Jan 14 2000

http://www.thelancet.com/cgi-bin/newlancet/sub/pg_discuss.cgi

The Lancet Interactive dissussion group:
Aspartame Toxicity: fact or fiction?

Re: Aspartame toxicity From russell@... 601-982-1175
Date: Thu, 29 Jul 1999 23:07:04 +0100 (BST)

Russell L. Blaylock Neurosurgeon

In reviewing the available literature on aspartame toxicity I have
developed several concerns. First, is the results of the GD Searle
study itself in 1977 which indicated a significant increase in brain
tumor induction in the aspartame fed animals. This appeared to be
secondary to a breakdown product, DKP. Follow up studies with DKP
were seriously flawed, as demonstrated by the Bressler report. It
should also be noted that other tumors appeared in the NutraSweet
group including breast tumors, pancreatic tumors, testicular tumors,
ovarian tumors and other tissues. Aspartame has been reported in
association with a cutaneous panniculitis as well in human cases.

The recent study using radiolabeled aspartame that indicated
attachment of the formaldehyde breakdown product to DNA and that the
formaldehyde was cumulative with each dose should cause all of us
concern. This is especially so in relation to oncogene activation and
in disorders associated with elevated rates of DNA damage, such as
lupus and the neurodegenerative disorders. I have found no studies
relating to possible elevation of free radicals with aspartame
exposure, but this certainly deserves review.

Shephard, et al found that aspartame was nitrosated in the GI tract
and that in this form was significantly mutagenic. Such nitrosation,
according to their findings, could also occur in endothelial cells
and stimulated macrophages. This would raise concern not only of
carcinogenic potential but also the stimulation of free radical
generation in blood vessels associated with atherosclerosis. Related
to this finding is another report by Hardcastle and Bruch, in which
they found that macrophages treated with aspartame produced an excess
of leukotrienes and other arachidonic acid metabolites. Yamada, et al
found that aspartic acid inhibited melatonin secretion from the pineal
gland. It has been shown that aspartame consumption does increase
aspartic acid blood levels, especially when consumed with MSG.
Another concern is the formation of stereoisomer when aspartame is
heated. Jeffry Bada has shown that when aspartame is heated there is
a significant conversion of the L-phenylalanine and aspartate to the
D-form. In addition, he found 6 to 10 decomposition products, some of
which are known to have deleterious neurological effects. Elevated
levels of D-aspartate have been described in several of the
neurodegenerative diseases.

The effect of aspartame feeding on blood phenylalanine is of concern
to the pregnant mother and those with newborns as well, since
phenylalanine has been associated with abnormal neural connectivity
in the immature brain. It has been established that PKU carriers
develop phenylalanine blood levels double that of normals. Further,
it has been shown that the placenta concentrates phenylalanine on
the fetal side of the circulation. Matalon, et al demonstrated that
in the human a loading dose of 34mg/kg increased phenylalanine levels
greater than 6mg/dl in 14% of normals and 35% of PKU carriers. Of
even more concern 5% of normals and 12% of carriers had blood Phe
levels exceeding 10mg/dl. The National Collaborative Study for
Maternal PKU has recommended that during pregnancy blood Phe should
not exceed 6mg/dl. This means that 14% of the general public could
exceed this level when consuming high intakes of aspartame and that
5% of normal people could exceed 10mg/dl. One in fifty persons
carries a heterozygous gene for PKU. Up to 35% of such unfortunate
individuals, and their babies, would be at risk without knowing it.
Especially, since the babies brain levels would even exceed that of
the mother.

With the complexity of the central nervous system it would be
irresponsible for the FDA to allow the widespread selling o
aspartame without further independent study of the
neurophysiological, neurobehavioral and neurochemical effects
of high intakes of this drug at all ages using chronic studies.
I think it is foolish to ignore the complaints of millions of
individuals reporting difficulties with this substance.

