Anxiety, Ammonia & the NMDA receptor
*Disclaimer: This article is my research in progress and is unfinished . It seems that using Resistant Starch and properly repopulating the gut with appropriate bacteria is the solution.
Excess ammonia production caused by:
- A +/- CBS upregulation leads to 10-15x higher ammonia production. (some controversy around this however)
- SNS dominance leads a higher degree of protein turnover (for energy creation) and production of ammonia.
- Glutathione depletion leads to higher rate of protein breakdown and thus ammonia creation, in order to feed amino acids into the citric acid cycle to create energy
- Bacteria in the gut producing excess ammonia.
- Possible tie in with ACAT…slow down there will increase protein turnover and thus ammonia production, in order to feed amino acids into citric acid cyle for energy support. Can you supplement ACAT, in order to decrease the demand on amino acids?
- MTHFR A1298C & NOS defects lead to compromised detoxification.
- Resistant Starch
- Yucca – mops up extra Ammonia
- Apple Pectin – can help remove aluminum from glutamine synthase in the brain, freeing up glutamine synthase for enhancing detox of ammonia
- Charcoal – also mops up ammonia HOWEVER also absorbs beneficial nutrients. Not recommended unless 3 hours after a meal.
- Urea Cycle support
- L-Ornithine – helps mop up ammonia…coverts to glutamate though?
- Citruline Malate
- Carnatine – helps transport ammonia out of the body – form fumerate?
- Glutamine possibly viz glutamine synthetase
- AOR NOx supplement – via NO
- Ammonia RNA
- CBS RNA
- NAG, Turmeric?
- molybdneum – helps w/ brain fog!? try diff form?
- ora kidney?
- small dose p5p – for cbs
- Spirulina appears to help according to Yasko
- Biotin and Mg are cofactors in the urea cycle (biotin deficency can cause ammonia issues in rats)
Posts by user “Vegas” articulating the cause of Ammonia excess due to gut dysbiosis (new update)
He uses fermented Milk, however recently it has been discovered that Resistant Starch may even be better.
The following posts are copied verbatim from: http://forums.phoenixrising.me/index.php?threads/sulfite-sulfate-and-ammonia-questions.27211/
“One can reduce ammonia by first cutting back on protein and other high-nitrogen foods and then gradually introducing bacteria that will both assist with the metabolism of these nitrogenous compounds, including NH3, but also lower the concentration of those species that are contributing to this problem. In my opinion the problem is not created by a collection of SNP’s, but an imbalance among nitrogen-fixing/urea-splitting bacteria. Many pathogenic strains of bacteria actually provide benefits in reducing this ammonia to less toxic metabolites, and the irony is that attempts to manipulate the intestinal microbiome (probiotics/antibiotics) often makes matters worse because the pathogenic organisms that are eradicated may have been simultaneously providing beneficial effects.
Consider trying Bifidobacterium strains, infantis and bifidum; these should be singularly cultured in milk for 24 hours. These will lower pH in the large intestine and dramatically reduce ammonia levels, inhibit the growth of pathogenic organisms, increase SCFA production, increase LAB numbers in the proximal bowel, inhibit/kill H. Pylori in the stomach, increase HCL production, dramatically reduce LPS concentrations in the intestinal lumen, dramatically reduce histamine, increase GSH locally and systemically, lower formaldehyde concentrations, produce b vitamins, folate & others, etc.
It’s not just the 1/2 kilo of bad bacteria in your GI tract that is keeping you ill, but rather the absence of necessary anaerobic species that counterbalance and correct this. Bifidobacteria have high GC-content and they stimulate MAF. What they also possess, however, is an ability to attenuate NF-kB and TNF-a. Lowering the inflammatory and histamine response is critical. One’s reactivity to “methylation” supplements is a consequence of dysbiosis.”
“As you probably know, people with ME/CFS are known to have hyporuricemia. In this regard, I don’t consider the low uric acid the problem, rather this is a consequence of the impaired metabolism of nitrogen, which I think is a consequence of dysbiosis. (Obviously limited cofactors like zinc, Mo, and low ATP don’t help this).
