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
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.
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).
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.
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.
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.
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.
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.
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
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.
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.
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
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.
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.
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.
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.
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.
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
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..."
"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.
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."
The 'Essential' Non Essential Amino Acid, Life Extension Magazine,
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.
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.
Chronic low-dose glutamate is toxic to retinal ganglion cells. Toxicity
blocked by memantine.
Vorwerk CK ; Lipton SA ; Zurakowski D ; Hyman BT ; Sabel BA ; Dreyer EB
Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, MA
Invest Ophthalmol Vis Sci, 37(8):1618-24 1996 Jul
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
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.
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 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.
evidence of neurodegeneration and excess glutamate + glutamine in
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.
expansions and neurodegenerative disease: a mechanism of
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.
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.
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.
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.
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:
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)
Other studies of interest:
Dietary glutamine supplementation reduces plasma nitrate levels in rats