Russell L. Blaylock Neurosurgeon 601-982-1175 russel@...
9 Lakeland Circle Jackson, Mississippi 39216

Blaylock RL. Hydrosyringomyelia of the conus medullaris associated
with a thoracic meningioma: case report.
J Neurosurg. 1981 Jun;54(6):833-5.
********************************************************************

Excitotoxins, Neurodegeneration and Neurodevelopment
by Russell L. Blaylock, M.D.

There are a growing number of clinicians and basic scientists who are
convinced that a group of compounds called excitotoxins play a critical
role in the development of several neurological disorders including
migraines, seizures, infections, abnormal neural development, certain
endocrine disorders, neuropsychiatric disorders, learning disorders in
children, AIDS dementia, episodic violence, lyme borreliosis, hepatic
encephalopathy, specific types of obesity, and especially the
neurodegenerative diseases, such as ALS, Parkinson's disease,
Alzheimer's disease, Huntington's disease, and olivopontocerebellar
degeneration.(1)

An enormous amount of both clinical and experimental evidence has
accumulated over the past decade supporting this basic premise. (2)
Yet, the FDA still refuses to recognize the immediate and long term
danger to the public caused by the practice of allowing various
excitotoxins to be added to the food supply, such as MSG, hydrolyzed
vegetable protein, and aspartame. The amount of these neurotoxins
added to our food has increased enormously since their first
introduction. For example, since 1948 the amount of MSG added to
foods has doubled every decade. By 1972 262,000 metric tons were being
added to foods. Over 800 million pounds of aspartame have been consumed
in various products since it was first approved. Ironically, these food
additives have nothing to do with preserving food or protecting its
integrity. They are all used to alter the taste of food. MSG,
hydrolyzed vegetable protein, and natural flavoring are used to enhance
the taste of food so that it tastes better. Aspartame is an artificial
sweetener.

These toxins (excitotoxins) are not present in just a few foods, but
rather in almost all processed foods. In many cases they are being
added in disguised forms, such as natural flavoring, spices, yeast
extract, textured protein, soy protein extract, etc. Experimentally, we
know that when subtoxic levels of excitotoxins are given to animals in
divided doses, they experience full toxicity, i.e.they are synergistic.
Also, liquid forms of excitotoxins, as occurs in soups, gravies and diet
soft drinks are more toxic than that added to solid foods. This is
because they are more rapidly absorbed and reach higher blood levels.

So, what is an excitotoxin? These are substances, usually acidic
amino acids, that react with specialized receptors in the brain in such
a way as to lead to destruction of certain types of neurons. Glutamate
is one of the more commonly known excitotoxins. MSG is the sodium salt
of glutamate. This amino acid is a normal neurotransmitter in the brain.
In fact, it is the most commonly used neurotransmitter by the brain.
Defenders of MSG and aspartame use, usually say: How could a substance
that is used normally by the brain cause harm? This is because,
glutamate, as a neurotransmitter, exists in the extracellular fluid
only in very, very small concentrations-- no more than 8 to 12uM.
When the concentration of this transmitter rises above this level the
neurons begin to fire abnormally. At higher concentrations, the cells
undergo a specialized process of delayed cell death known as
excitotoxicity, that is, they are excited to death.

It should also be appreciated that the effects of excitotoxin food
additives generally are not dramatic. Some individuals may be especially
sensitive and develop severe symptoms and even sudden death from cardiac
irritability, but in most instances the effects are subtle and develop
over a long period of time. While the food additives, MSG and aspartame,
are probably not direct causes of the neurodegenerative diseases, such
as Alzheimer's dementia, Parkinson's disease, or amyotrophic lateral
sclerosis, they may well precipitate these disorders and certainly
worsen their pathology, as we shall see. It may be that many people
with a propensity for developing one of these diseases would never
develop a full blown disorder had it not been for their exposure to
high levels of food borne excitotoxin additives. Some may have had a
very mild form of the disease had it not been for the exposure.
Likewise, food borne excitotoxins may be harmful to those suffering from
strokes, head injury and HIV infection and certainly should not be used
in a hospital setting.