It has taken me years to understand some of the food “sensitivities” and understand how to correct them. In fact this really came about by accident when I started “rebalancing” my intestinal microbiome and as a result became extremely sensitive to many foods. In other words large amounts of probiotic rich foods resulted in a very uncomfortable reaction to nitrogen-rich foods. The purine alkaloids were probably at the top of the list. I’m guessing this is what you are describing. It became clear that the displacement of normally pathogenic organisms left me without the full-complement of species required to handle nitrogen byproducts. That is, pathogenic organisms were filling a void and species like psuedomonas were reducing the toxic nitrogen metabolites to less harmful byproducts.
At first I was looking for a microbial solution to rebalance the nitrogen “problem,” but the solution ended up being much more comprehensive. The solution I came up with was that those organisms that were most beneficial were truly anearobic species, and it was my conclusion that the lack of commensal anaerobes was what was keeping me (and probably others) from healing the gut, lessening the immune response, translocating bacteria, etc.
Bifidobacteria and their unique hexose metabolism and certain species of LAB that rely upon obligative heterofermentation appear to be the winners. The similarities in what would happen if one developed a scarcity of these organisms is really striking when compared to the observations in ME/CFS. In fact I have come to find many more similarities in other seemingly unrelated diseases. Disruptions in the purine/pyrimidine metabolism have just in the last year been identified in a number of GI diseases, and riboflavin perturbations are also common as are SCFA imbalances. These are signatures of bifidobacteria. I’ve also learned that the importance and numbers of Bifidobacteria have been greatly underestimated, and traditional tests not combined with pcr analysis are not likely useful.
Through careful testing, I learned that single strain bifidobacteria yields much more potent results, especially when compared to LAB mixed with bifido strains. A commercial starter culture will be dominated by LAB, and many of these homofermentative strains are not desirable. They are energetically inefficient.
I would suggest starting out with one of the bifido strains from Natren and culturing in milk for 24 hours. Both B. Infantis and B. Bifidum have histamine-degrading ability. They also don’t create unwanted metabolites, like biogenic amines. LAB strains are similarly important and these predominantly colonize the small intestine, but I think altering the pH in the large intestine and the inherent ability to metabolize nitrogen, and bolstering SCFA production is the priority in healing the intestinal tract. This has so many implications including glutamine availability, creating a bacteriocidic effect, lowering pro-inflammatory response, etc. It is a bottom-up approach, and as I have found if you displace too many pathogenic organisms in the proximal colon, you can create collateral problems.
Use raw milk if you have it, but otherwise just sterilize it at 170 degrees before you culture it. I anaerobically ferment this with C02 off-gassing, but I am not convinced that this is necessary. The key is getting the right strains and not combining them. Different strains have different effects, and different culturing methods greatly influence the properties of each strain. For example many strains of bacteria will provide tremendous ability to degrade formaldehyde if they are anaerobically cultured, but culturing in oxygen will completely inhibit the capacity of this trait. It has become clear to me that the formaldehyde concentrations that people with ME/CFS demonstrate are a product of their own intestinal microbiomes. The by-products of the histamine degradation are aldehyde, ammonia and hydrogen.Tetrahydrofolate is critical to the metabolism of aldehydes. It acts as a donor of a group with one carbon atom.
As I see it, the lack of the right bifidus strains has adverse consequences on the conversion to reduced forms of folates, it potentially reduces the availability of biotin and riboflavin, hinders the recycling of ADP, reduces NADP availability, results in the accumulation of gram-negative bacteria, increases the pH of the large intestine, diminishes the metabolism of histamine, aldehydes, and ammonia, reduce the availability of energy available (about 15%) due to SCFA’s.
Making cultured bifidus strains is easy, just take it slow because its effects as an immune stimulant will build over time. If you have intestinal permeability, the lower lymphatic vessels will become noticeably engaged (sore, painful, cytokines). (LAB strains that populate the upper GI tract will more prominently effect the messenteric lymph nodes-e paraspinal and brach off to the axillary. These strains are highly adherent, in fact you will struggle to clean this fermented milk from a glass jar. Milk is the preferred substrate, and the substrate does influence the adhesion efficiency. This is not an overnight fix, but it works. It seems to be particularly effective at re-balancing fluid levels, which I think is simply a consequence of lowered ammonia. In other words, you don’t need as much fluid to dilute the caustic substances, so once one starts getting bifidus strains on board, they may notice having to urinate a lot for a little while.”
