Just how safe is Glutamine?
JerryCSR
interested in hearing from people who know or have used this
supplement as just about every single bodybuilder seems to use it.
This is one article I read, which is negative, but the overwhelming
articles have been postive. However, this article seems to have some
good points. It can be read below where I cut and pasted it, or read
it at its website: http://www.optexinc.com/glutaminerisks.htm
Thanks for replying.
Glutamine Based Growth Hormone Releasing Products: A Bad Idea?
One should not assume that health food stores are safe havens from
these excitotoxins. In fact, I have found that many products,
including supplements as well as foods, contain one or more of these
toxic compounds. For example, at least one product claiming to improve
memory and boost brain power, contains large doses of both glutamate
and glutamine.
-Russell Blaylock, M.D., Excitotoxins: The Taste that Kills
--------------------------------------------------------------------------------
Introduction
Much has been written about the benefits of amino acid
supplementation, especially for purposes of stimulating growth hormone
(GH) release from the pituitary gland for anti-aging purposes.
Multi-level marketing companies are aggressively promoting glutamine
based GH releasing products to their customers and distributors.
Self-styled anti-aging experts are promoting glutamine to their
friends and acquaintances on the internet with little apparent thought
to the consequences.
There is very little discussion of the possible risks of such
supplementation. This web page is designed to fill that void -- to
give the other side of the story -- especially with regard to
glutamine and its excitatory and potentially excitotoxic metabolite
glutamate. Note that this web page is not designed to explore the
benefits of glutamine supplementation, of which there are some. This
page is biased intentionally toward a discussion of the risks rather
than the benefits. The reader should have no difficulty finding
pro-glutamine literature on the web or elsewhere, but I would
challenge the reader to find literature that adequately addresses the
concerns I express below.
Definition : For purposes of this discussion, "glutamine GH
supplementation" is defined as the practice of ingesting one or more
grams of glutamine, in capsule form or mixed in liquid, chronically
and on an empty stomach by people who are not deficient in glutamine,
for purposes of stimulating the hypothalamic/pituitary axis to release
growth hormone as part of a life-long anti-aging regimen.
Typically, glutamine GH supplementation entails ingesting from 2 to 25
grams of supplemental glutamine per day on an empty stomach. 2 gram
doses are almost certainly safer than 25 gram doses, but I've yet to
see any evidence that 2 gram doses should be exempt from the arguments
I present here.
Glutamine taken in small sub-gram quantities or with meals containing
complete proteins is not at issue, nor is such supplementation likely
to result in an increase in GH release. Occasional or temporary
glutamine supplementation is also not at issue, nor is glutamine taken
for medicinal purposes or for supporting the unique needs of athletes.
This page concerns only the practice of chronic megadosing with
glutamine by people who are not deficient in the substance, as defined
above.
The reader should keep in mind that the opinions expressed here are
controversial and do not represent the views of some health
professionals, including many in the field of alternative medicine.
The standard disclaimers apply (i.e., talk to your doctor before
making any major health decisions).
--------------------------------------------------------------------------------
My Hypothesis
Glutamine when ingested on an empty stomach acts as a growth hormone
secretagogue via its excitotoxic metabolite glutamate. Glutamate acts
by stimulating the hypothalamus to secrete growth hormone releasing
hormone (GHRH) which causes the pituitary to release growth hormone
(GH). Sharp increases in brain glutamate levels are hazardous to the
brain and nervous system and glutamine GH supplementation may create
sharp increases in brain glutamate levels. Glutamine GH
supplementation therefore poses a risk to the nervous system.
Some explanation:
This medical dictionary defines "Excitotoxin" as follows:
Class of substances that damage neurons through paroxysmal
overactivity. The best known excitotoxins are the excitatory amino
acids, that can produce lesions in the central nervous system similar
to those of Huntingdon's chorea or Alzheimer's disease. Excitotoxicity
is thought to contribute to neuronal cell death associated with
stroke.
Glutamate is a neurotransmitter, an excitatory amino acid (EAA) and an
excitotoxin. Normal levels of glutamate are healthy and necessary for
brain function but abnormally high levels can be toxic to neurons.
Glutamine converts to glutamate in the presence of an enzyme and
water. Much such conversion occurs in the brain and nervous system.
An increase in brain glutamine can cause an increase in the release of
glutamate by the neurons into the spaces between the neurons. If the
increase is not modulated correctly by the brain and nervous system
then the result will be a phenomenon known as "glutamate
excitotoxicity". Glutamate excitotoxity is the necrosis (premature
death) of neurons by paroxysmal overactivity (overexcitation) by
glutamate.
Under ideal conditions, excess extracellular glutamate is eliminated
by the protective actions of glial cells, also known as astrocytes.
The astrocytes retrieve extracellular glutamate and convert it back to
glutamine. This protective mechanism requires large amounts of energy
in the form of ATP -- energy which may not be available under less
than ideal conditions.
N-methyl-D-aspartate (NMDA) receptors are receptors for the glutamate
molecule, and for molecules similar to glutamate, which exist on
approximately 50% of the neurons of the forebrain. All such neurons
are potentially vulnerable to glutamate excitotoxicity.
Extracellular glutamate comes in contact with the NMDA receptor on the
dendrite or body of the neuron, in combination with glycine, opening a
calcium channel. Calcium then flows into the neuron causing the neuron
to fire. This entry of calcium into the neuron initiates a sequence of
events inside the neuron that requires energy in the form of ATP and
which also unleashes free-radicals inside the neuron. If excessive
calcium enters the cell then the quantity of free-radicals released
can damage or destroy the neuron. It is important to understand that
neurons can be damaged by excess glutamate without being killed. Such
damaged neurons then become more vulnerable to future exposure to
glutamate.