How Excitotoxins Were Discovered
In 1957, two opthalmology residents, Lucas and Newhouse, were
conducting an experiment on mice to study a particular eye disorder.(3)
During the course of this experiment they fed newborn mice MSG and
discovered that all demonstrated widespread destruction of the inner
nerve layer of the retina. Similar destruction was also seen in adult
mice but not as severe as the newborns. The results of their experiment
were published in the Archives of Opthalmology and soon forgotten. For
ten years prior to this report, large amounts of MSG were being added
not only to adult foods but also to baby foods in doses equal to those
of the experimental animals.

Then in 1969, Dr. John Olney, a neuroscientist and neuropathologist
working out of the Department of Psychiatry at Washington University in
St. Louis, repeated Lucas and Newhouse's experiment.(4) His lab
assistant noticed that the newborn of MSG exposed mice were grossly
obese and short in statue. Further examination also demonstrated
hypoplastic organs, including pituitary, thyroid, adrenal as well as
reproductive dysfunction. Physiologically, they demonstrated
multiple endocrine deficiencies, including TSH, growth hormone, LH, FSH,
and ACTH. When Dr. Olney examined the animal's brain, he discovered
discrete lesions of the arcuate nucleus as well as less severe
destruction of other hypothalamic nuclei. Recent studies have shown that
glutamate is the most important neurotransmitter in the hypothalamus.(5)
Since this early observation, monosodium glutamate and other excitatory
substances have become the standard tool in studying the function of the
hypothalamus. Later studies indicated that the damage by monosodium
glutamate was much more widespread, including the hippocampus,
circumventricular organs, locus cereulus, amygdala-limbic system,
subthalamus, and striatum.(6)

More recent molecular studies have disclosed the mechanism of this
destruction in some detail.(7) Early on, it was observed that when
neurons in vitro were exposed to glutamate and then washed
clean, the cells appeared perfectly normal for approximately an hour,
at which time they rapidly underwent cell death. It was discovered that
when calcium was removed from the medium, the cells continued to
survive. Subsequent studies have shown that glutamate, and other
excitatory amino acids, attach to a specialized family of receptors
(NMDA, kainate, AMPA and metabotrophic), which in turn, either directly
or indirectly, opens the calcium channel on the neuron cell membrane,
allowing calcium to flood into the cell. If unchecked, this calcium will
trigger a cascade of reactions, including free radical generation,
eicosanoid production, and lipid peroxidation, which will destroy the
cell. With this calcium triggered stimulation, the neuron becomes very
excited, firing its impulses repetitively until the point of cell
death, hence the name, excitotoxin. The activation of the calcium
channel via the NMDA type receptors also involves other membrane
receptors such as the zinc, magnesium, phencyclidine, and glycine
receptors.

In many disorders connected to excitotoxicity, some of the glutamate
and aspartate is indogenous. We know that when brain cells are
injured they release large amounts of glutamate from surrounding
astrocytes, and this glutamate can further damage surrounding normal
neuronal cells. This appears to be the case in strokes, seizures and
brain trauma. But, food born excitotoxins can add significantly to this
accumulation of toxins.

The FDA's Response
In July, 1995 the Federation of American Societies for Experimental
Biology (FASEB) conducted a definitive study for the FDA on the
question of safety of MSG.(8) The FDA wrote a very deceptive summary
of the report, in which they implied that, except possibly for asthma
patients, MSG was found to be safe by the FASEB researchers. But, in
fact, that is not what the report said at all. I summarized, in detail,
my criticism of this widely reported FDA deception in the revised
paperback edition of my book,"Excitotoxins: The Taste That Kills", by
analyzing exactly what the report said, and failed to say.(9)
For example, it never said that MSG did not aggravate neurodegenerative
diseases. What they said was, there were no studies indicating such a
link. Specifically, that no one has conducted any studies, positive or
negative, to see if there is a link. A vital difference.

