Discussion in 'Fibromyalgia Main Forum' started by standessin, Jul 30, 2007.
Does annyone know a good supplement to get amonia levels down? Thanks
Believe I read a while back that L Glutamine helps with this.
Are you talking about serum ammonia levels or urinary ammonia levels? These are 2 different things. Elevated serum ammonia is bad. Elevated urinary ammonia doesn't necessarily mean anything. Most urinary ammonia is formed by the kidneys to normalize urinary ph levels. It doesn't enter the circulation, and thus doesn't cause toxic problems like serum ammonia can. - Mark
[This Message was Edited on 10/15/2007]
source: PDR Health (Internet)
"L-glutamine helps protect the body against ammonia toxicity by transporting ammonia, in the form of L-glutamine's amide group, from peripheral tissues to visceral organs, where it can be excreted as ammonium by the kidneys or converted to urea by the liver."
[This Message was Edited on 10/15/2007]
I used to have big problems with ammonia from the methylation supplements (folates and B12 only). This is what I found out.
* L-glutamine. This is what the body uses to detoxify ammonia. It thus works like a charm. Amy Yasko & Co. strongly disapprove because they believe that the GABA/glutamate ratio is largely responsible for autism. (l-glutamine is related to glutamate.) Whether GABA/glutamate ratios are relevant to CFS sufferers is undetermined. I use a small amount of l-glutamine (500 mg) along with 1 mg Klonopin each night. The GABA-enhancing effects of the Klonopin may nullify the l-glutamine effect, if indeed it's an issue for all CFS sufferers. (I do think it may be an issue for me if I don't take it at the same time as the Klonopin.) Other GABA-enhancing substances might tilt the balance away from too much glutamate as well.
* Manganese. This seems to make a difference for me, since my ammonia problems have decreased since I started it. I am taking 50 mg per day.
* RNA Ammonia. This is a supplement that Amy Yasko sells. It's expensive (nearly $100 per bottle). The Yasko folks claim it works. I'm not as convinced, based on my experience.
* Kill gut bugs. Bacteria (and maybe only/especially bacteria in the gut) contributes to ammonia, regardless of whether people are CBS+. Various methods of killing bacteria are available. These include herbs (and other natural stuff like coconut oil), prescription antibiotics, probiotics (may crowd out the bad stuff), colloidal silver, "zapper". I'm sure there are others I'm not thinking about at the moment. (Note that I am just listing these without necessarily recommending any. All have disadvantages, as far as I can tell.)
* Activated charcoal. The problem with this is that it sucks up prescription drugs (a fatal flaw for CFS sufferers who use prescription drugs). It also can suck up other supplements and even vitamins from food. I see it more as an emergency measure, though the Yasko folks use it a lot. I used it a couple of times and it does seem to work for ammonia. Take it well away from prescription drugs (at least a few hours) though.
* Questram. This is a prescription substance for cholesterol that works pretty much like activated charcoal. However, it is formulated so that it does not suck up most prescription drugs. Pharmacies can do an interaction check on their computers to make sure it won't suck up whatever you might be taking. It does have the potential to suck up other supplements and even nutrients though. I took it once with no immediate negative side effects, though I can't judge its efficacy for ammonia since I wasn't having that problem at the time. I would much rather use this than activated charcoal (since I have a doctor to prescribe it), but still see it kind of as an emergency measure.
* Lactulose. This is a prescription laxative that is natural and very mild. It is available over the counter in pretty much every country except the U.S. My doctor claims it helps with ammonia. I don't think it works very well though, since I continued to have ammonia problems even after I started taking it. (Maybe the problems would have been worse without it though.) The main problem is that it's sweet, and so I suspect it feeds yeast.
* Low protein diet. Many of the kids on the Yasko program are fed extremely small amounts of protein per day (e.g. total of one ounce). I personally think this is very unhealthy for any child, though maybe if you believe in the Yasko program strongly enough and can't get ammonia down any other way it would be worth it. Rich van K said that he did not recommend it for CFS sufferers, since he believes they need protein. (One of the ways that I knew that I had an ammonia problem was an extreme aversion to protein, which went away immediately as soon as I took one l-glutamine capsule. I also started to have a toxic sort of brain fog--as if I was smelling bleach or some such--that was unusual for me.)