Note also that both the processes described above require energy. If
an unnaturally large amount of glutamate is released into the
extracellular space in response to an unnaturally large intake of
glutamine then the astrocytes will require an unnaturally large amount
of energy to protect the neurons from that excess glutamate.
Similarly, if the astrocytes fail to remove the excess in time then
the neurons will be forced to expend unnaturally large amounts of
energy handling the excess excitation caused by the excess glutamate.
Excessive calcium can enter the cell if the exposure to glutamate is
excessive, even if that exposure is brief. In some cases the calcium
channel can "lock" in the open position and allow calcium to continue
streaming into the cell until the neuron dies from overexcitation. The
actual cell death in such cases may occur several hours after the
exposure to excess glutamate.
It is known that increases in brain glutamine cause increases in
extracellular glutamate. If the magnitude of glutamate increase is
great enough and/or the brain is energy compromised due to age or low
blood sugar or any other reason, and/or the neurons or astrocytes are
otherwise compromised as a result of drugs or as a result of a low
supply of oxygen or as a result of what may be normal wear from
ordinary free-radical damage from normal living (or perhaps as a
result of excessive free-radical damage caused by chronic megadosing
with glutamine), then the result will be further damage or death of
those neurons. There is no reason to think such damage would be severe
enough to be noticed each time it occurs. It might be subtle, nearly
undetectable neurological damage that happens gradually over a long
period of time as a result of chronic daily megadosing on glutamine.
It is not necessary that glutamine GH supplementation cause an
extremely high concentration of CFS glutamate to cause CNS damage.
Relatively low concentrations of excess glutamate can injure and
impair neurons, making them more vulnerable to future exposures to
excess glutamate. Repeated exposures would tend to weaken some neurons
while killing others that had been weakened from prior exposures. In
this scenario there might be an acceleration of normal age-related
mental decline from chronic glutamine GH supplementation which might
never be attributed to the glutamine in the absence of a controlled
study, and this is my primary concern. In the worst case scenario such
supplementation could even play a role in precipitating any of the
various devastating neurodegenerative diseases in which glutamate
excitotoxicity is known to be a factor.
Note that it is not my contention that the damage I describe above
must occur as a consequence of glutamine GH supplementation. It is
rather my contention that chronic, unnaturally large increases in
glutamine from glutamine GH supplementaion are hazardous to the brain
and nervous system because we know glutamate is hazardous, because we
know glutamine promotes glutamate, and because we have no evidence to
show that the brain can always properly control the sudden increases
in glutamate that can and may always result from such sudden increases
in glutamine, especially if the brain is subjected to this unnatural
stress repeatedly on a daily or semi-daily basis over many years as
part of any supposed anti-aging regimen. Given that lack of evidence,
and in light of the generally irreversible nature of brain and nervous
system damage, the risks of long-term glutamine GH supplementation are
considerable and should be unacceptable to many.
The risks should be especially unacceptable to those whose brains and
nervous systems no longer enjoy the natural protections of youth. It
is an ironic and perhaps tragic fact that these are the same people
who are most inclined to be drawn to glutamine GH supplementation as a
seemingly risk-free and inexpensive means of slowing the aging
process.
Note regarding a competing hypothesis for mechanism of action:
As above, I accept the hypothesis that glutamine works for GH release
in humans via glutamate's excitatory effects on the neurons of the
hypothalamus responsible for GHRH (I suspect I am not the actual
originator of this hypothesis, and so I accept it while also proposing
it and forwarding it.) However there is a competing hypothesis to
explain the GH releasing effects of glutamine. There is some rationale
for it but no evidence that I can find. In that competing hypothesis
glutamine works for GH release by increasing the serum levels of the
amino acid arginine. Arginine is known to be a GH secretagogue, and
one which seems to work by a mechanism other than that which I present
here for glutamine. However this competing explanation for the GH
releasing effect of glutamine seems unlikely to me for several
reasons, the most obvious of which is the vast disparity in the
quantities of amino acids involved. Endocrinologists find it necessary
to infuse up to 30 grams of pure arginine to evoke the arginine GH
response. In the case of glutamine, Welbourne found that two grams
taken orally mixed in a cola drink was sufficient to stimulate a
dramatic response in GH. It seems improbable that two grams of oral
glutamine can promote synthesis of the necessary quantity of arginine.
And even if true, it is unclear whether the mechanisms involved in
this competing hypothesis would allay the risks of glutamate
excitotoxicity as described above.
--------------------------------------------------------------------------------
Have amino acids been proven safe for long term use as GH releasers?
No. There is no published, peer-reviewed research to support the
hypothesis that amino acid GH secretagogues are either safe or
effective when used long term.
I believe most of the current sensationalism about glutamine for GH
can be traced back to the writings on a single page of a single book
by a single doctor of alternative medicine named Ronald Klatz. Dr.
Klatz' book Grow Young with HGH is about the virtues of injectable
growth hormone. The book is popular and written for the lay-person. In
my opinion it is worthwhile reading for people considering the use of
injectable GH. Klatz mentions glutamine almost as an after-thought,
near the end in a chapter about alternatives to injectable GH, under
the sub-title "New kid on the block."