Unfortunately, for the consumer, the corporate food processors not
only continue to add MSG to our foods, but they have gone to great links
to disguise these harmful additives. For example, they use such names as
hydrolyzed vegetable protein, vegetable protein, textured protein,
hydrolyzed plant protein, soy protein extract, caseinate, yeast extract,
and natural flavoring. We know experimentally that when these
excitotoxin taste enhancers are added together they become much
more toxic than is seen individually. (10) In fact, excitotoxins in
subtoxic concentrations can be fully toxic to specialized brain cells
when used in combination. Frequently, I see processed foods on
supermarket shelves, especially frozen or diet foods, that contain two,
three or even four types of excitotoxins. We also know, as stated, that
excitotoxins in liquid forms are much more toxic than solid forms
because they are rapidly absorbed and attain high concentration in the
blood. This means that many of the commercial soups, sauces, and gravies
containing MSG are very dangerous to nervous system health, and should
especially be avoided by those either having one of the above mentioned
disorders, or who are at a high risk of developing one of them. They
should also be avoided by cancer patients and those at high risk for
cancer, because of the associated generation of free radicals and
lipid peroxidation.(11)

In the case of ALS, amyotrophic lateral sclerosis, we know that
consumption of red meats and especially MSG itself, can significantly
elevate blood glutamate, much higher than is seen in the normal
population.(12) Similar studies, as far as I am aware, have not been
conducted in patients with Alzheimer's disease or Parkinson's disease.
But, as a general rule I would certainly suggest that persons with
either of these diseases avoid MSG containing foods as well as red
meats, cheeses, and pureed tomatoes, all of which are known to have
higher levels of glutamate.

It must be remembered that it is the glutamate molecule that is
toxic in MSG ( monosodium glutamate). Glutamate is a naturally occurring
amino acid found in varying concentrations in many foods. Defenders of
MSG safety allude to this fact in their defense. But, it is free
glutamate that is the culprit. Bound glutamate, found naturally in
foods, is less dangerous because it is slowly broken down and absorbed
by the gut, so that it can be utilized by the tissues, especially
muscle, before toxic concentrations can build up. Therefore, a whole
tomato is safer than a pureed tomato. The only exception to this as
stated, based on present knowledge, is in the case of ALS. Also, the
tomato plant contains several powerful antioxidants known to block
glutamate toxicity.(13)

Hydrolyzed vegetable protein is a common food additive and may contain
at least two excitotoxins, glutamate and cysteic acid. Hydrolyzed
vegetable protein is made by a chemical process that breaks down the
vegetable's protein structure to purposefully free the glutamate, as
well as aspartate, another excitotoxin. This brown powdery substance
is used to enhance the flavor of foods, especially meat dishes, soups,
and sauces. Despite the fact that some health food manufacturers have
attempted to sell the idea that this flavor enhancer is "all natural"
and "safe" because it is made from vegetables, it is not. It is the
same substance added to processed foods. Experimentally, one can
produce the same brain lesions using hydrolyzed vegetable protein as by
using MSG or aspartate.(14)

A growing list of excitotoxins are being discovered, including several
that are found naturally. For example, L-cysteine is a very powerful
excitotoxin. Recently, it has been added to certain bread doughs and
is sold in health food stores as a supplement. Homocysteine, a metabolic
derivative, is also an excitotoxin.(15) Interestingly, elevated blood
levels of homocysteine has recently been shown to be a major, if not
the major, indicator of cardiovascular disease and stroke. Equally
interesting, is the finding that elevated levels have also been
implicated in neurodevelopmental disorders, especially anencephaly and
spinal dysraphism ( neural tube defects).(16) It is thought that this
is the protective mechanism of action associated with the use of the
prenatal vitamins B12, B6, and folate when used in combination. It
remains to be seen if the toxic effect is excitatory or by some other
mechanism. If it is excitatory, then unborn infants would be endangered
as well by glutamate, aspartate (part of the aspartame molecule), and
the other excitotoxins. Recently, several studies have been done in
which it was found that all Alzheimer's patients examined had elevated
levels of homocysteine.(17)

One interesting study found that persons affected by Alzheimer's disease
also have widespread destruction of their retinal ganglion cells.(18)
Interestingly, this is the area found to be affected when Lucas and
Newhouse first discovered the excitotoxicity of MSG. While this does not
prove that dietary glutamate and other excitotoxins cause or aggravate
Alzheimer's disease, it is powerful circumstantial evidence. When all
of the information known concerning excitatory food additives is
analyzed, it is hard to justify continued approval by the FDA for the
widespread use of these food additives.

