Aspartame has three principal components: aspartic acid, phenylalanine,
and a methyl ester variously referred to as methanol or wood alcohol.
Each has lethal properties. In this paper, we
provide evidence of the toxicity of aspartic acid.
Neurotoxicity
The aspartic acid
component of aspartame is a structural analogue of the glutamic acid found in
monosodium glutamate. Both are known to load on the same receptors in the
brain, kill brain cells, cause neuroendocrine disorders in laboratory animals,
and work in an additive fashion.[1],[2],[3]
Evidence of aspartic acid neurotoxicity comes in part from
studies of glutamic acid.
Having found
that
glutamic acid and aspartic
acid load on the same receptors in the brain and nervous system and cause the
same neuroendocrine disorders; and having found that monosodium glutamate
(brand name Accent) could be used in place of pharmaceutical grade glutamic
acid and could be purchased inexpensively in grocery stores;[4] relatively
little early research on the toxic effects of aspartic acid per se has been
done. It is for that reason that in
offering evidence of the toxic potential of aspartame, we include data that
demonstrate the toxicity of glutamic acid.
Retinal
degeneration
In
1957, Lucas and Newhouse first noticed that severe retinal lesions could be
produced in suckling mice (and to some extent in adult mice) by a single
injection of glutamate.
[5]
Studies confirming their findings using neonatal rodents
[6],[7],[8],[9]
and adult rabbits
[10]
followed shortly, with others being reported from time to time.
[11],[12],[13],[14],[15]
These
studies concerned themselves not only with the confirmation of monosodium
glutamate induced retinal lesions, but with the formulation and testing of
hypotheses to explain the phenomenon.
In 2002, Ohguro et al.
[16]
found that rats fed 10 grams of sodium glutamate (97.5% sodium glutamate
and 2.5% sodium ribonucleotide) added to a 100 gram daily diet for as little as
3 months had a significant increase in amount of glutamic acid in vitreous, had
damage to the retina, and had deficits in retinal function. Ohguro et al. also
documented the cumulative effect of damage caused by daily ingestion of monosodium
glutamate.
Other reports of toxic effects of monosodium glutamate have
come from studies at the University of Pecs, Hungary, where the
neuroprotective effects of PACAP in the retina have been studied.
[17],[18]
Lesions in the arcuate nucleus of the
hypothalamus of neonatal and infant animals
In
the late 60s, Olney became suspicious that obesity in mice, which was observed
after neonatal mice were treated with monosodium glutamate for purposes of
inducing and studying retinal pathology, might be associated with hypothalamic
lesions caused by monosodium glutamate treatment; and in 1969 he first reported
that monosodium glutamate treatment did indeed cause brain lesions, particularly
acute neuronal necrosis in several regions of the developing brain of neonatal
mice, and acute lesions in the brains of adult mice given 5 to 7 mg/g of v
subcutaneously.
[19]
Research that followed confirmed that monosodium
glutamate, which was routinely given as the sodium salt, monosodium glutamate
(brand name Accent), induces hypothalamic damage when given to immature animals
after either subcutaneous
[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38]
or oral[
1],[26],[32],[33],[35],[39],[40],[41],[42] doses.
Work by Lemkey-Johnston and Reynolds published in 1974
included an extensive review of the data on brain lesions in mice.[42] They confirmed the phenomenon of monosodium
glutamate induced neurotoxicity; described the sequence of the lesions; and
emphasized the critical aspects of species variation, developmental age, route
of administration, time of examination of brain material after insult, and
thoroughness of tissue sampling methods. A review of monosodium glutamate
induced neurotoxicity, published by Olney in 1976 2 mentioned species (immature mice, rats, rabbits,
guinea pigs, chicks, and rhesus monkeys) demonstrating monosodium glutamate
induced neurotoxicity, and efficiency of both oral and subcutaneous
administration of monosodium glutamate in producing acute neuronal necrosis;
discussed the nature and extent of the damage done by monosodium glutamate
administration and the impact of monosodium glutamate administration to
monosodium glutamate levels in both brain and blood; and discussed the similar
neurotoxic effects of a variety of acidic structural analogues.