The Welbourne study upon which Klatz bases much of his opinion
supports the hypothesis that two gram doses of glutamine are effective
for GH release for diagnostic purposes. The Welbourne study merely
provides endocrinologists with another possible diagnostic tool. For
example endocrinologists might now use an oral load of glutamine,
rather than the more usual intraveneous administration of arginine, as
a GH secretagogue in a clinical test of growth hormone deficiency
(GHD). Normally the endocrinologist would prescribe injectable GH if
the patient's pituitary gland failed to secrete adequate GH in
response to the secretagogue. The GHD patient would then inject GH on
a regular basis much like a diabetic injects insulin.
As should be clear, the Welbourne study did very little to support the
highly popularized idea that ingesting two grams of glutamine on an
empty stomach one or more times per day is safe and effective as part
of a life-long anti-aging protocol.
X-rays are a good example of the principle involved here. Like
concentrated amino acid GH secretagogues, concentrated x-rays have
been proven safe and effective for diagnostic purposes. However, also
like x-rays, high concentrations of glutamine have not been shown safe
and effective for long term use on a daily or semi-daily basis. In the
case of chronic concentrated head x-rays, the long term consequences
are an increased probability of developing brain cancer. The long term
consequences of chronic megadoses of glutamine are not yet known.
--------------------------------------------------------------------------------
I thought amino acids were natural. How could something natural be
dangerous?
Many physicians do not accept even the notion that people should
supplement with one gram of vitamin C per day, much less several grams
of a single amino acid on an empty stomach. The medical community is
cautious about such things because such supplementation is not natural
. It is quite difficult for a human to consume a full gram of vitamin
C in one day from natural foods. Also many valuable nutrients are
known to be toxic when consumed in unnaturally large amounts for
extended time periods. Vitamin A is a good example.
The above does not mean that one should not consume one gram or more
of vitamin C per day. Many people do consume a gram or more of vitamin
C each day. While not yet accepted by mainstream medicine, megadoses
of vitamin C are considered reasonably safe because there is a
tremendous amount of research to support the hypothesis that daily
megadoses of vitamin C are safe and beneficial.
Relative to something like vitamin C, practically no research exists
into the safety of ingesting single amino acids, much less ingesting
large doses of single amino acids chronically on an empty stomach. It
is simply unknown whether such supplementation will be on balance
harmful or beneficial to people in the long run.
Our bodies expect to receive amino acids as part of proteins, in the
company of other amino acids which may be necessary to prevent
toxicity. In nature no single amino acid is given exclusive access to
the blood-brain barrier. Especially worrisome therefore is the idea of
taking large doses of a single amino acid on an empty stomach for
purposes of transporting it across the blood-brain barrier in a
concentration high enough to stimulate GH release. This practice
places an unusual and unnatural stress on the brain.
In nature the human brain is never subjected to concentrated doses of
any single amino acid, especially one that acts in the brain as a
direct precursor to an excitatory neurotransmitter and a potential
excitotoxin, as does glutamine. The long term health consequences of
such concentrated "brain treatments" are currently untested and
unknown and therefore uncertain and unsafe . People who do it are
human guinea pigs.
--------------------------------------------------------------------------------
What about evidence?
The burden of proof should be on those who promote chronic use of the
supplement. It is their hypothesis that healthy people not deficient
in glutamine should deviate permanently from a natural unsupplemented
diet by adding unnaturally concentrated doses of pure glutamine.
However they have no peer reviewed research to support the long term
safety of their glutamine hypothesis that I have seen.
To rule out glutamate excitotoxicity and accept the glutamine-for-GH
hypothesis without raising our risk threshold as it pertains to our
nervous systems, it would be necessary to measure the level of
glutamate in the cerebrospinal fluid (CSF) following the oral
administration of glutamine, or in some other way measure the level to
which nerve cells were exposed to any increase in glutamate, and
determine that glutamate levels remained unchanged or did not increase
enough to present a danger. I have seen no such measurements or
determinations. Measurements of glutamate in the blood serum after
ingestion of glutamine are certainly not measures of CSF glutamate.
Glutamate excitotoxicity is a hot topic in current research and there
are valid reasons to think that those who take glutamine for GH
releasing purposes (i.e., large doses on an empty stomach) should be
concerned about the dangers of glutamate excitotoxicity. I've
enumerated some of those reasons here. I'll be adding more research
and information as time allows.
The apparent mechanism of action of glutamine for GH release is itself
strong evidence of the hazard it poses. It appears that glutamine GH
supplementation works by inducing a significant increase in the level
of brain glutamate, which induces a release of growth hormone. The
glutamate increase is of unknown magnitude and duration.
The following research abstracts and discussions illustrate how
glutamine appears to work for GH release.
Effects of naloxone and neonatal treatment with monosodium-L-glutamate
on growth hormone and prolactin release induced by electrical
stimulation of the medial-basal hypothalamus in rats .
Researchers in the study above used electricity to stimulate the
hypothalamus in the brains of rats. The electrical stimulation caused
an immediate subsequent release of growth hormone. The GH response was
diminished in rats that had lesions of the hypothalamus from exposure
to glutamate from monosodium glutamate (MSG).
The key part of the brain for stimulating the release of GH releasing
hormone (GHRH), and which the researchers stimulated here by
artificial means, appears to be a group of neurons called the arcuate
nucleus located on the medial-basal hypothalamus. This is also a part
of the brain that is stimulated by exposure to excess dietary
glutamate and which can be permanently or temporarily damaged by such
exposure. Glutamate is an excitatory amino acid (EAA) and a
neurotransmitter. When present in excess it is an excitotoxin.