The Free Radical Connection
It is interesting to note that many of the same neurological diseases
associated with excitotoxic injury are also associated with
accumulations of toxic free radicals and destructive lipid oxidation
products.(19) For example, the brains of Alzheimer's disease patients
have been found to contain high concentration of lipid peroxidation
products and evidence of free radical accumulation and damage.(20,21,22)

In the case of Parkinson's disease, we know that one of the early
changes is the loss of one of the primary antioxidant defense
systems, glutathione, from the neurons of the striate system, and
especially in the substantia nigra.(23) It is this nucleus that is
primarily affected in this disorder. Accompanying this, is an
accumulation of free iron, which is one of the most powerful free
radical generators known.(24) One of the highest concentrations of iron
in the body is within the globus pallidus and the substantia nigra. The
neurons within the latter are especially vulnerable to oxidant stress
because the catabolic metabolism of the transmitter-- dopamine-- can
proceed to the creation of very powerful free radicals. That is, it
can auto-oxidize to peroxide,which is normally detoxified by
glutathione. As we have seen, glutathione loss in the substantia nigra
is one of the earliest deficiencies seen in Parkinson's disease. In the
presence of high concentrations of free iron, the peroxide is converted
into the dangerous, and very powerful free radical, hydroxide.
As the hydroxide radical diffuses throughout the cell, destruction of
the lipid components of the cell takes place, a process called lipid
peroxidation. Of equal importance is the generation of the powerful
peroxynitrite radical, which has been shown to produce serious injury
to cellular proteins and DNA, both mitochondrial and nuclear.(25)

Using a laser microprobe mass analyzer, researchers have recently
discovered that iron accumulation in Parkinson's disease is primarily
localized in the neuromelanin granules (which gives the nucleus its
black color).(26) It has also been shown that there is dramatic
accumulation of aluminum within these granules.(27) Most likely, the
aluminum displaces the bound iron, releasing highly reactive free iron.
It is known that even low concentrations of aluminum salts can enhance
iron-induced lipid peroxidation by almost an order of magnitude.
Further, direct infusion of iron into the substantia nigra nucleus in
rodents can induce a Parkinsonian syndrome, and a dose related
decline in dopamine. Recent studies indicate that individuals having
Parkinson's disease also have defective iron metabolism.(28)

Another early finding in Parkinson's disease is the reduction in
complex I enzymes within the mitochondria of this nucleus.(29) It is
well known that the complex I enzymes are particularly sensitive to free
radical injury. These enzymes are critical to the production of cellular
energy. As we shall see, when cellular energy is decreased, the toxic
effect of excitatory amino acids increases dramatically.

In the case of ALS there is growing evidence that similar free radical
damage, most likely triggered by toxic concentrations of excitotoxins,
plays a major role in the disorder.(30) Several studies have
demonstrated lipid peroxidation product accumulation within the spinal
cords of ALS victims as well as iron accumulation.(31)

It is now known that glutamate acts on its receptor via a nitric
oxide mechanism.(32) Overstimulation of the glutamate receptor can
produce an accumulation of reactive nitrogen species, resulting in the
generation of several species of dangerous free radicals, including
peroxynitrite. There is growing evidence that, at least in part,
this is how excess glutamate damages nerve cells.(33) In a multitude of
studies, a close link has been demonstrated between excitotoxicity and
free radical generation.(34-37)

