New, Inexpensive CBS Ammonia Fix

[Lance S]

Aaron,

I am quite a ways behind you knowledge wise, but thanks for this post. Because our SNPs are similar (I know it comes down to how things get expressed), was wondering what your supplement regimen looked like.

From what I could tell:

molybdenum - 1500 mcg per day
B6 - 8mg
Malic Acid - 2400mcg (3 pills)

Interestingly, you didn't seem to take any methylfolate. Was curious to see if you had ever tried it and whether it seemed to hold any benefits for you. Being homozygous for MTHFR I wondered if I would see any benefits. For me it seemed to give me a ton of mental clarity. Unfortunately, I think my dose was too high and some intermediaries got depleted, when I tried to supplement and clear I began to understand my homozygous CBS status was a hot stove.

I have two interests in this.

First, I am usually on a ketogenic diet (do some carb cycling), which depletes oxaloacetate (malic acid is precursor). Not sure how that will play out because oxaloacetate may keep my Krebs cycle running on glucose and oxygen. For a n=1, one day, today I took one 800mcg of malic and a 500mcg B12 Methylcobalamin and I feel much better today. The ketogenic diet typically gives me a ton of brain fog, so I have to supplement with salt, potassium, B12, sometimes curcumin, and tried to use methylfolate (1000mcg). That combination with methylfolate cleared my brain unbelievably, but as I took it 4-5 days something was slowly increasing my blood pressure. I figured I needed B2, some B6 as it seemed perhaps I was getting depleted on BH4, thereby decreasing NO and slowly increasing BP. After pumping in too much B6... YIKES!!!... 5 days of flight or fight ( I wanted to see how long it took to go away without chasing it with supplements) later and I was done with B6 and methylfolate. Let me just clear the brain fog a bit and be done with it! It might be that malic acid and some B12 might be a solution there... we'll have to see how it goes. Not the greatest solution but it might work. Also might be that the involvement of the TCA cycle might bring the best and/or worst of glycolitic and ketogenic energy pathways, but I'll have to play with that.

Second, am thinking that if I cut my prior dosages in half, I might be able to fit
molybdenum - if I need it/ when I need it
B6 - 7.5mg
Malic Acid - 2400 mcg
methlyfolate - 500 mcg
B2 - TBD how much
B12 - 500 mcg

When I take about 3mg of B6 the next day I suffer from some fight or flight. One pill of malic seemed to calm me down... so if tolerated I might give the methyl another shot. I am hopeful that this should allow my BH4 to not be overwhelmed by ammonia issues. We'll see I can smell a little ammonia today... so I may be too optimistic. But would be awesome to have the mental clarity I had with methyl along with some functioning BH4 capacity.

Anyway. Thanks for posting this. Who knows if it works out but it gives me something to experiment with and am crossing fingers it works as a solution for me.

My SNPs:
++: MAO A (R297R); MTHFR (C677T); CBS (C699T); VDR Bsm

+-: MTRR (K350A); MTRR (A664A); BHMT-08; AHCY-01; AHCY-19;

 

[aaron_c]

Hi @Lance S

First off, I will just repeat that I am a (somewhat) educated amateur. But it is pretty cool what we can learn given enough time, motivation, and health!

Here is an approximation of my supplement regimen.

5-htp100mg
Lithium (Orotate)35mg
5-MTHF6mg
Vitamin B-1 (actually Benfotiamine)50mg
Vitamin B-3 (Niacinamide)40mg
Vitamin B-12 (methylcobalamin)6mg
Vitamin B-12 (hydroxycobalamin)2mg
Vitamin B-12 (adenosylcobalamin)6mg
Vitamin C1500mg
Vitamin C0.6g
Vitamin D5000iu
Vitamin E (succinate)400iu
Vitamin K14000mcg
Vitamin K2-4mcg
Vitamin K2-7mcg
Animal Pancreas425mg
Animal Duodenum
Intrinsic Factor
Animal Kidney435mg
Animal Adrenal160mg
Lactoferrin350mg
Co-Q 1050mg
Grape Seed Extract100mg
Policosanol (membrane fluidity)10mg
NADH7.5mg
Pine Bark Extract (or Pycnogenol)100mg
Idebenone150mg
Selenium400mg

Manganese (arginate)0

magnesium (liposomal)1-6 (?)g
Molybdenum (amino acid chelate)1500mcg
Fish Oil1t
GAGs150mg
Sodium-Butyrate1.8g
Carnitine-Fumarate4275mg
Choline CDP500mg
GABA0.819672131147541g
Vitamin B-2 (Riboflavin-5-phosphate)0.05g
Vitamin B-5 (d-calcium pantothenate)0.5g
Vitamin B-6 (p-5-p)8 mg
Vitamin B-7 (Biotin)5000mcg
Inositol hexaphosphate (IP6)0.025g
Acetyl-L-Carnitine1 g
Betaine HCl (TMG)0.5g
DMG HCl1g
Zinc Picolinate0.275g
L-Glutamine1 g
Vitamin B-8 (Phosphatidyl Inositol aka Inositol)0.025g
Phosphatidylserine200mg
Choline (bitartrate)0mg
Phosphatidylcholine0T
Yucca Root Powder3 tablespoons
Digestive Enzymes7pills
Psillium Husks3T
ATP20mg
Acai2T
Animal Thymus1mg
Animal Spleen0
Animal Lymph0
Animal Placenta0
Animal Parotid0
Animal Bone Marrow0
Nucleotides300mg
Sunflower Lecithin40 g
BH425mg

Uridine Monophosphate10-50 ?mg
Licorice Rootin tea with meals


Glucosamine HCl1.5 pills
Milk Thistle Extract150+ mg

I know, it is a lot. B6 I get entirely from kombucha at this point, but that isn't a general recommendation, just what seems to work for me right now. I take my malic acid in a liposomal form, so the actual malic acid content is very low...maybe 10 mg? I am not sure. Liposomal stuff tends to be more potent, but this seems more than the increase in potency one might get with, say, vitamin c.