“I recommend B. Infantis and Bifidus for their full complement of enzymes able to convert and interconvert all forms of folate, but for the specific purpose of lowering ammonia, B. Bifidus is going to be the most effective. This process happens via a number of different mechanisms.
First, the Bifidus through production of bacteriocins and organic acids results in the displacement of pathogenic organisms that are net producers of ammonia (or other nitrogenous products that contribute to this). While I see individual variances in organisms that predominate in many different inflammatory diseases down to something as specific as ME/CFS, the broadest classification of organisms creating the dysbiosis is the predominance of PROTEOBACTERIA. These gram-positive, largely anaerobic species need to be displaced from the lower intestinal tract; the void needs to be filled with organisms that can reside there. This means you need competing species that will fill this largely anaerobic niche. Like proteobacteria, bifidus species, will occupy that niche. They are obligatively or facultatively, anaerobic, like most proteobacteria, yet they are gram positive and non-pathogenic.
(Other aerobic organisms and the deamination of proteins and other nitrogenous compounds also contribute to this, but I don’t want to get too complicated).
The second, method whereby the Bifidum will decrease plasma ammonia is through it’s ability to alter pH. Lower pH reduces the production of ammonia by intestinal organisms. What I think is more consequential though is that a lower, and more acidic pH will enhance hydrolysis. In the lower pH of the large intestine ammonia (NH3) can more readily bond with Hydrogen, creating ammonium (NH4). The importance of this reaction is that ammonium cannot pass through the bowel wall into the blood. Reducing pH in the colon thus allows for ammonia to be converted to a less toxic form, and one that does not diffuse into the blood.
The nitrogenous compounds that will create problems don’t just include ammonia. Protein catabolism and the one’s metabolism and disassimilation of amino acids can create a number of toxic byproducts. I think that some people who take enzymes do poorly because they are freeing compounds that cannot be readily metabolized. Perhaps the failure to fully breakdown proteins that is nearly universal in ME/CFS has a protective purpose. These toxic compounds include, cresols, phenols, indoles, hydrogen sufide, amines, etc. Purine alkaloids from plants are simply amines. Another problematic category is threonine, which is metabolized into aldehydes. (Check out foods high in threonine to see if you have trouble with any of these) Threonine is toxic to me, yet it is an important molecule in maintaining the integrity of the intestinal lining. For those who use GcMAF, it is a sugar attached to the threonine amino acid that makes the Gc protein “glycosylated.”
In vivo and vitro studies do show that these organism can lower plasma ammonia, and other toxic compounds like phenols. Sure, an “upregulated” enzyme involved in cysteine biosynthesis might make you a bit more symptomatic, but this is not the underlying cause of the disordered metabolism. Adults have 10x’s higher plasma ammonia than children, and they have, by proportion, about 1/4 to 1/5 the number of bifidus organisms. I see many with ME/CFS who have 10 x’s the concentration of plasma ammonia than the average adult. What I think many people don’t realize though, and I believe I mentioned this, but many pathogenic organisms are involved in nitrogen fixation and denitrification, so while all must go, their diminishment can make matters worse unless the appropriate organisms are left in their place.
I read where Dr. Ruggiero said that his GcMAF “yogurt” formulation was dominated by bacterial organisms that predominate in infants. This is exactly what I am suggesting, re-populate with those human strains that healthy infants possess. I do, however, believe many strains, particularly homofermentative LAB are to be initially avoided, i think the full ability to synthesize and convert all forms of folate should be incorporated, and I also believe that one needs to concentrate on repopulating with COLONIZING strains.
Unfortunately, gram-positive bacteria are, by nature, extremely hostile. They have tough outer layers of lipopolysaccharide (LPS) that make them resilient to many antibiotics. (Conversely, many of the commensal organisms, like those most should receive at birth, are highly sensitive to these antibiotics..thanks Fleming.) Lipid A takes no prisoners, and it’s antigenic friend O-antigen will help stimulate some more unwanted symptoms. Bifidobacteria can neutralize some of this, but once you start displacing organisms these components of the dead bacterial cell walls will elicit a powerful immune response and cause huge amounts of ROS and NOS, which will call upon your GSH stores and occupy the lympathic networks as they make their way to the liver. Go too quickly, and your symptoms will tell you. Modifying the human intestinal microbiome takes time, but it seems to be worth it. Like others who have made very pronounced recoveries from ME/CFS, I always considered the GI component a secondary complication, but I know feel confident that it was primary in the pathogenesis of my illness.”