Others have shown that certain free radical scavengers (antioxidants),
have successfully blocked excitotoxic destruction of neurons. For
example, vitamin E is known to completely block glutamate toxicity in
vitro.(38) Whether it will be as efficient in vivo is not known. But,
it is interesting in light of the recent observations that vitamin E
combined with other antioxidant vitamins slows the course of Alzheimer's
disease and has been suggested to reduce the rate of advance in a
subgroup of Parkinson's disease patients as well. In the DATATOP study
of the effect of alpha-tocopherol alone, no reduction in disease
progression was seen. The problem with this study was the low dose that
was used and the fact that the DL-alpha-tocopherol used is known to have
a much lower antioxidant potency than D-alpha-tocopherol. Stanley Fahn
found that a combination of D-alpha-tocopherol and ascorbic acid in high
doses reduced progression of the disease by 2.5 years.(39) Tocotrienol
may have even greater benefits, especially when used in combination
with other antioxidants. There is some clinical evidence, including my
own observations, that vitamin E also slows the course of ALS as well,
especially in the form of D- alpha-tocopherol. I would caution that
antioxidants work best in combination and when use separately can have
opposite, harmful, effects. That is, when antioxidants, such as ascorbic
acid and alpha tocopherol, become oxidized themselves, such as in the
case of dehydroascorbic acid, they no longer protect, but rather act as
free radicals themselves. The same is true of alpha-tocopherol.(40)

Again, it should be realized that excessive glutamate stimulation
triggers a chain of events that in turn sparks the generation of large
numbers of free radical species, both as nitrogen and oxygen species.
These free radicals have been shown to damage cellular proteins (protein
carbonyl products) and DNA . The most immediate DNA damage is to the
mitochondrial DNA, which controls protein expression within that
particular cell and its progeny, producing rather profound changes in
cellular energy production. It is suspected that at least some of the
neurodegenerative diseases, Parkinson's disease in particular, are
affected in this way.(41) Chronic free radical accumulation would
result in an impaired functional reserve of antioxidant
vitamins/minerals and enzymes, and thiol compounds necessary for neural
protection. Chronic unrelieved stress, chronic infection, free radical
generating metals and toxins, and impaired DNA repair enzymes all add to
this damage.

We know that there are four main endogenous sources of oxidants:
1. Those produced naturally from aerobic metabolism of
glucose.
2. Those produced during phagocytic cell attack on bacteria, viruses,
and parasites, especially with chronic infections.
3. Those produced during the degradation of fatty acids and other
molecules that produce H2O2 as a by-product. ( This is important in
stress, which has been shown to significantly increase brain levels of
free radicals.)
And 4. Oxidants produced during the course of p450 degradation of
natural toxins. And, as we have seen, one of the major endogenous
sources of free radicals is from the exposure of tissues to free iron,
especially in the presence of ascorbate. Unfortunately, iron is one
mineral heavily promoted by the health industry, and is frequently added
to many foods, especially breads and pastas. Copper is also a powerful
free radical generator and has been shown to be elevated within the
substantia nigra of Parkinsonian brains.(42)

What has been shown in all these studies is a direct connection between
excitotoxicity and free radical generation in a multitude of diseases
and disorders such as seizures, strokes, brain trauma,viral infections,
and neurodegenerative diseases. Interestingly, free radicals have also
been shown to prevent glutamate uptake by astrocytes as well, which
would significantly increase extracellular glutamate levels.(43) This
creates a vicious cycle that will multiply any resulting damage and
malfunctioning of neurophysiological systems, such as plasticity.

The Blood-Brain Barrier
One of the MSG industry's chief arguments for the safety of their
product is that glutamate in the blood cannot enter the brain because
of the blood-brain barrier (BBB), a system of specialized capillary
structures designed to exclude toxic substance from entering the brain.
There are several criticisms of their defense. For example, it is known
that the brain, even in the adult, has several areas that normally do
not have a barrier system, called the circumventricular organs. These
include the hypothalamus, the subfornical organ, organium vasculosum,
area postrema, pineal gland, and the subcommisural organ. Of these, the
most important is the hypothalamus, since it is the controlling center
for all neuroendocrine regulation, sleep wake cycles, emotional control,
caloric intake regulation, immune system regulation and regulation of
the autonomic nervous system. As stated, glutamate is the most important
neurotransmitter in the hypothalamus. Therefore, careful regulation of
blood levels of glutamate is very important, since high blood
concentrations of glutamate would be expected to increase hypothalamic
levels as well. One of the earliest and most consistent findings with
exposure to MSG is damage to an area of the hypothalamus known as the
arcuate nucleus.This small hypothalamic nucleus controls a multitude of
neuroendocrine functions, as well as being intimately connected to
several other hypothalamic nuclei. It has also been demonstrated that
high concentrations of blood glutamate and aspartate (from foods) can
enter the so-called "protected brain" by seeping through the unprotected
areas, such as the hypothalamus or other circumventricular organs.