* Yucca. This is supposed to reduce the ammonia that is formed as a result of eating protein. The Yasko folks recommend taking it with protein or even sprinkling it on protein. I took it a few times and didn't notice any immediate effect. I think there may be some sort of estrogenic activity associated with yucca, though I've not studied it enough to find out.
That's all I've been able to find. For me, the combination of the manganese and a small amount of l-glutamine has solved the problem.
Note that "going fast" with the methylation increases ammonia problems (if present).
[This Message was Edited on 10/16/2007]
What are the symptoms of too much or not getting rid of ammonia?
The relationship between glutamine and ammonia has been misrepresented by web pages selling L-glutamine supplements. The body gets rid of ammonia arising in peripheral tissue, by combining glutamate with ammonia to FORM glutamine, and then the glutamine is transported to the kidneys. Thus, taking L-glutamine will not detoxify ammonia. It is only the production of glutamine that does this. For an explanation of this process, see the following web page:
Hyperammonemia, Bane of the Brain
Robert M. Cohn, MD
Karl S. Roth, MD
Creighton University School of Medicine, Omaha, NE
Ammonia, normally produced from catabolism of amino acids, is a deadly neurotoxin. As such, the concentration of free ammonia in the blood is very tightly regulated and is exceeded by two orders of magnitude by its physiologic derivative, urea. The normal capacity for urea production far exceeds the rate of free ammonia production by protein catabolism under normal circumstances, such that any increase in free blood ammonia concentration is a reflection of either biochemical or pharmacologic impairment of urea cycle function or fairly extensive hepatic damage. Clinical signs of hyperammonemia occur at concentrations > 60 µmol/L and include anorexia, irritability, lethargy, vomiting, somnolence, disorientation, asterixis, cerebral edema, coma, and death; appearance of these findings is generally proportional to free ammonia concentration, is progressive, and is independent of the primary etiology. Causes of hyperammonemia include genetic defects in the urea cycle ("primary") or organic acidemias ("secondary"), as well as genetic or acquired disorders resulting in significant hepatic dysfunction. Thus, because of the neurotoxic implications of hyperammonemia and the typical absence of other specific laboratory abnormalities, appearance of the clinical signs should trigger an emergent search for elevated blood ammonia concentration
[This Message was Edited on 10/16/2007]
This is from the PDR Health. If people don't think it's a legitimate enough source I guess I could look harder for more info, at some point when I'm up to it.
My doctor (M.D., Indiana University Medical School, board certified internist) stated at my last appointment that l-glutamine should help me with ammonia problems.
L-glutamine is a protein amino acid found in proteins of all life forms. It is classified as a semi-essential or conditionally essential amino acid. This means that under normal circumstances the body can synthesize sufficient L-glutamine to meet physiological demands. However, there are conditions where the body cannot do so. Recently, L-glutamine has come to be regarded as one of the most important of the amino acids when the body is subjected to such metabolic stress situations as trauma (including surgical trauma), cancer, sepsis and burns. Under such conditions, L-glutamine becomes an essential amino acid, and it is therefore very important to ensure adequate intakes of the amino acid in order to meet the increased physiological demands created by these situations.
L-glutamine is the most abundant amino acid in the body, and plasma glutamine levels are the highest of any amino acid. L-glutamine is predominantly synthesized and stored in skeletal muscle. The amino acid L-glutamate is metabolized to L-glutamine in a reaction catalyzed by the enzyme glutamine synthase, a reaction which, in addition to L-glutamate, requires ammonia, ATP and magnesium.