Studies of sub-human primates were thought to be
particularly meaningful because monosodium glutamate toxicity found in
sub-human primates might be relevant to humans. As early as 1969, Olney[21]
had suggested that monosodium glutamate could be involved in the unexplained
brain damage syndromes occurring in the course of human ontogenesis. Olney[21]
demonstrated that the infant rhesus monkey (Macaca mulatta) is susceptible to
monosodium glutamate-induced brain damage when administered 2.7g monosodium
glutamate/kg of body weight subcutaneously.
Olney et al.[33]
expanded Olney's earlier work with a study of
eight additional infant rhesus monkeys and, using light microscopy and the
electron microscope, reconfirmed Olney's earlier findings of hypothalamic
lesions, and discussed the findings of both Abraham et al.[34]
Reynolds et al.
[43] who had questioned his work. Olney
found his data to be entirely consistent with studies done previously by his
own and other laboratories on all species of animals tested.
Neuroendocrine
Disorders
Olney
found not only hypothalamic lesions in 1969, but described stunted skeletal
development, obesity, and female sterility, as well as a spate of observed
pathological changes found in several brain regions associated with endocrine
function in maturing mice which had been given monosodium glutamate as neonates.[19]
Longitudinal
studies in which neonatal/infant animals were given doses of monosodium
glutamate and then observed over a period of time before being sacrificed for
brain examination, repeatedly supported Olney's early findings of abnormal
development, behavioral aberration, and neuroendocrine disorder. Animals
treated with monosodium glutamate as neonates or in the first 12 days of life were
shown to suffer neuroendocrine disturbances including obesity and stunting,
abnormalities of the reproductive system, and underdevelopment of certain
endocrine glands[19],[27],[29],[39],[43],
[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],
and possible learning deficits
either immediately or in later life.[46],[49],[50],
[61],[62],[63],[64],[65],[66]
In addition, there were reports of
behavioral reactions including somnolence and seizures;
[67],[68],[69],[70],[71],[72],[73],[74]
tail automutilation;[48],[62] and learned taste aversion.[
64] Irritability to touch was interpreted as
conspicuous emotional change by Nemeroff.[
48]
Lynch
[75]
reported hyperglycemia along with growth suppression. He noted that
hyperglycemia did not occur when subjects were given intact protein containing
a large amount of glutamate.
Olney et al.
[76],[77],[78] have written a number of review
articles which summarize the data on neuroendocrine dysfunction following
monosodium glutamate treatment. Nemeroff
[79] has written another.
Ad libitum feeding studies
Findings of neurotoxicity and neuroendocrine
dysfunction in laboratory animals raised questions about the effects that
monosodium glutamate might have on humans. Since it would be unthinkable to
administer doses of monosodium glutamate that might produce the same sorts of
neurotoxicity and neuroendocrine dysfunction as found in laboratory animals,
researchers had no alternative but to make decisions based on the best of the
animal studies. "Best," in this case, would be studies that would
most closely parallel the true human condition.
At the time, a seemingly logical first step was to
study the effects of monosodium glutamate on subhuman primates; and, as already
noted, hypothalamic lesions had been demonstrated in monkeys as early as 1969.[21]
A seemingly logical second step was to study "normal" ingestion of
monosodium glutamate as opposed to some kind of forced feeding. Many felt that
ad libitum feeding of laboratory animals parallels the human situation more
closely than either subcutaneous or gavage administration of monosodium
glutamate, and that ad libitum feeding studies were, therefore, the vehicle of
choice. Ad libitum feeding would give animals free access to feed or water
thereby allowing the animal to self-regulate intake. Some tended to disagree,
feeling that the ad libitum feeding studies were, by and large, studies that
had the greatest potential for minimizing the amount of monosodium glutamate
actually ingested while registering the irrelevant amount of monosodium glutamate
available.