It seems to be no coincidence that concentrated doses of glutamine
(the precursor to glutamate) taken on an empty stomach can evoke GH
release in humans. If such supplementation results in a sharp increase
in glutamate at the hypothalamus then it can be expected to have the
same excitatory effects as electricity on the neurons of the arcuate
nucleus, which in turn signal for the release of GH. Chronic use of
glutamine on an empty stomach would then have the same dulling effect
on the hypothalamus as chronic exposure to the glutamate from MSG, as
seen in the lab rats in the research study. Depending on dosage and
frequency, exposure to excess glutamate can over time desensitize or
damage or even kill the neurons of the arcuate nucleus so important
for natural GH release.
Comparison of glutamine-enhanced glutamate release from slices and
primary cultures of rat brain.
Glutamine enhances glutamate release in preference to
gamma-aminobutyrate release in hippocampal slices .
Researchers in the two studies above explore the enhancement of
glutamate release by glutamine. They determine that adding additional
glutamine to brain tissue results in an increase in the amount of
glutamate released into the extracellular space. "Results suggest that
the availability of extracellular glutamine regulates the release of
glutamate."
These studies are in direct contradiction to the misinformation being
promulgated by those who believe in magic and risk-free silver
bullets. Consider for example this false statement: "Increasing
Glutamine levels and/or the rate of increase will have NO effect on
the intercellular level of Glutamate. If this were not so, not only
for Glutamate but for many other chemicals, we would have died a long
time ago." This false statement appears at the website of one very
vocal Australian proponent of glutamine for GH release.
Aspartate and glutamate modulation of growth hormone secretion in the
pig: possible site of action.
Few people involved in the anti-aging movement seem to have any idea
how glutamine acts to cause GH release. Apparently the proponents of
glutamine for GH release prescribe it to others merely because it
worked in one published study, while hoping its mechanism of action is
harmless. However in this study researchers confirm my hypothesis that
glutamate is effective for GH release, which quite easily explains the
GH releasing effect of its precursor glutamine.
As an excitatory amino acid and a neurotransmitter, additional
glutamate can stimulate neurons and cause them to behave in ways they
would not otherwise behave. In this case, as supported by these
studies, it appears additional glutamate stimulates the neurons of the
arcuate nucleus of the hypothalamus, causing the hypothalamus to
secrete GHRH, which in turn causes the pituitary to release GH. These
researchers also conclude, similar to the researchers in the first
study above, that the hypothalamus is the likely site of action of
glutamate for GH releasing purposes.
Glutamate: a major excitatory transmitter in neuroendocrine regulation
This paper further confirms the hypothesis that glutamate is involved
in regulating the release of hormones from the hypothalamus. (Though
it has never been tested experimentally, we can infer from this paper
that glutamine GH supplementation may also stimulate production of sex
hormones in humans.)
I'll add more supporting abstracts as I find them.
The studies above taken together support my opinion that chronic
supplementation with glutamine, taken on an empty stomach to maximize
penetration of glutamine past the blood-brain barrier, is likely to be
effective as a GH secretagogue via its metabolite glutamate, at least
in the short term while the hypothalamus is healthy, but that such
supplementation is also hazardous to the cells of the hypothalamus and
perhaps hazardous to the entire brain and nervous system. The hazard
is due to the fact that glutamine promotes increased levels of brain
glutamate. The risk most likely increases with age, with frequency of
exposure, and with dosage.
Defenders of glutamine GH supplementation rely heavily on the
protective power of glial cells in the brain, which can under optimum
youthful conditions help a great deal by eliminating the excess
glutamate.
However glutamine for GH release is an idea that is being marketed
heavily to aging people as a means of slowing the aging process. The
risk of damage from excess glutamate increases with age, as aging
glial cells become less effective at eliminating excess glutamate.
In fact it is theorized that accumulations of excess glutamate and
GABA in the aging brain are two major causes of ordinary senility
(Senile Dementia). Glutamine acts in the brain as a precursor to both
glutamate and GABA, so pushing extra glutamine into the brain may
promote excess production of these two chemicals and hasten the onset
of senility. More on this below.
--------------------------------------------------------------------------------
What about the idea I heard that people can take other supplements
like taurine to help protect the brain from the risks of glutamine GH
supplementation?
Yes, unlike large doses of glutamine on an empty stomach, some
supplement ideas are probably safe and beneficial to the brain and
nervous system. The amino acid taurine and the herb gingko biloba and
other supplements have neuroprotective and antioxidant capabilities
which can help protect the brain from the dangers of excess glutamate.
If you feel you must take large amounts of glutamine then it would be
wise to take supplements such as taurine, ginkgo biloba,
methylcobalomine, billberry extract, and green tea extract (See
"Glutamine: The Essential 'Non Essential' Amino Acid", Life Extension
Magazine, Sept 99).
However, you might want to think first about the curious practice of
taking supplements as antidotes for other supplements. It may be wiser
and better for your brain to take these other supplements above but
without the glutamine.
--------------------------------------------------------------------------------
My multi-vitamin contains glutamine. Should I stop taking it?
In my view small daily doses of glutamine or glutamate as might be
found in some multivitamins are not a matter for concern.
Also it should be noted that the typical person consumes several grams
of glutamine each day as part of complete proteins.
Glutamine is not however an essential part of the human diet except
perhaps under conditions of great physical stress or after physical
trauma. There is good reason to believe that body-builders and other
athletes have a unique need for extra glutamine. Glutamine is used
also to treat certain intestinal disorders.