L-glutamine is a very versatile amino acid and participates in many reactions in the body. It is important in the regulation of acid-base balance. L-glutamine allows the kidneys to excrete an acid load, protecting the body against acidosis. This is accomplished by the production of ammonia, which binds hydrogen ions, to produce ammonium cations that are excreted in the urine along with chloride anions. Bicarbonate ions are simultaneously released into the bloodstream. L-glutamine helps protect the body against ammonia toxicity by transporting ammonia, in the form of L-glutamine's amide group, from peripheral tissues to visceral organs, where it can be excreted as ammonium by the kidneys or converted to urea by the liver.
The amide group can also participate in other metabolic activities, as can the amino group of L-glutamine. L-glutamine serves as the most important nitrogen shuttle, supplying nitrogen for metabolic purposes (from glutamine-producing tissues, such as skeletal muscle) to glutamine-consuming tissues.
L-glutamine participates in the formation of purine and pyrimidine nucleotides, amino sugars (such as glucosamine), L-glutamate and other amino acids, nicotinamide adenine dinucleotide and glutathione. It also participates in protein synthesis, energy production and, if necessary, the production of D-glucose and glycogen. Importantly, L-glutamine can serve as the primary respiratory substrate for the production of energy in enterocytes and lymphocytes. L-glutamine is considered an immunonutrient, and supplemental L-glutamine is used in medical foods for such stress situations as trauma, cancer, infections and burns.
I originally stated above that I was taking 300 mg of manganese per day.
The actual amount is 50 mg.
Manufacturers of the supplement called alpha keto-glutaric acid claim that it reduces ammonia. I don't know if their claims are true or not. AKG is made by Vital Life, Klaire, and Kirkman Labs. There may be other companies as well.
Lisa - I'm not surprised that your doctor is wrong about glutamine. Lots of literature put out by the supplement companies say similarly wrong things, like "Glutamine also buffers the body from high levels of ammonia by binding to it." This is all misinformation. Perhaps they are confusing glutamate and glutamine (as you did in the title of your post, by saying l-glutamate). Glutamine is FORMED by ammonia combining with Glutamate. This is exactly what the web page you quoted from says. "L-glutamate is metabolized to L-glutamine in a reaction catalyzed by the enzyme glutamine synthase, a reaction which, in addition to L-glutamate, requires ammonia, ATP and magnesium." And the following statement from that web page is what probably confuses a lot of people: "L-glutamine helps protect the body against ammonia toxicity by transporting ammonia, in the form of L-glutamine's amide group." That doesn't mean that glutamine binds to ammonia. What it means is that the neurotoxic glutamate and ammonia is combined together to form glutamine, which is not neurotoxic, and thus can be transported to the kidneys in a safe form. The "amide group" which is referred to, is simply part of glutamine's chemical formula. That part of the formula is formed by the introduction of ammonia.
Now, if you are feeling better from L-glutamine, perhaps it's due to the fact that oral L-glutamine can increase brain GABA levels:
However, as that study points out, excess brain glutamine and GABA can cause serious side effects, and I've known people who have had bad reactions to L-glutamine, so people should be very careful if they decide to use that supplement. - Mark
I was talking about fortifying my intestinal health at the same time as the potential ammonia problem during my visit to my doctor, and so it's possible that I could have misunderstood what he said l-glutamine would be helpful for.
I will have to do some more reading to figure out exactly what it is that l-glutamine is doing for me at this time.
This is a comment from Amy Yasko, listed on Dr. Amy's Forum.
For what's it's worth. I haven't tried further to figure this out yet.
Hopefully this will help to clarify what I see as the CBS C699T
relationship between ammonia, BH4 and the urea cycle. Also I have heard
that there has been a lot of talk about ammonia on this site lately.
Perhaps this will help to get parents up to date on where I am in
understanding this process.
If an individual has the CBS up regulation (C699T), then they will break
down homocysteine more rapidly. This depletes intermediates in the
methionine cycle as well as making more products from homocysteine.
Homocysteine will be converted to cystathionine. This in turn goes to
produce cysteine plus alpha keto glutarate and AMMONIA. What happens next
depends in part on the level of cysteine. When there are higher doses of
cysteine the body will then convert these intermediates to taurine.