Two
studies that demonstrate neurotoxic reactions after ad libitum feeding of
monosodium glutamate are reported here. In a 1979 study done as part of a
project designed to evaluate a developmental test battery for neurobehavioral
toxicity in rats, in which rats were exposed to monosodium glutamate and other
food additives mixed with ground Purina rat chow beginning five days after
arrival at the laboratory,[
63]
it was demonstrated that high doses of dietary monosodium glutamate produce
behavioral variations. Monosodium glutamate was mixed with food as opposed to
being administered subcutaneously or by gavage. A year later, dietary studies
demonstrated that weanling mice will voluntarily ingest monosodium glutamate
and that such voluntary ingestion results in readily detectable brain damage.
[80]
Focus on Older Animals
Most studies demonstrating retinal necrosis, brain
lesions and/or neuroendocrine dysfunction, focused on neonatal or infant
animals. Researchers were primarily interested in producing lesions in order to
expand their knowledge of brain function; and lesions were most easily produced
in the young. It was, however, also of scientific interest to understand the
relationship of age of animal to type and severity of lesion or dysfunction.
Thus, older animals were studied, but not to the same extent as the young.
Hypothalamic lesions have been produced in adult
animals using considerably greater doses of monosodium glutamate than those
required to produce lesions in younger animals. Nemeroff [
79]
reported that the least effective dose for a ten day old mouse, given orally,
is .5g/kg of body weight, and given subcutaneously is .35g/kg of body weight.
According to Olney
[81]
the dose required to damage the adult rodent brain is given as 1.5-2 mg/g of
body weight as compared to 0.3-0.5mg/g required to damage the brain of an
infant rodent. Only minimal damage is induced unless very high doses (4-8 mg/g)
are used.[
77]
Although advances in technology have facilitated the
observation of brain lesions to some extent, it is still true today, as it was
in the 1960s, that simple light microscopes are adequate to identifying
monosodium glutamate induced lesions if one looks in sensitive locations within
4-5 hours of monosodium glutamate administration. By 24 hours after insult,
lesions will be filled in ("healed") with cells other than neurons.
Thus the "hole" is filled in, but lost neurons are not replaced. The
damage will have been done, but will be virtually impossible to see. Although
it is now possible under optimal circumstances to count neurons in well defined
areas, the arcuate nucleus of the hypothalamus is not a well defined area, and
lesions in that area will defy detection after as little as 24 hours after
monosodium glutamate administration. One could not, therefore, ascertain
whether or not an adult animal given monosodium glutamate as an infant, had
suffered a lesion in the arcuate nucleus.
Aspartic acid
Given that the details of neurotoxic glutamic acid
applied equally to neurotoxic aspartic acid, by the end of the 1980s, there had
been no need for further studies of the toxic potential of either glutamic acid
or aspartic acid. The following are
studies from those cited above that specifically mentioned aspartic acid:
[1] Olney JW, Ho OL. Brain
damage in infant mice following oral intake of glutamate, aspartate or cysteine.
Nature. 1970;227:609-611.
[2] Olney, J. W. Brain damage and oral intake of certain amino
acids. In: Transport Phenomena in the Nervous System: Physiological and
Pathological Aspects Levi, G., Battistin, L., and Lajtha, A. Eds. New York:
Plenum Press, 1976.
[3] Kizer, J.S., Nemeroff, C.B., and Youngblood, W.W. (1978).
Neurotoxic amino acids and structurally related analogs. Pharmacological
Reviews.1978;29(4):301-318.
[20] Olney JW, Ho OL, Rhee V. Cytotoxic effects of acidic and
sulphur containing amino acids on the infant mouse central nervous system. Exp
Brain Res. 1971;14(1):61-76.
[68] Johnston GAR. Convulsions induced in 10-day-old rats by
intraperitoneal injection of monosodium glutamate and related excitant amino
acids. Biochem Pharmacol. 1973;22(1):137-140.