As mentioned in the first section of this article, the concerns I
describe here pertain only to chronic megadoses of glutamine taken on
an empty stomach by people who are not deficient in glutamine, usually
for purposes of stimulating GH release as part of a life-long
anti-aging regimen.
--------------------------------------------------------------------------------
What is the significance of the empty stomach?
Normally the blood-brain barrier protects the brain from excessive
amounts of any single amino acid. However that protection is reduced
dramatically when the amino acid is taken on an empty stomach in
isolation from other amino acids. In fact it is because of the natural
protection of the blood-brain barrier that it is considered necessary
to take glutamine on an empty stomach for purposes of stimulating the
release of growth hormone. If the glutamine is taken as part of
complete proteins, with a meal or on a full stomach, then it will be
forced to compete with other nutrients and amino acids for entrance to
the brain. But that competition between amino acids for entrance to
the brain is the normal state of nature; it ensures that no single
amino acid will flood the brain in isolation. Glutamine works for
stimulating GH release only if we intentionally defeat mother nature's
built-in protections, which in itself is an indication that some risks
are involved.
Another concern is that the brain is more vulnerable to excitotoxicity
when the body is fasting. The brain derives most of its energy from
glucose (sugar), and it needs that energy to defend against any sudden
increase in glutamate. The worst time to take large amounts of
glutamine is in the morning before breakfast on an empty stomach, when
the body has been fasting overnight and blood sugar is low.
--------------------------------------------------------------------------------
The Life Extension Foundation
In December of 1999 I discussed glutamine GH supplementation with Tom
Matthews in the public Life Extension Foundation (LEF) online forum.
Tom is a very knowledgeable fellow who was at that time a paid
consultant to LEF and the moderator of the LEF forum. LEF is an
organization that sells many health supplements including glutamine.
Tom had a more favorable view of glutamine than me. His eventual
agreement with my position was buried in a barrage of objections. This
was the key exchange:
Me: "It is very ironic that the risk of damage from excess glutamate
increases with age, as aging glial cells become less efficient in
their ability to eliminate excess glutamate."
Tom Matthews: "However, you have a valid point here. Because there may
be localized hypoxia and reduced brain cell fuel in age, glutamine
should certainly not be the GH releaser of choice for older people,
especially for anyone with symptoms of such cerebral vascular
insufficiency. I think this caution may well be worth putting into any
promotional literature regarding glutamine for GH release purposes."
As above, Tom agreed that the glutamate from glutamine presents a risk
to older people, and agreed that glutamine based GH releasing products
are certainly not the best choice for these older people, and that
literature about these products should include a caution about the
dangers of glutamate. Perhaps future literature for any future LEF
glutamine based GH product will include a warning about the risks of
glutamate, if not for everyone then at least for "older" people.
To prevent any confusion or false charges about quoting out of
context, here are the links to the forum threads for those with the
interest and the patience to wade through the messy discussion. You'll
find the exchange above, which I consider most important. If you read
carefully you'll be able also to guess when an unnamed third party may
have entered the picture behind the scenes to start trouble.
By the way I have no idea at what age "younger people" become "older
people" and I am aware of no tests to determine when a person has
changed from younger to older. It seems to me that the change from
younger to older is subtle and gradual. This would mean that glutamine
based GH releasing products, marketed to help people stay young,
actually become more dangerous for people on average each day as they
grow older.
LEF had a position on this subject that I would consider prudent as
recently as August of 1998:
"One cause of brain cell death is glutamate toxicity. Brain cells use
glutamate as a neurotransmitter, but unfortunately glutamate is a
double-edged sword in that it can also kill aging brain cells. The
release
of glutamate from the synapses is a usual means by which neurons
communicate with each other.
Effective communication means controlled release of glutamate at the
right time to the right cells, but when glutamate is released in
excessive amounts, intercellular communication ceases. The flood of
glutamate onto the receiving neurons drives them into hyperactivity,
and the excessive activity leads to cellular degradation. The Life
Extension Foundation has never recommended glutamine supplements for
healthy people because of concern about glutamine-induced brain cell
damage."
-LEF Magazine August 1998
However, judging by the word and tone of the Sept 99 glutamine article
, the "official" LEF position on glutamine supplementation seems
currently to depend on the dubious assumption that all people have
either an obvious neurodegenerative disease (in which case glutamine
is contraindicated) or a perfectly healthy, impervious nervous system
(in which case pure glutamine can be consumed in just about any amount
with little or no risk).
The more recent '99 article is however excellent and worth reading. It
is well-written and informative. I encourage all readers here to take
the time to read that article for a different perspective on this
subject. While the '99 article is certainly open to interpretation, my
only criticism is that it is a bit too idealistic. Perfect
bullet-proof nervous systems with complete immunity to excitotoxic
injury from glutamine/glutamate probably exist only in the idealistic
world of textbook theory. Normal age-related mental decline with its
associated vulnerabilities begins in mid-life and then accelerates
with age.
--------------------------------------------------------------------------------
Russell Blaylock, M.D.
While debating this matter with others on the internet, someone
brought to my attention the work of Russell Blaylock, M.D. Dr.
Blaylock is a board certified neurosurgeon and is considered the
leading authority on the subject of excitotoxins. I purchased his book
and learned he is even more concerned about the risks of glutamine
than myself. I am concerned only about concentrated doses of glutamine
on an empty stomach designed to maximixe its transport across the
blood-brain barrier. Dr. Blaylock however condemns even the use of
glutamine enriched food in hospitals.