(Taurine can be broken down into AMMONIA by bacteria in the gut.) However
if there are lower amounts of cysteine the body will choose to make
glutathione. So, first of all, the amount of cysteine will help to
determine whether we make glutathione or taurine. (J. Nutr. 133:2697-2702,
September 2003). If we have the CBS C699T we will be creating higher
levels of cysteine (due to enhanced breakdown of homocysteine) so we will
almost always be generating taurine rather than glutathione. While the
temptation may be to add glutathione (due to low glutathione levels), this
can create problems. High levels of certain sulfur byproducts can cause
problems in the body. The CBS up regulation is generating so many sulfur
products that added glutathione may be a problem for these individuals. So
a sensitivity to sulfur products and sulfur containing antibiotics may
also be indicative of this mutation. Molybdenum is used to help to convert
the neurotoxic sulfite to sulfate. This reaction will be heavily taxed in
individuals with CBS C69T + + and so you will often see low levels of
molybdenum in spite of constant supplementation. So individuals with a
homozygous CBS C699T will often have no homocysteine, high levels of
taurine (without supplementation) and low levels of glutathione on a urine
amino acid test, as well as low levels of molybdenum on an essential
element urine test.
What may more be of greater importance is that ?when the need is for
energy, and not for cysteine, homocysteine produced is metabolized by
homocysteine desulfhydrase to alpha KG, NH3 and H2S.?(see series of
articles by Stipanuk, MH). Because we are dealing with mitochondrial
issues in most cases we are energy depleted. Methylation cycle mutations
will compound this energy problem as SAMe is used as a methyl donor for
carnitine and COQ 10, both important energy components of mitochondria.
Due to the enhanced conversion of homocysteine we are constantly depleting
intermediates of the methylation cycle. This includes SAMe (needed in this
case for carnitne and COQ10) as well as methionine. Both methionine and
SAMe are also useful for dealing with ammonia, however due to the CBS
C699T we are generating more ammonia and less methionine and SAME. The
more we supplement (which we need to do) the more ammonia we generate, a
true catch 22.
So AMMONIA is generated as a result of transulfuration when cystathionine
is converted to cysteine, from taurine as well as from alpha KG. Under
ideal conditions ammonia will be absorbed in reactions between glutamine,
glutamate and alpha KG. However, (see slides 113 to 116 from MTHFr, Metals
and Methylation ppt) aluminum interferes with glutamate dehydrogenase and
mercury interferes with glutamine synthase. This impairs the pathways that
are normally used for addressing ammonia. In addition, in some individuals
the GAD enzyme may be impaired as a result of viral infection and
methylation status (discussed in the autism book and in the Boston DVDs).
This will create a possible scenario where excess alpha keto glutarate is
being generated by breakdown of homocysteine but it cannot convert
properly to form ie GABA. However this excess alpha KG can combine with
the excess ammonia to form more glutamate. I have previously discussed at
length the relationship between glutamate, excitotoxins and nerve damage.
The ammonia problem can worsen with viral infection. So for an individual
with the homozygous CBS it is a real catch 22. We need the SAMe and
methionine (and Folapro and Intrinsic B12 for that matter) in order to
have methylation so that we can silence the virus and reduce the viral
load. However, every time we add anything that helps the cycle to flow
properly we end up generating more homocysteine, which flows directly to
make more ammonia and sulfur groups, and taurine. We need to address this
part of the cycle in order to get out of the catch 22 we are in. We are
currently evaluating RNAs that may be helpful to support healthy ammonia
Ammonia will be converted to urea via the urea cycle. This is an expensive
process from the standpoint of BH4 as it uses two molecules of BH4. So the
conversion of elevated levels of ammonia can quickly drain limited stores
of BH4. This can then impact the levels of serotonin and dopamine. I
believe that this is part of the reason why the combination of a CBS C699T
+ + with the A1298C homozygous mutation (which I believe impacts the
reverse reaction through the MTHFR to generate BH4) can have such a
You are correct that arginine is a starting point in the urea cycle.