[69] Mushahwar IK, Koeppe RE. The toxicity of monosodium glutamate
in young rats. Biochem Biophys Acta. 1971;244(2):318-321.
[76] Olney JW, Price MT. Neuroendocrine interactions of excitatory
and inhibitory amino acids. Brain Res Bull. 1980;5:Suppl 2, 361-368.
[77] Olney JW, Price MT. Excitotoxic amino acids as neuroendocrine
probes. In: McGeer EG, Olney JW, McGeer PL eds. Kainic Acid as a Tool in
Neurobiology New York: Raven Press; 1978.
[78] Olney JW. Excitotoxic amino acids: research applications and
safety implications. In: Filer LJ Jr, Garattini S, Kare MR, Reynolds WA,
Wurtman RJ, eds. Glutamic Acid: Advances in Biochemistry and Physiology.
New York: Raven Press; 1979:287-319.
[80] Olney JW, Labruyere J, De Gubareff T. Brain damage in mice
from voluntary ingestion of glutamate and aspartate. Neurobehav Toxicol.
1980;2(2):125-129.
By the
early 1980s the neurotoxic effects of glutamic acid had become undeniable, and
neuroscientists were using glutamic acid (sometimes in the form of monosodium
glutamate) as an ablative or provocative tool with which to selectively kill
brain cells in order to study brain function and promote drug development. Animals had been shown to suffer obesity and
stunting, abnormalities of the reproductive system, underdevelopment of certain
endocrine glands, and possible learning deficits either immediately or in later
life. In addition, there were reports of behavioral reactions including
somnolence and seizures.
Had it not been for the producers of monosodium glutamate and aspartame,
there would have been no issue, for the fact of neurotoxicity of these two
amino acids was undeniable.
But in 1968,
faced with allegations that MSG had toxic potential,
19
Ajinomoto U.S.A., Inc.,
established a nonprofit corporation, recruited scientists and others to defend
the safety of its product, and unleashed a well conceived public relations campaign.
[82]
In the 1970s and 80s, Ajinomoto attempted to counter the studies that had
demonstrated the neurotoxic effects of glutamic acid.
They
claimed that their studies were replications
of those studies that had demonstrated the toxic potential of glutamic acid and
aspartic acid; but their procedures were different enough to guarantee that
toxic doses of glutamic acid had not been administered, and/or to guarantee that
all evidence that nerve cells had died would have been obscured prior to
examination. Later, Ajinomoto produced badly flawed human studies wherein
either 1) aspartame and/or 2) ingredients other than monosodium glutamate that
contained processed free glutamic acid (MSG), were used in placebos; and they illogically
claimed that having found no statistically significant difference between
monosodium glutamate test material and placebo, they had demonstrated the
safety of monosodium glutamate. All false claims of the safety of monosodium
glutamate have been, and continue to be, widely distributed by the glutamate
industry and the FDA; and all information that said or says otherwise, was, and
continues to be, effectively suppressed.[
82]
Aspartame and the free aspartic acid contained in it are neurotoxic.
That fact is undeniable.
FOOTNOTE
According
to Ajinomoto (http://www.aji-aspartame.com/about/about_us.asp
Accessed April 8, 2013), Ajinomoto Co Inc is one of Japan's largest
manufacturers of food products, including seasonings, edible oils, processed
food and beverages and dairy products. The company is also a world leader in
amino-acid technologies and develops and manufactures pharmaceuticals,
amino-acids and specialty chemicals. Ajinomoto's operations have long been
characterized by a global perspective, and encompass manufacturing and
marketing facilities in 20 countries. In the year ending March 2009, turnover
was $14.2 billion.
According
to the same source, the Nutrition and Health Division of Ajinomoto North
America, Inc. markets Ajinomoto Aspartame in the United States, Canada and
Mexico.
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Phenomena in the Nervous System: Physiological and Pathological Aspects
Levi G, Battistin L, Lajtha A. Eds. New York: Plenum Press, 1976.
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structurally related analogs. Pharmacological
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