“Ammonia is produced whenever amino acids, either free form or from proteins, are broken down and burned to produce energy. The nitrogen that is left over from this process is in the form of ammonia, which is normally carried to the liver (if it originates in the muscles, where much of the breakdown of amino acids occurs) as part of the glutamine molecule and is processed by the urea cycle in the liver to form urea, which passes to the kidneys via the blood and is excreted in the urine. The breakdown of excess amino acids is a normal process in the body.
However, in CFS, according to the GD-MCB hypothesis, amino acids are broken down at a higher rate than normal to produce energy, because the use of the normal energy sources, carbohydrates and fats, is hindered by a partial block at aconitase, early in the Krebs cycle. Since both carbs and fats have to enter the cycle at acetyl-CoA, which is not far before this partial block, they cannot be used by the cycle at normal rates. Amino acids, on the other hand, can enter the cycle at later points, beyond the partial block. Thus, the cells resort to burning amino acids, as occurs in starvation (in that case because carbs and fats are just not available, so the body burns amino acids from its muscle protein as a last resort to preserve life, as in the Holocaust survivors). Note that this process requires transamination reactions that convert one amino acid to another, so that they can be fed into the Krebs cycle.
These reactions require vitamin B6 as a cofactor. B6 is often found to be low in PWCs, and I suspect that it gets worn out in these reactions. This then hinders the utilization of amino acids for fuel, also.Another source of ammonia in the body, which can be major in PWCs, because of the high prevalence of gut dysbiosis in CFS, is the breakdown of amino acids by unfriendly bacteria in the gut. This ammonia enters the blood and also places a load on the urea cycle in the liver.Dr. Yasko has suggested that another significant source of ammonia in autism (and presumably also in CFS) is that some people have upregulating polymorphisms in the CBS enzyme, and that leads to greater flow from the methylation cycle into the transsulfuration pathway. In the presence of excess flow, she has suggested that there is a reaction that breaks down cystathionine or cysteine to produce ammonia and sulfur compounds. In this case, the nitrogen in the ammonia would originate from the amino acid methionine.
Uric acid is a horse of another color. It gets its name because it is also excreted in the urine, but it is not related to the breakdown of amino acids or protein. Rather, it comes from the breakdown of the purines (guanine and adenine). It’s true that uric acid is often found to be low in CFS. Dr. Cheney has suggested that it’s because uric acid is an antioxidant, and it is oxidized because of the state of high oxidative stress in CFS. I would like to suggest a different explanation.
The synthesis of purines in the body requires the help of folate. Because of the partial block in the methylation cycle, which is linked to the folate metabolism, folate metabolites drain from the cells into the blood via the socalled methyl trap mechanism. One of the results of this is lowered production of purines, and hence, lowered production of uric acid from the breakdown of purines.
The body has a mechanism of recycling purines when they are in short supply, and I think that is what accounts for the low uric acid in CFS. This is the opposite of the situation in gout, which results from too high a level of uric acid in the blood.On taking charcoal, it would seem to me that bedtime, well after dinner, would be a good time to take it. By then, most of the nutrients will have been absorbed, and the charcoal will be in a good position to bind the toxins that come into the gut with the bile and make sure that they are carried out in the stools. Most of the processing of toxins by the liver occurs in the wee hours of the morning.” (source)
“Ammonia is produced in the body in three ways that I know of. Normally, the main one is the burning of amino acids for fuel by the mitochondria. When this is done, the nitrogen has to be disposed of, and that is done by carrying it, mostly in glutamine, via the blood to the liver, where the urea cycle converts it into urea. The urea is put back into the blood and is extracted by the kidneys, which excrete it into the urine.
Ammonia can also be produced via the transsulfuration pathway, which is why Dr. Yasko recommends lowering the B6 intake if a person has an upregulated CBS enzyme.