However, I do not believe that arginine is the rate limiting factor here.
I think that BH4 is the rate limiting factor in most cases. Arginine can
stimulate the growth of virus. This has been particularly well studied for
herpes virus. So adding additional arginine may lead to increased growth
of herpes virus and may not help the urea cycle if it is not the rate
Arginine that is not used by the urea cycle can be used to make
creatinine. So if we can decrease the amount of ammonia that is generated.
Then we are using less BH4 and less arginine in the urea cycle. This will
free up BH4 for serotonin and dopamine. It will also free up arginine for
This is all lovely in theory, but what do we actually see in practice?
When we go to a low protein diet, we observe an increase in creatinine and
an increase in metal excretion. This would suggest that we may be on the
right track in addressing this problem. This is another reason to monitor
urines carefully as it may appear as if behaviors are deteriorating and
that a low protein diet is not working, when in fact this is a result of
increased creatinine and metal excretion. I suspect that some of the
behaviors that have been attributed to yeast (silly behavior following
food) may in fact be high ammonia levels generated as a result of CBS up
regulation. This imbalance in ammonia levels will most likely contribute
to gut imbalances and exacerbate yeast issues.
I have also been spending a lot of time looking at Reye's syndrome. This
occurs following a viral infection and the use of aspirin or other
salicylates. It appears that the salicylates have an effect on
mitochondrial energy production.(another tie in between energy,
mitochondria, virus and metals) In susceptible individuals this affect on
the mitochondria leads to ammonia buildup and a drop in blood sugar
levels. Children with mutations in the urea cycle will have the greatest
issue with Reye's syndrome. Some of these elements should sound
familiar...virus, sensitivity to salicylates, high ammonia, blood sugar
issues. So I am looking in to this area to see if there are some answers
for us here. The use of carnitine and ATP to aid in energy production
should be beneficial. Recently I have been contacted by a number of
parents of children with Mitochondrial Disease. I think that this is
related to CFS, FM and many of the factors discussed here relate directly
to Mitochondrial Disease.
The good news is that the more we understand what is going on the easier
it is to address it. We are in the process of evaluating the benefits of
low protein diets, RNAs and the possible use of BH4 supplementation to
address these mutations. Each day we move a little bit closer to getting
the necessary answers to know how to address these issues.
The following is from wikipedia.
It seems to suggest that glutamine and glutamate convert back and forth from one another easily, which would explain why supplementing with l-glutamine (which then would transform into glutamate as needed) might help to decrease ammonia.
One could supplement directly with glutamate, but this seems a bad idea since that has a "potentially toxic excitatory effect."
Hopefully I'm understanding this correctly, but please supply more info if I'm wrong!
In addition to removing excess glutamate from the synapse and packaging it into vesicles, glutamate transporters also recycle glutamate after it is used as a neurotransmitter. The glutamate is taken up into glia and converted into the amino acid glutamine, which lacks the potentially toxic excitatory effect of glutamate. The glutamine is released from glia and transported back into neurons, converted back into glutamate, packaged into vesicles by VGLUTs, and stored for later release. This process is called the glutamate-glutamine cycle.
I've addressed Amy's claims about CBS on this web page:
However, regarding a specific claim from the post you made:
"if there are lower amounts of cysteine the body will choose to make glutathione. So, first of all, the amount of cysteine will help to determine whether we make glutathione or taurine. (J. Nutr. 133:2697-2702, September 2003). If we have the CBS C699T we will be creating higher levels of cysteine (due to enhanced breakdown of homocysteine) so we will almost always be generating taurine rather than glutathione."
Amy refers to a study by Martha H. Stipanuk to support her claim. However, Amy has made a common mistake which Stipanuk herself writes about in another article, which is that Amy has assumed that a lower enzyme [E} rate for glutathione (GSH) production means lower GSH. But that is not the case, because the substrate [S}, in this case cysteine, also increases, so there is no actual decrease in GSH. To quote Stipanuk from the article:
"Surprising insights that aren’t so surprising in the modeling of sulfur amino acid metabolism."