These quotes are from his book "Excitotoxins: The Taste That Kills".
In this quote Dr Blaylock condemns the sale of glutamine in health
food stores to people who are not deficient in the substance...
"One should not assume that health food stores are safe havens from
these excitotoxins. In fact, I have found that many products,
including supplements as well as foods, contain one or more of these
toxic compounds. For example, at least one product claiming to improve
memory and boost brain power, contains large doses of both glutamate
and glutamine."
He continues in his condemnation of glutamate and glutamine,
condemning the use of glutamine in hospital food...
"Some hospitals add these excitotoxin food additives to patient's
food. In fact, several nutritionists are recommending that glutamine
(the precursor of glutamate) be added to the diet of seriously ill
patients to improve intestinal function..."
--------------------------------------------------------------------------------
Can too much glutamine cause disease?
"Cause" may be too strong a word. The words precipitate or aggravate
might however be appropriate. It is very possible that excess
glutamate from glutamine can precipitate and/or aggravate many
neurodegenerative diseases, including the disease of ordinary
senility.
Senile Dementia
Some neuroscientists believe the symptoms of ordinary senility are
"caused" by accumulations of excess glutamate, GABA and ammonia in the
brain, which result from the gradual age-related degeneration of the
brain's ability to regulate these chemicals properly.
"If the glia are dysfunctional due to reduced aerobic metabolism, or
the release and/or activity of the glial cell glutamine synthase is
inhibited in any way (free radical damage, toxins, certain drugs), not
only glutamate, but GABA as well might accumulate in excess, possibly
causing lethargy and cognitive dysfunction. It has been suggested that
this too is one of the phenomena we see in the aging brain. On the one
hand, glutamate excitotoxicity damages or destroys some neurons,
leading to deficiencies in memory and learning; on the other hand,
excess of GABA can lead to lethargy. At the same time, excess ammonia,
not detoxified through sufficient glutamine synthesis by the glia,
leads to further neural damage."
-Glutamine: The 'Essential' Non Essential Amino Acid, Life
Extension Magazine, Sept 99
Glutamine acts in the brain as a precursor to glutamate, GABA and
ammonia. As above, these are three chemicals which in excess are
thought to cause symptoms of senility (lethargy and cognitive
dysfunction). It is therefore at least possible if not likely that
pushing unnaturally high amounts of glutamine into the aging brain on
a daily basis can promote excess production of one or more of these
chemicals and precipitate or aggravate the symptoms of senility. The
addition of precursors tends to promote production of metabolites and
experimental evidence suggests that this is true for the production of
glutamate from glutamine in brain tissue.
From the point of view of the nervous system, it appears glutamine GH
supplementation may actually add fuel to the fire of aging. In older
people it might cause a temporary increase in alertness but at a dear
price.
Glaucoma
Glutamate excitotoxicity can cause blindness and is thought to be the
cause of retinal nerve damage in glaucoma. People with glaucoma or at
risk of glaucoma should probably avoid glutamine.
Title
Chronic low-dose glutamate is toxic to retinal ganglion cells.
Toxicity
blocked by memantine.
Author
Vorwerk CK ; Lipton SA ; Zurakowski D ; Hyman BT ; Sabel BA ; Dreyer
EB
Address
Department of Ophthalmology, Massachusetts Eye and Ear Infirmary,
Boston, MA
02114, USA.
Source
Invest Ophthalmol Vis Sci, 37(8):1618-24 1996 Jul
Abstract
PURPOSE: It is well known that acute exposure to high concentrations
of
glutamate is toxic to central mammalian neurons. However, the effect
of a
chronic, minor elevation over endogenous glutamate levels has not been
explored. The authors have suggested that such chronic exposure may
play a
role in glaucomatous neuronal loss. In the current study, they sought
to
explore whether a chronic, low-dose elevation in vitreal glutamate was
toxic
to retinal ganglion cells and whether this toxicity could be prevented
with
memantine, a glutamate antagonist. METHODS: Rats were injected
serially and
intravitreally with glutamate to induce chronic elevations in
glutamate
concentration. A second group of rats was treated with intraperitoneal
memantine and glutamate. Control groups received vehicle injection
with or
without concurrent memantine therapy. After 3 months, the animals were
killed, and ganglion cell survival was evaluated. RESULTS:
Intravitreal
injections raised the intravitreal glutamate levels from an endogenous
range
of 5 to 12 microM glutamate to 26 to 34 microM. This chronic glutamate
elevation killed 42% of the retinal ganglion cells after 3 months.
Memantine
treatment alone had no effect on ganglion cell survival. However, when
memantine was given concurrently with low-dose glutamate, memantine
was
partially protective against glutamate toxicity. CONCLUSIONS: These
data
suggest that minor elevations in glutamate concentration can be toxic
to
ganglion cells if this elevation is maintained for 3 months.
Furthermore,
memantine is efficacious at protecting ganglion cells from chronic
low-dose
glutamate toxicity.
Language
Eng
Unique Identifier
96295379
Mental Illness
This is a summary of two case studies that appeared in a report in the
American Journal of Psychiatry in 1984, in which glutamine
supplementation appears to have caused mania.
GLUTAMINE/MENTAL SYMPTOMS
Two men taking L-glutamine, an amino acid sold in health food stores,
developed manic behavior (excitement unstable attention, increased
activity). Symptoms disappeared after the glutamine use was stopped.
Glutamine is sold as a cognitive aid and brain stimulant.