The third way ammonia is produced is by anaerobic bacteria in the gut. If this gets too high, and the liver cannot deal with it, so that the ammonia level rises in the blood, it can cause trouble in the brain, called hepatic encephalopathy.
If the urine tends to be too much on the acid side, because of a person’s diet or another cause, the kidneys can produce ammonia from glutamine and put it in the urine to balance the acid. This prevents frying one’s nether parts!
If the bacteria in the gut are producing too much ammonia, they will need to be dealt with. The treatment for high ammonia in the blood coming from the gut includes giving oral levulose. Bacteria in the gut will convert this to lactic acid, pushing the pH in the gut in the acid direction. That will cause ammonia (NH3), which is a gas, to shift more to NH4+, ammonium ion, which will stay in solution and pass out in the stools rather than diffusing from the gut into the bloodstream.
The situation involving B6 is complicated. If a person has a CBS upregulating SNP, it’s a good idea not to go too high on B6 until this is dealt with. Later on, it is important to have enough B6 so that the transsulfuration pathway can proceed at a normal rate. Also, B6 is needed to make some of the neurotransmitters, and it’s also very important in the metabolism of the amino acids, to name a few. So in the longer term, B6 needs to be brought up, and B2 is needed also, to convert B6 to its active form, P5P. ” (source)
Ornithine & Citrulline
Urea Cycle Reactions (source)
- Ammonia -> carbamoyl phosphate (biotin and Mg are cofactors here)
- cabamoyl phosphate + ornithine = citrulline
- citrulline + aspartate = argininosuccinate
- When L-citrulline converts to L-arginine, it creates ornithine! (source)
- When L-Arginine converts to L-citruline, it creates a nitric oxide! (source)
6-15g of citrulline per day just before exercise seems to be the best estimate so far for maximising ergogenic effects.
- http://www.mrsupplement.com.au/arginine-citrulline – Interesting Article
Citrulline Malate Studies:
” CM ingestion resulted in a significant reduction in the sensation of fatigue, a 34% increase in the rate of oxidative ATP production during exercise, and a 20% increase in the rate of phosphocreatine recovery after exercise, indicating a larger contribution of oxidative ATP synthesis to energy production. ”
“Citrulline is involved in the urea cycle and allows detoxification of ammonia. In comparison with placebo, it has been shown that treatment with CM led to a significant increase in levels of bicarbonate, ornithine, arginine, and citrulline.5 Previous investigations of the metabolic effects of CM on whole body measurements have shown an increased rate of ammonia clearance with no effect on the extent of accumulation during bicycle exercise.3 This faster clearance has been interpreted as a direct effect of citrulline.”
alpha-ketoglutarate as a possible ammonia binder?
“α-Ketoglutaric acid is sold as a dietary supplement and to body builders as AKG or a-KG with the claim that it improves peak athletic performance. This claim is based on studies that show excess ammonia in the body can combine with alpha-ketoglutarate, reducing problems associated with ammonia toxicity. However, the only studies that show alpha-ketoglutarate can reduce ammonia toxicity have been performed in hemodialysis patients. “(source)
For people with a CBS mutation supplementing with AKG is not advisable since they are already producing excess AKG via trans-sulfuration dumping. This could speed up glutamate production leading to increased excitotoxicity. (source)
How alpha-ketoglutarate binds ammonia to create glutamate:
alpha-ketoglutarate can also bind aspartate to create glutamate:
Concerns and Questions:
- Would taking AKG or OKG potentially increase excitoxicity by producing more glutamate?
- What is a worse excitoxin; glutamate or ammonia?
Other possible Anti-Anxiety….
- Magnesium lowers NMDA activation
- Holy Basil COX-2 inhibotr
- Ketamine & Ibogaine
I started taking Yucca (500mg) about an hour after each meal, and it has made a remarkable difference. I have much less anxiety and muscle tension in my upper back and neck has diminished considerably.
Most of the anxiety I experienced occurred in the early morning hours, during REM state, leading to consciously uncontrollable dream states of stress which would exhaust me so much that by the time I woke up I was anything but rested making me feel fatigued for most of the day. Often i would wake up feeling like i had been hit by a semi-truck. One thing that your body does in the early morning hours is detoxify, so thus taking yucca before bedtime I find is crucial and has the best payoff.