"Glutamate-cysteine ligase (GCL) catalyzes the first step in the pathway for GSH synthesis from cysteine. Regulation of GCL activity is complex, with regulation involving changes in the concentration of both the catalytic and modifier subunits of the enzyme and by changes in the activity state of both the holoenzyme and the catalytic subunit alone. The activity of GCL is downregulated in response to an increase in cysteine availability (e.g., high protein diet). Despite this decrease in enzyme concentration, flux through the GSH production pathway increases because of the increase in substrate (cysteine) concentration. The Km of glutamate-cysteine ligase for cysteine is 0.1 mM, near the upper end of the physiological range of hepatic cysteine concentrations, but low enough that changes in still have a marked effect on V (Chen et al., 2005). In studies with intact rats, the increase in has a bigger overall effect than the decrease in [E] in determining the V of the reaction or tissue GSH levels (Bella et al., 1999a, b; Lee et al., 2004). Feeding a high protein diet resulted in a decrease in GCL activity but an increase in cysteine concentration and an increase in GSH production despite the decrease in GCL activity. Thus, as for CSD, we see that, while both the change in and [E] concentration have some effect, the change in has a greater effect than the change in [E] under typical physiological conditions."
Stipanuk herself has written about what she sees as a possible danger of too much cysteine production:
Nowhere does she mention lowered GSH or excess ammonia as being a problem.
"Summary and relation of cysteine metabolism to amino acid supplement safety. The mammalian liver tightly regulates its free cysteine pool, and intracellular cysteine in rat liver is maintained between 20 and 100 nmol/g even when sulfur amino acid intakes are deficient or excessive. By keeping cysteine levels within a narrow range and by regulating the synthesis of glutathione, which serves as a reservoir of cysteine, the liver addresses both the need to have adequate cysteine to support normal metabolism and the need to keep cysteine levels below the threshold of toxicity. Elevated tissue cysteine levels should be avoided because they may lead to autooxidation of cysteine to form cystine and ROS, oxidation of protein thiol groups, neurotoxicity mediated by NMDA-type glutamate receptors or membrane cystine/glutamate exchanger activity, or excess production of H2S via desulfhydration reactions."
Thus, as Stipanuk mentions, the liver regulates cysteine metabolism to avoid excess cysteine, so you either need a huge increase in CBS (not possible due to the CBS SNPs), or you need to be using gobs of amino acid supplements.
I have to get time to read the rest of Amy's post later, maybe after the Sox game tonight. - Mark
[This Message was Edited on 10/18/2007]
So do you think that ammonia excess ever is a problem when using methylation supplements? (Meaning for some reason other than the CBS upregulation hypothesis?)
From what I've read, while glutamine is a source of glutamate in the brain, oral glutamine is not a major source for glutamate production, as glutamine barely crosses the blood brain barrier. Instead, it's the BCAAs that are the important source for producing glutamine in the brain, not glutatmine from the circulation. Indeed, the production of glutamine in the brain uses up ammonia. So if you were able to supply glutamine to the brain, then that would mean that actual glutamine production would go down, and that would seem to cause more ammonia in the brain, not less. Promoting the production of glutamine would use up ammonia.
L-glutamine may have a lot of uses, but ammonia detoxification apparently is not one of them, from everything I've read.
And no, I don't think ammonia is a problem with regard to methylation problems of any sort. I've not found one study that implies that, even in Autism. - Mark
And FWIW, I've not found any medical articles that supports Yasko's belief that the urea cycle uses up BH4, as she states:
"Ammonia will be converted to urea via the urea cycle. This is an expensive process from the standpoint of BH4 as it uses two molecules of BH4. So the conversion of elevated levels of ammonia can quickly drain limited stores of BH4."
Also, if this was true, then I would think that people with a true BH4 deficiency would have ammonia problems, but I've not read that anywhere.
So if anyone can find anything to support this theory, I'd appreciate knowing. - Mark
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