(American Journal of Psychiatry 141:1302-1303, 1984)
Glutamine is seldom marketed today as a "cognitive aid" or "brain
stimulant". I suspect this is because neuroscientists have learned
much in the last two decades about the function of glutamate in the
brain as well as its dangers, such that responsible supplement vendors
no longer recklessly promote glutamine/glutamate as a cognitive aid or
brain stimulant.
In addition to mania, glutamine GH supplementation might also cause
depression in some people. Here is the testimony of a person I met on
the internet. I have removed the name of the Australian who
recommended the glutamine.
I tried [someone's] suggested 2 grams of L-Glutamine before bed. I did
this for 2 weeks, but was having so much trouble sleeping, I switched
to taking it in the morning, which I did for another 2 weeks. The main
result was an incredible crop of cold sores - I used to get them a lot
in the 70's, haven't had more than 1 per year since then.
I had a bad situation during the time I was on the L-Glutamine -
an incident which seriously depressed me. (Again, I used to have
serious problems with depression back in the 60's and 70's - none at
all in the last 15 years at least.) I got even more depressed because
no one else understood why that incident would concern me, let alone
depress me. Toward the end of that time, I felt that if I could just
lay undisturbed for an hour or so, I would have a stroke and be out of
my misery. I was really upset with all the people who kept disturbing
me.
The thing that really disturbs me now, is that the day after I
quit taking the Glutamine, I suddenly saw this incident just as
everyone else saw it - no reason to even be upset - let alone
depressed about it, certainly not that depressed. While I was on the
Glutamine, I didn't even consider that the two could be related. The
way the problem just evaporated so soon after I quit the Glutamine, I
personally am convinced the depression was a direct result of the
Glutamine.
While these reports of mania and depression are a bit alarming, I do
not believe they are common side effects of glutamine supplementation.
If mental illness were a major problem with glutamine then there would
likely be more reports such as these and researchers would be studying
the problem with stricter controls. However these reports do
underscore the important fact that glutamine can have psychoactive
properties; it acts on the delicate mechanisms of the brain via the
excitatory and potentially excitotoxic neurotransmitter glutamate, of
which it is the direct precursor.
Insomnia
Insomnia and nervous stimulation are very common side-effects of
glutamine GH supplementation. These common side-effects are almost
certainly due to the unnaturally high levels of glutamate in the brain
and nervous system created by glutamine supplementation. The insomnia
and stimulation side-effects are important evidence in support of my
hypothesis that megadoses of glutamine create potentially dangerous
surges in brain glutamate; glutamine itself has no excitatory
properties. Only its metabolite glutamate is excitatory. This means
insomnia is strong evidence that glutamate production increases to
unhealthy levels following ingestion of glutamine.
Apparently some people believe the nervous stimulation from glutamine
is a "good" side-effect because it "feels good" and makes them feel
"awake". I note that the drug amphetamine is also reported to feel
good and that amphetamine causes people to feel very healthy and
strong and awake. And like excess glutamate, amphetamine stimulates
the release of growth hormone. Amphetamine and its derivatives like
methamphetamine ("speed") are drugs of abuse and known neurotoxins.
Glutamate is not a chemical analog to these dangerous drugs, however.
My point is simply that one should not assume that nervous stimulation
from glutamine is beneficial merely because it might cause a pleasant
stimulating sensation. I believe the opposite is more likely to be
true. No one knows for certain but it seems at least intuitively
reasonable to think those who feel the excitatory effects of glutamate
on their nervous systems are at greater than average risk of damage
from glutamate excitotoxicity.
Amyotropic Lateral Sclerosis (ALS, or "Lou Gehrig's Disease") and
other neurodegenerative diseases including ordinary senility
The following research abstracts are interesting and worthy of study.
However I would caution the casual reader from drawing any premature
conclusions.
1H-MRS evidence of neurodegeneration and excess glutamate + glutamine
in ALS medulla.
This research shows that glutamine and glutamate are found in high
concentrations in the brains of ALS patients. While the fundamental
cause of ALS is unknown, it is well known that glutamate exitotoxicity
is is the mechanism underlying the devastating nervous degeneration
that characterizes this disease. The FDA approved a drug for treating
ALS called Riluzole. The drug slows the progression of the disease by
inhibiting glutamate.
Trinucleotide-repeat expansions and neurodegenerative disease: a
mechanism of pathogenesis.
These neuroscience researchers propose that changes in brain glutamine
levels may precipitate hereditary neurodegenerative diseases in people
who are genetically at risk for them. We see that the researchers have
postulated that "subtle alterations in glutamine" are responsible for
the onset of some neurodegenerative diseases. We see also from the
same sentence that subtle alterations in glutamine levels are known to
change glutamate levels.
Does impairment of energy metabolism result in excitotoxic neuronal
death in neurodegenerative illnesses?
In this study researchers explore the relationship between age-related
impairment of energy metabolism and excitotoxicity. "The delayed onset
of neurodegenerative illnesses could be related to the progressive
impairment of mitochondrial oxidative phosphorylation, which
accompanies normal aging." The general implication is that neurons
become more vulnerable to glutamate in age, and that exposure to
glutamate in age might precipitate or aggravate neurodegenerative
diseases like Huntington's disease, Parkinson's disease, ALS, and
Alzheimer's disease.
Neurotoxicity at the N-methyl-D-aspartate receptor in
energy-compromised neurons. An hypothesis for cell death in aging and
disease.
In this study researchers examine the close relationship between
normal aging and increased risk of neuron loss from glutamate
excitotoxicity.