The anxiety, ammonia, NMDA receptor, excitotoxicity hypothesis definitely holds true for me and is undoubtedly one of the biggest causal factors in my CFS. I’m glad its seemingly relatively easy to treat.
When I started taking it, it felt as if my brain had this fuzzy depleted like feeling. As if my brain were detoxing something…probably ammonia.
Another thing is I often woke up with a really sore back, and now I don’t. I also feel like I don’t engage in bruxism as much.
That ammonia was causing all my muscles to tighten along my spine, and put them in a state of permanent tension.
I had 1 or 2 nights last week, where I woke up actually feeling relatively rejuvenated. Sometimes when I wake up now, my spine feels incredibly relaxed, in ways it hasn’t felt in over 12 years. It feels amazing!!!!
In any case since the Yucca worked so dramatically, I’m wondering if there is anything else I can do?
1). Other supplements to help with ammonia? Ammonia vs CBS RNA? Ora Kidney? What can I do to support my body while it does it’s huge detox at night? I’m also concerned about dysbiosis and what can be done about that? Any stool tests for potent ammonia producing bacteria in the gut?
2). There are liquid yucca supplements and capsules. D you guys know if one works better than the other?
Is it possible to take too much yucca?
3). In terms of probiotics, the ones recommended in the write up, I can’t buy them from Canada, since live cultures can’t be shipped across the border from Holistic Heal. What specific strains do you recommend? I might be able to find them here.
4). Apple Pectin – can help remove aluminum from glutamine synthase in the brain, freeing up glutamine synthase for enhancing detox of ammonia. What else can I take to remove aluminum from my body? How serious of an issue might this be, compared to bacteria?
5). Urea Cycle support
• L-Ornithine – helps mop up ammonia…however may coverts to glutamate though!? – need clarification
• Citrulline Malate…also binds to aspartate
• alpha-ketoglutarate OKG…..possibly converts to glutamate by binding with ammonia…maybe not a good idea? What’s a worse excitotoxin….ammonia or glutamate???
6). Carnatine – helps transport ammonia out of the body, but what exactly is the mechanism of action here? What form do I take, regular, acetyl, fumerate?
7). L-Cystine….based on the recommendations of Rich van K…rationale:
” I believe that the increase in excitotoxicity results from a further drop in the glutathione levels in the astrocytes (helper cells) in the brain, when the protocol is begun. (We know
from the recent MRS measurements of Shungu et al. that glutathione is already somewhat depleted in the brain in ME/CFS.) The further drop in glutathione lowers the production of ATP by the mitochondria of these cells, and they then have less energy for pumping glutamate out of the synapses and recycling it. When glutamate builds up, it overexcites the NMDA receptors, and that produces excitotoxicity.
If this is true, then it would seem that we may be able to lower the excitotoxicity if we can support the glutathione levels in the astrocytes as this protocol is begun.
According to the Dringen model, the astrocytes make their glutathione using cystine as their source of cysteine. Cystine is obtained from the blood, and is able to pass through the blood-brain barrier.
How does cystine normally get into the blood? The liver produces glutathione from the constituent amino acids that it receives from the diet via the intestine and the portal vein blood flow. The liver exports some of its glutathione to the circulating blood, and enzymes break down the glutathione into its constituent amino acids. The cysteine is mostly oxidized to cystine, and some of this is taken up from the blood by the brain.”
8). D-Aspartic Acid…………..can’t figure out for the life of me if this is an excitotoxin, and how it helps remove ammonia from the body – very confused….D form has very different effects in the body than L form.
9) Whats up with P5P and CBS? How much to take? P5P supposedly speeds CBS up… yet you need P5P for other parts of the body, so if you don’t take enough it becomes depleted. This is two contradictory statements of logic….
10) Yasko seems to be big on spirulina for ammonia. What is the mechanism of action here? Is there anything else good she recommends?
11) Possible tie in with ACAT…slow down there will increase protein turnover and thus ammonia production, in order to feed amino acids into citric acid cyle for energy support. Can you supplement ACAT, in order to decrease the demand on amino acids?