Wurtman to FDA 4/21/86

POSSIBLE RELATIONSHIP BETWEEN Aspartame (NutraSweet) CONSUMPTION,
SEIZURES, AND OTHER CNS ABNORMALITIES

(Introductory comments presented to the Food and Drug Administration,
April 21, 1986.)

Thank you for inviting Dr. Schomer, Ms. Hazerjian, and myself to meet
with you today to discuss available data, and plan future studies,
relevant to the possible association between aspartame (NutraSweet)
consumption, the occurrence of grand mal seizures, and other, possibly-
related CNS abnormalities like migraine and other types of severe
headache. We have several goals for this meeting:

1. To initiate what we hope will be a fruitful collaboration with our
colleagues in the FDA We believe that we and the FDA share a commitment
to discovering the scientific and medical truth about the aspartame-
seizure relationship, and to seeing to it that that truth is applied
fairly and expeditiously in protecting the Public's health. We do not
see the FDA's role - as was suggested, perhaps in jest, by an FDA
scientist - as that of an umpire, mediating between university
scientists and the companies that manufacture and use aspartame; rather,
the FDA must, just like university scientists, be intellectually
aggressive in continuing to search for adverse reactions to compounds
like aspartame that it admits to the Nation's food supply. It seems
clear to us that, although the FDA has developed effective mechanisms
for evaluating in advance the risks that certain types of adverse
reactions will occur (e.g., those involving carcinogenesis and
mutagenesis), it was not as well equipped as it might have been to deal
with the risks posed by compounds like aspartame, that may act in adults
not by killing cells nor by transforming their genetic material but by
changing such functional properties as their synthesis of
neurotransmitters. Indeed, as you well know, the whole concept of the
'ADI" and the method by which it is calculated fail to deal at all with
these properties, nor with the topics that we are discussing today:
seizures and headaches. Perhaps out of the aspartame story will come new
strategies by which the FDA evaluates the risks posed by brain-active
food constituents.

2. To present and discuss some of the "case history" data that we have
been collecting on previously healthy young adults who suffered seizures
possibly related to aspartame consumption. At present we are evaluating
about 80 such people, and adding one or two new cases each week. (It's
surprising that we have accumulated this large a number of possible
cases in the few months since my original letter, describing 3 cases,
appeared in The Lancet: Certainly NutraSweet's manufacturer, the
Monsanto Chemical Co., is not advising consumers with seizures to get in
touch with us, nor, we imagine, is the FDA.) As you will note, our
typical subject is a woman in her thirties, whose seizure was preceded
by a prodrome of weeks or months, usually including severe headaches.
This apparent relationship between headaches and, ultimately, seizures -
plus the evidence, discussed below, that aspartame exacerbates
migraine,
and the well-known relationship between migraine and seizures - raises
the possibility that individuals at special risk to develop aspartame-
related seizures may be largely identifiable in advance.

Our data, when complete, will be the subject of a publication, perhaps
modeled after one on pyridoxine toxicity published in the New England
Journal of Medicine several years ago. That study described six women
who developed a peripheral neuropathy concurrent with consuming
supplemental pyridoxine; the neuropathy disappeared when the pyridoxine
was stopped. Based on that temporal correlation, the authors proposed
that the pyridoxine had, indeed, been the etiologic agent producing the
disease, and recommended that people without a special need for
pyridoxine megadose stop taking them. (I understand that the FDA
concurred in that conclusion and recommendation.) We believe that the
available evidence relating NutraSweet to seizures parallels the
evidence used by those authors to relate excess pyridoxine to the
peripheral neuropathy: They made no attempt to compare the incidence of
the neuropathy in the perhaps-millions of pyridoxine-users with that in
the general population, nor, of course, did they attempt to re-induce
the neuropathy by giving their cured patients pyridoxine megadose. We
hope that you will agree and will now issue a warning to physicians that
aspartame consumption may be associated with a syndrome including
severe
headaches and, in some cases grand mal seizures. We believe that people
who do develop severe headaches following aspartame consumption -
whether they be migraineurs or those normally lacking a headache problem
should now be advised to stop consuming the aspartame, lest their
symptoms evolve into something far more serious and potentially life-
threatening: seizures.

3. To discuss with you the protocol of a study directed by us, that is
about to begin in MIT's NIH-funded Clinical Research Center. It should
be pointed out that though that facility has adequate NIH support, our
particular project is without any grant support, industry having chosen,
perhaps not surprisingly, after about a year of deliberations not to
support it. Perhaps that is for the best: The present system, in which
the companies that sell our synthetic foods - like NutraSweet - fund
virtually all of the studies, FDA-mandated or not, of their safety is
too vulnerable to misuse: As we can discuss, if you like, when outside
investigators propose studies that might yield the "wrong" answer, a
large bag of "dirty tricks" is available for derailing those studies. We
hope that the evolving aspartame story will provide impetus for a new
mechanism, in which companies that manufacture new, synthetic food
constituents (like NutraSweet's manufacturer, Monsanto), or those that
insert it into their foods (like Coca-Cola, or Pepsi-Cola, or the makers
of Kool-Aid or Crystal Lite) will be obligated to support the research
that affirms their product's safety, but will not be allowed to choose
exactly what studies are done, nor who conducts them.

