships,
  and challenge tests did not support the claim that the occurrences of
  the seizures were linked to consumption of aspartame."

Monsanto scientists repeated the FDA conclusion in their postmarketing
surveillance report published in 1994 (Butchko 1994). Shaywitz (1994) also
used this FDA report to bolster their conclusion.

What they do not mention is that this FDA analysis has major flaws and is
provably biased, rendering it useless.

A short summary is in order for those who have not yet read the History of
Aspartame Frequently Asked Questions (FAQs) report. During the FDA
approval process, a number of government officials were rewarded with jobs
connected to the aspartame industry (GAO 1986). This included two US
Attorneys investigating the manufacturer for pre-approval research fraud
who were hired by the manufacturer's law firm (one during the
investigation itself). The Director of the FDA's Bureau of Foods was given
a job as the Vice President of the National Soft Drink Associaton (GAO
1986). The FDA Commissioner was rewarded with a high-paying consulting
position with the public relations company of the manufacturer (Burston
Marsteller) not long after approving aspartame (GAO 1986). After these and
other employees were given jobs related to the aspartame industry, the FDA
supported the manufacturer unconditionally. The FDA redirected aspartame
reaction reports to the AIDS Hotline (Turner 1987). In addition, the FDA
told its regional offices to not report aspartame toxicity reactions to
the Washington, D.C.  headquarters (CNI 1984). The extreme FDA bias
continues to this day leading some people to refer to the FDA as a
Monsanto subsidiary.

Tollefson (1992) Flaws

- Tollefson inappropriately classified seizures as "Group D -- highly
  unlikely" related to aspartame if the subjects refused to release their
  medical records. This shows extreme bias as such cases would
  obviously be more appropriately categorized in a "possible aspartame
  reaction" category since the cases may or may not be caused by
  aspartame -- more information was needed.

- Tollefson inapropriately classified seizures as "Group D -- highly
  unlikely" related to aspartame if there was any possible factor in the
  patient's life that could have caused or contributed to those seizures.
  This is akin as categorizing smoking or stress as "highly unlikely" for
  contributing to heart disease if the patient eats a diet which could
  contribute to heart disease! Clearly, these patients should have been
  classified in a "possible aspartame reaction" category.

- The authors inappropriately declared ineligable, 35% of the non-Group
  D seizure victims because the seizures occured more than 13 hours
  after ingestion of aspartame. This is absurd because 1) it is thought
  that aspartame may lower the seizure threshold and therefore,
  aspartame-caused seizures could occur long after phenylalanine levels
  return to normal; 2) an animal study has shown that excitotoxins can
  accumulate in areas of the brain not protected by the blood brain
  barrier and remain there for as much as 24 hours (Inouye 1976); 3)
  formaldehyde adducts appear to accumulate from aspartame ingestion
  (Trocho 1998); and 4) a journal article immediately following this
  biased analysis, Carroll (1992), points out that food reactions can be
  delayed up to 48 hours after ingestion!

- The authors claim that only 251 cases of seizures due to aspartame
  ingestion have been reported to the FDA. In reality, the FDA splits the
  categories into: "Seizures and Convulsions," "Grand Mal," "Petit Mal,"
  "Complex Partial Seizures," and "Simple Partial Seizures." The 251
  cases quoted by the authors referred only to the "Seizures and
  Convulsions" category as of 1995. There have been over 500 seizures
  reported to the FDA (DHHS 1995) at probably a reporting rate of far
  less 1% (Gold 1996) leading to well over 50,000 cases of seizures
  which have already been linked to aspartame consumption.

- Even with the major flaws in classifying adverse reaction reports, 76 of
  251 cases were still categorized as Group A and Group B meaning that
  a rechallenge with aspartame lead to furthur seizures. Clearly, one
  cannot possibly conclude that this analysis shows no link between
  aspartame and seizures as implied in the abstract.

What is particularly disturbing about this analysis -- aside from its
major flaws -- is that independent research was totally ignored in favor
of aspartame industry-sponsored research. For example, the one-day
industry study of aspartame and headache (Schiffman 1987) was listed, but
not the much longer independent study (Koehler 1988). An aspartame
industry-sponsored International Workshop was cited (Dews 1987), but the
authors completely ignored an International Conference which invited both
independent and industry researchers and which focused largely on the
aspartame and seizure issue (Wurtman 1988). Most of the rest of the
citations are from publications of aspartame industry-funded scientists.

Aspartame Industry Pumps Out Its Own Animal Research

Not surprisingly, the aspartame industry has its own selection animals
studies which claim that aspartame does not lower the seizure threshhold
(Cain 1989, Dailey 1987, Dailey 1988, Dailey 1989, Dailey 1991, Jobe 1988,
Lasley 1988, Meldrum 1988, Nevins 1986, Thai 1988, Tilson 1989). The
discussion sections of some of these studies and the review by Sze (1989)
points to the huge doses of aspartame in rodents needed to lower the
seizure threshold in many of the independent studies. The implication is
that normal doses of aspartame ingested by humans could not possibly cause
lower the seizure threshold.

What these researchers fail to mention is that Wurtman (1988)  showed that
it takes approximately 60 times more phenylalanine given to rodents to
cause the changes in phenylalanine/LNAA ratio seen in humans. Therefore,
the aspartame doses given to the rodents in these experiments are really
not very high after adjusting for differences between rodent and human
metabolism. If the seizures from aspartame are caused by the combination
of methanol/formaldehyde and the excitotoxic amino acid from aspartame as
I believe may be the case, it is important to note that methanol is 10
times more acutely toxic in humans than in rodents (Roe 1982) and it takes
five times more excitotoxins given to rodents to simulate human ingestion
(Olney 1988, Stegink 1979, page 90).

It is also not surprising that Monsanto/NutraSweet attempted to challenge
the Wurtman (1988) conclusion that it takes 60 times the dose of
phenyalanine given to rodents to change the phenylalanine to LNAA ratio
similar to what happens in humans (Hjelle 1992). The results in this study
are ridiculous and do not even come close to matching the results of
other, independent research (Perego 1988, Pinto 1988, Wurtman 1983,
Yokogoshi 1984). The numerous studies that Hjelle (1992) claims their
results are similar to actually have results far different. This will be
discussed in more detail when the research abuses related to aspartame and
phenylalanine are looked at.

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