Another interesting observation is that chronic elevations of blood
glutamate can even seep through the normal blood-brain barrier when
these high concentrations are maintained over a long period of time.(44)
This would be the situation seen when individuals consume, on a daily
> basis, foods high in the excitotoxins- MSG,
aspartame and L-cysteine. Most experiments cited by the defenders of
MSG safety were conducted to test the efficiency of the BBB acutely. In
nature, except in the case of metabolic dysfunction ( such as with ALS),
glutamate and aspartate levels are not normally elevated on a continuous
basis. Sustained elevations of these excitotoxins are peculiar to the
modern diet. (and in the ancient diets of the Orientals, but not in as
high a concentration.)

An additional critical factor ignored by the defenders of excitotoxin
food safety is the fact that many people in a large population have
disorders known to alter the permeability of the blood-brain barrier.
The list of condition associated with barrier disruption include:
hypertension, diabetes, ministrokes, major strokes, head trauma,
multiple sclerosis, brain tumors, chemotherapy, radiation treatments
to the nervous system, collagen-vascular diseases (lupus), AIDS, brain
infections, certain drugs, Alzheimer's disease, and as a consequence
of natural aging. There may be many other conditions also associated
with barrier disruption that are as yet not known.

When the barrier is dysfunctional due to one of these conditions, brain
levels of glutamate and aspartate reflect blood levels. That is, foods
containing high concentrations of these excitotoxins will increase
brain concentrations to toxic levels as well. Take for example, multiple
sclerosis. We know that when a person with MS has an exacerbation of
symptoms, the blood-brain barrier near the lesions breaks down, leaving
the surrounding brain vulnerable to excitotoxin entry from the blood,
i.e. the diet.(45) But, not only is the adjacent brain vulnerable, but
the openings act as points of entry, eventually exposing the entire
brain to potentially toxic levels of glutamate. Several clinicians have
remarked that their MS patients were made worse following exposure to
dietary excitotoxins. I have seen this myself. It is logical to assume
that patients with the other neurodegenerative disorders, such as
Alzheimer's disease, Parkinson's disease, and ALS will be made worse on
diets high in excitotoxins. Barrier disruption has been demonstrated in
the case of Alzheimer's disease.(46)

Recently, it has been shown that not only can free radicals open the
blood-brain barrier, but excitotoxins can as well.(47) In fact,
glutamate receptors have been demonstrated on the barrier itself.(48)
In a carefully designed experiment, researchers produced opening of the
blood-brain barrier using injected iron as a free radical generator.
When a powerful free radical scavenger (U-74006F) was used in this
model, opening of the barrier was significantly blocked. But, the
glutamate blocker MK-801 acted even more effectively to protect the
barrier. The authors of this study concluded that glutamate appears
to be an important regulator of brain capillary transport and stability,
and that overstimulation of NMDA (glutamate) receptors on the
blood-brain barrier appears to play an important role in breakdown of
the barrier system. What this also means is that high levels of dietary
glutamate or aspartate may very well disrupt the normal blood-brain
barrier, thus allowing more glutamate to enter the brain, creating
a vicious cycle.

Relation to Cellular Energy Production
Excitotoxin damage is heavily dependent on the energy state of the
cell.(49) Cells with a normal energy generation systems are very
resistant to such toxicity. When cells are energy deficient, no matter
the cause-- hypoxia, starvation, metabolic poisons, hypoglycemia-- they
become infinitely more susceptible to excitotoxic injury or death. Even
normal concentrations of glutamate are toxic to energy deficient cells.