Our study - which has, of course, been approved by the Institutional
Review Boards at MIT and Harvard, as well as by the Clinical Research
Center's Advisory Committee - may yield false negatives, in which event
further studies will have to be done. For example, we may be giving the
subjects the aspartame for too short a period: Analysis of the case
records reveals that most of our subjects consumed aspartame for weeks
or months prior to having their seizure, and many had a definite
prodrome, characterized by headaches or personality changes, or even
deja vu, for days or weeks prior to the seizure. Aspartame related
seizures may thus be a tardive phenomenon, akin to the slow effect of
antidepressant drugs on clinical depression, or the slow appearance of
tardive dyskinesia in patients taking neuroleptics; an 18-day test
period may not be adequate. Another source of false negatives may be the
aspartame-breakdown products present in soft drinks, like the
diketopiperazines and beta-aspartame: Perhaps these compounds, and not
the "pure" aspartame that we are administering, cause the seizures. (As
you all well know, the existence of beta-aspartame in soft drinks was
discovered only a year ago, after perhaps 100,000,000 Americans had
consumed generous amounts of it, and virtually no information is
available in the Literature concerning its metabolism, absorption,
uptake into the brain, and neurochemical effects. I have tried to obtain
some of this compound from the NutraSweet Division of the Monsanto
Chemical Co., without success, in order to carry out such studies. I
would be grateful for your assistance in this regard.)

4. To urge the FDA to require quantity labeling for aspartame. There
seems no good reason why in the United States, alone of the countries
that allow aspartame to be included in foods, neither the consumer nor
the physician has any way of determining his aspartame intake, nor of
limiting that intake to a set daily dose. While I personally concur with
the view of Dr. Louis Elsas that no pregnant woman should ever consume
aspartame in any amount, I would feel a little better about the risk
that its consumption imposes on her baby's brain if there were some way
that she and her obstetrician could agree on a "personal ADI" of, say
250 milligrams per day, - and she could then implement that decision.
Similar arguments would hold for people in other at-risk categories,
i.e., small children; patients taking drugs that interact with the
phenylalanlne in aspartame (like L-dopa, or MAO inhibitors, or alpha-
methyldopa); people with a migraine history who have not yet noted an
association between headache frequency and aspartame intake.

One question that arises in any discussion of aspartame's side effects
is that of dosage: How much of the artificial sweetener need one take to
increase the likelihood of seizures or migraine, and how much do
Americans actually consume, - for example, in beverages on hot summer
days? As you will note in reviewing our case reports, most of our
subjects have taken a lot of it - perhaps 2-3 grams per day - but some
have consumed surprisingly small amounts. In our forthcoming study, we
intend to give the subjects the quantities that they believe they were
taking during the period of their grand mal seizure. But how much
aspartame do "average" Americans now consume? Our data indicate that
many people consume very large amounts, - far in excess of the ADI (even
though, as mentioned above, even the ADI figure is of no obvious value
in assessing a "safe" dose from the standpoint of brain function). One
example: We were telephoned by a woman whose two-year-old child was
having seizures. Right after birth, the woman's dentist told her that
"sugar causes cavities", so she thereupon weaned her infant onto Diet
Kool Aid (!). It would be interesting - and distressing - to estimate
the concentrations of phenylalanlne in that infant's brain. We have
numerous case reports of adults consuming five and even six liters of
diet soft drinks per day. Why do people consume so much aspartame? One
probable reason is that no one's telling them not to do so: NutraSweet
is advertised on television as a "natural" compound (which it most
assuredly is not), somehow related to cows and bucolic scenes; actors
are shown opening a packet of "Equal" and swallowing its contents,
undiluted. I hope very much that the FDA and, perhaps, the FTC will take
steps to curtail this misleading and even dangerous advertising. I have
seen last year's estimates, provided to you by what was then the Searle
Company, of average aspartame intake by the various percentiles of the
population. I believe that those numbers are spurious: They show, among
other things, that people consume less aspartame in the summer than in
other months, - a finding which violates good sense and reason. (This
probably reflects the fact - affirmed in our laboratories at MIT - that
people have much more difficulty accurately remembering snack than meal
intakes--------and most of the aspartame in the American diet comes via
cold beverages and other snack foods.)

Lastly, I would point out that, - although animal data are of limited
value in anticipating aspartame's effects on the human brain (because
the human's liver is so much less able than livers of test animals to
metabolize the phenylalanlne in aspartame) - there is evidence from
animal studies suggesting an aspartame-seizure relationship. One such
study, well known to the FDA, was the "first monkey study", carried out
at the University of Wisconsin, in which five of the six monkeys
receiving high aspartame doses for a long period went on to develop
seizures. (The other animal died.) A subsequent study, using lower doses
and a shorter treatment period, carried out at the University of
Illinois, failed to produce seizures, and, somehow, it was concluded
that the negative study cancelled out the positive one. (In most
laboratories, when an experiment done in two different ways yields
opposite answers, additional experiments are done.) Another study,
conducted by Dr. Timothy Maher at the Mass. College of Pharmacy, has
shown that the fraction of rodents developing seizures after receiving
the drug pentylenetetrazole is markedly enhanced if the animals are also
given sufficient aspartame to raise brain phenylalanine (but not
tyrosine, which protects the brain from the effects of the
phenylalanine) levels, - as would occur in people eating the synthetic
sweetener. Of course, humans differ from the highly-inbred rodents,
maintained in controlled environments, in that each person has a unique
brain, with its own genetic material, its own history of trauma and
diseases, and - consequently - its own seizure susceptibility. Thus,
perhaps unfortunately, the only "experimental animal" in which the
question of aspartame's relationship to seizures can be realistically
addressed is an individual person who believes he has suffered such an
event. There apparently is no shortage of such people, nor of good
hypotheses that might explain why aspartame could facilitate seizures or
headaches, perhaps starting with the one that led us first to focus on
seizures, i.e., that the phenylalanlne in aspartame suppresses the
synthesis of monoaminergic neurotransmitters which are known both to
raise seizure thresholds in experimental animals, and to be involved in
the pathogenesis of migraine.

Other good candidates include the diketopiperazines, beta-aspartame,
and, sadly, additional aspartame breakdown products yet to be
discovered.

(Scanned Wednesday, January 9, 2002)