Glutamate excitotoxicity in a model of multiple sclerosis
These researchers report about the role of glutamate excitotoxicity in
MS.
Chronic Fatigue Syndrome
Glutathione is an important antioxidant. People of any age with
depleted levels of reduced glutathione are especially vulnerable to
the free-radical damage associated with glutamate excitotoxicity. CFS
is a condition associated with low glutathione.
"There is evidence that depletion of reduced glutathione makes neurons
more susceptible to excitotoxicity, and that intact mitochondrial
function is essential for neuronal resistance to to excitotoxic
attack. It is believed, for example, that reduced levels of the energy
currency of the cell (ATP) that accompanies loss of mitochondrial
function causes depolarization of neuronal membrane, which exposes
NMDA receptors to excessive levels of glutamate. The resulting
neurohormonal cascade leads, in many cases, to the death of neurons in
the brain, and central and peripheral nervous systems. "
- LEF Magazine March 1996
In discussions with people on the internet I found at least one person
who suffers from CFS who was also taking glutamine on an empty
stomach. She started taking two grams at night as recommended by
someone she met on the internet. She suffered from insomnia as a
result of nervous stimulation from the two grams and found that she
was able to sleep at night only if she reduced her dose to one gram. I
question whether she should be supplementing glutamine in any amount
on an empty stomach. On the one hand glutamine is a substrate of
glutathione but on the other hand its metabolite glutamate poses a
special risk to her nervous system. Probably she should take modest
amounts of glutamine with meals containing complete proteins and find
another method for increasing GH.
Conclusion
I'll be adding more to this section as my research continues. There is
much academic research in this area but in truth little is actually
known about the cause or cure of most neurodegenerative diseases. Such
diseases may be unavoidable in those who are genetically at risk.
There is no research into the long term effects of glutamine GH
supplementation and therefore no way to know with complete certainty
whether exposure to the increased glutamate from such supplementation
can actually cause or precipitate these diseases. The following
abstract seems to be a fine summary of the current state of knowledge:
Title
The role of excitotoxicity in neurodegenerative disease: implications
for therapy.
Author
Doble A
Address
Neuroscience Dept. Rh矣ne-Poulenc Rorer S.A., Antony, France.
Source
Pharmacol Ther, 81(3):163-221 1999 Mar
Abstract
Glutamic acid [glutamate] is the principal excitatory neurotransmitter
in the mammalian central nervous system. Glutamic acid binds to a
variety of excitatory amino acid receptors, which are ligand-gated ion
channels. It is activation of these receptors that leads to
depolarisation and neuronal excitation. In normal synaptic
functioning, activation of excitatory amino acid receptors is
transitory. However, if, for any reason, receptor activation becomes
excessive or prolonged, the target neurones become damaged and
eventually die. This process of neuronal death is called
excitotoxicity and appears to involve sustained elevations of
intracellular calcium levels. Impairment of neuronal energy metabolism
may sensitise neurones to excitotoxic cell death. The principle of
excitotoxicity has been well-established experimentally, both in in
vitro systems and in vivo, following administration of excitatory
amino acids into the nervous system. A role for excitotoxicity in the
aetiology or progression of several human neurodegenerative diseases
has been proposed, which has stimulated much research recently. This
has led to the hope that compounds that interfere with glutamatergic
neurotransmission may be of clinical benefit in treating such
diseases. However, except in the case of a few very rare conditions,
direct evidence for a pathogenic role for excitotoxicity in
neurological disease is missing. Much attention has been directed at
obtaining evidence for a role for excitotoxicity in the neurological
sequelae of stroke, and there now seems to be little doubt that such a
process is indeed a determining factor in the extent of the lesions
observed. Several clinical trials have evaluated the potential of
antiglutamate drugs to improve outcome following acute ischaemic
stroke, but to date, the results of these have been disappointing. In
amyotrophic lateral sclerosis, neurolathyrism, and human
immunodeficiency virus dementia complex, several lines of
circumstantial evidence suggest that excitotoxicity may contribute to
the pathogenic process. An antiglutamate drug, riluzole, recently has
been shown to provide some therapeutic benefit in the treatment of
amyotrophic lateral sclerosis. Parkinson's disease and Huntington's
disease are examples of neurodegenerative diseases where mitochondrial
dysfunction may sensitise specific populations of neurones to
excitotoxicity from synaptic glutamic acid. The first clinical trials
aimed at providing neuroprotection with antiglutamate drugs are
currently in progress for these two diseases.
Language
Eng
Unique Identifier
99265830
Until more is known about the risks of glutamine and glutamate, the
best we can say is that multiple gram doses of glutamine on an empty
stomach should almost certainly not be a part of the daily regimen of
aging people who have or who hope to avoid or postpone
neurodegenerative diseases.
Dr. Blaylock, mentioned above, decided to write his book about the
dangers of excitotoxins after his own father died with Parkinson's
disease. I have a very dear friend who is terminally ill with ALS. I
share Dr. Blaylock's hope that proper diet and nutrition can help
people avoid or postpone the devastation of senility and other
neurodegenerative diseases.
These opinions expressed above are my own and do not represent the
position of any company or organization. I am not an M.D. I welcome
comments and corrections by email, especially from credentialed
individuals with no financial connection to the sale of dietary
supplements.
Gordon Swobe (gts at optexinc dot com)
Home
Other studies of interest:
Dietary glutamine supplementation reduces plasma nitrate levels in
rats
--------------------------------------------------------------------------------