It is known that in many of the neurodegenerative disorders, neuron
energy deficiency often precedes the clinical onset of the disease
by years, if not decades.(50) This has been demonstrated in the case of
Huntington's disease and Alzheimer's disease, using the PET scanner,
which measures brain metabolism. In the case of Parkinson's disease,
several groups have demonstrated that one of the early deficits of the
disorder is an impaired energy production by the complex I group of
enzymes within the mitochondria of the substantia nigra.(51,52)
Interestingly, it is known that the complex I system is very sensitive
to free radical damage.

Recently, it has been shown that when striatal neurons are exposed to
microinjected excitotoxins there is a dramatic, and rapid fall in
energy production by these neurons. CoEnzyme Q10 has been shown, in this
model, to restore energy production but not to prevent cellular death.
But when combined with niacinamide, both cellular energy production and
neuron protection is seen.(53) I recommend for those with
neurodegenerative disorders, a combination of CoQ10, acetyl-L
carnitine, niacinamide, riboflavin, methylcobalamin, and thiamine.

One of the newer revelation of modern molecular biology, is the
discovery of mitochondrial diseases, of which cellular energy deficiency
is a hallmark. In many of these disorders, significant clinical
improvement has been seen following a similar regimen of vitamins
combined with CoQ10 and L-carnitine.(54) Acetyl L-carnitine enters the
brain in higher concentrations and also increases brain acetylcholine,
necessary for normal memory function. While these particular substances
have been found to significantly boost brain energy function they are
not alone in this important property. Phosphotidyl serine, Ginkgo
Biloba, B12, folate, magnesium, Vitamin K and several others are also
being shown to be important.

While mitochrondial dysfunction is important in explaining why some
are more vulnerable to excitotoxin damage than others, it does not
explain injury in those with normal cellular metabolism. There are
several conditions under which energy metabolism is impaired. We know,
for example, approximately one third of Americans suffer from reactive
hypoglycemia. That is, they respond to a meal composed of either simple
sugars or carbohydrates (that are quickly broken down into simple
sugars,i.e. a high glycemic index.) by secreting excessive amounts
of insulin. This causes a dramatic lowering of the blood sugar.

When the blood sugar falls, the body responds by releasing a burst of
epinephrine from the adrenal glands, in an effort to raise the blood
sugar. We feel this release as nervousness, palpitations of our heart,
tremulousness, and profuse sweating. Occasionally, one can have a slower
fall in the blood sugar that will not produce a reactive release of
epinephrine, thereby producing few symptoms. This can be more dangerous,
since we are unaware that our glucose reserve is falling until we
develop obvious neurological symptoms, such as difficulty thinking and
a sensation of lightheadedness.

The brain is one of the most glucose dependent organs known, since it
has a limited ability to metabolize other substrates such as fats.
There is some evidence that several of the neurodegenerative diseases
are related to either excessive insulin release, as with Alzheimer's
disease, or impaired glucose utilization, as we have seen in the case
of Parkinson's disease and Huntington's disease.(55)

It is my firm belief, based on clinical experience and physiological
principles, that many of these diseases occur primarily in the face of
either reactive hypoglycemia or " brain hypoglycemia", a condition
where the blood sugar is normal and the brain is hypoglycemic in
isolation. In at least two well conducted studies it was found that
pure Alzheimer's dementia was rare in those with normal blood sugar
profiles, and that in most cases Alzheimer's patients had low blood
sugars, and high CSF (cerebrospinal fluid) insulin levels.(56,57)
In my own limited experience with Parkinson's and ALS patients I have
found a disproportionately high number suffering from reactive
hypoglycemia.

I found it interesting that several ALS patients have observed an
association between their symptoms and gluten. That is, when they
adhere to a gluten free diet they improve clinically. It may be that
by avoiding gluten containing products, such as bread, crackers,
cereal, pasta ,etc, they are also avoiding products that are high on the
glycemic index, i.e. that produce reactive hypoglycemia. Also, all of
these food items are high in free iron. Clinically, hypoglycemia will
worsen the symptoms of most neurological disorders. We know that severe
hypoglycemia can, in fact, mimic ALS both clinically and athologically.
(58) It is also known that many of the symptoms of Alzheimer's disease
resemble hypoglycemia, as if the brain is hypoglycemic in isolation.