Although (regular) malic acid has been used for fibromyalgia, I think you are the first person on this thread to say that regular malic acid is working for your ammonia issues--and it seems like we are only guessing that it helped with ammonia, right?

I googled methylfolate and blood pressure, and found a post by Freddd suggesting that a few days after taking both methylfolate and methylcobalamin, the body's need for potassium increases somewhat dramatically, and that insufficient potassium can cause high blood pressure. Too much or too little potassium can kill you, so I would be careful with adding a bunch of potassium. I actually have very little experience with potassium dosing, but Freddd would know more.

Hmm. I cannot find a way that low BH4 would cause "fight or flight," but heartfixer has a good bit on sulfates and sulfites. Apparently sulfates (the less toxic variety) can increase your adrenaline and cortisol. Perhaps your high protein diet is contributing to high sulfates, and the whole thing explodes when you take b6 as that is necessary for CBS to function?

EDIT: I realized this theory doesn't explain why the malic acid would help bring you down from the fight of flight. So to state the obvious, it would seem that either 1) You are right, and BH4 deficiency causes the fight or flight in some way we do not know; 2) I am right, and sulfates are pumping you full of adrenaline, and malic acid helps alleviate this somehow; 3) My theory might also pan out if the malic acid-adrenaline connection was just a coincidence. Sorry I couldn't be of more help. Pretty cool thing to chew on, although I am sure it doesn't feel so hot to go through. END EDIT

Here is Heartfixer on sulfites and sulfates:

Sulfite is neurotoxic. Sulfite will be over produced by the CBS up regulation, and then requires conversion in to the less toxic sulfate molecule by the enzyme Sulfite Oxidase (SUOX). SUOX can easily be overwhelmed. Molybdenum is required for SUOX function, and is typically depleted in CBS (+/+) or (+/-) individuals. Molybdenum supplementation (3 drops or 75 mcg of e-lyte Molybdenum twice a day), Boron 3 mg/day, Vitamin E succinate 400 IU/day, and hydroxy-B12 2000 mcg/day are also utilized to speed up SUOX activity.

While sulfate is less toxic than is sulfite, it will stimulate the adrenergic (fight or flight) limb of the autonomic nervous system and stimulate a cortisol stress response, revving you up into an unrelenting biochemical overdrive. If you have a CBS defect, we need to restrict your sulfur intake, at least until your urine sulfate (and your body sulfate burden) has decreased. The amino acids methionine, taurine, and cysteine all contain sulfur; they are concentrated in animal protein (thus the restriction on animal protein intake). Many nutritional supplements (MSM, N-acetyl cysteine, glutathione) that are good for most people are a problem for you. While certain aspects of your health will benefit from these agents, they will add to your sulfate/sulfite overload problem, adversely affecting the Methyl Cycle

Have you considered taking a multi-b vitamin? I admit, I am not sure how they might all fit with your picture, but I imagine taking only some b vitamins could easily cause some kind of imbalance.

One final question: Do you have chronic fatigue or fibromyalgia? My whole reasoning about malic acid only holds for people experiencing mitochondrial dysfunction as seen in CFS/FM and maybe autism.

Best of luck, Lance!

Aaron C

 

[ahmo]

@aaron_c

I think you are the first person on this thread to say that regular malic acid is working for your ammonia issues--and it seems like we are only guessing that it helped with ammonia, right?

Malic is the only thing I'm using now, w/ exception of buytrate. And I no longer self-test for butyrate w/ every meal, as I had in past. No more need for citrulline, arginine, ornithine, lysine. All those bottles are in the long-term storage. I found an Aus supplier, good price on bulk. Thanks so much for your discovery and post, Aaron.

 

[aaron_c]

Haha, I didn't mean to steal your thunder @ahmo, and it is great to hear that it is still helping you! I suppose I should have said "the first taking regular malic acid orally." Assuming you are still doing it all via footbath? Since we are on the subject, how much malic acid do you add for a soak?

 

[ahmo]

No stealing thunder Just crowing about how much I appreciate your findings.
I'm taking 3x 800mg caps generally, once or twice/day. Once in awhile a 4th. As far as I can understand through my dialogs w/ body, this is a great aid by shifting the response further up in the cycle.

 

[aaron_c]

Are you taking those caps orally?

 

[ahmo]

No, still using footbaths.

BTW, I'm now frequently only needing the footbaths once a day instead of twice. That means malic, GABA, glycine, K+ only once/day. I'm not sure what's shifted this, as in addition to switching to malic, I've also > thyroid and been using low dose naltrexone over the last 3 months.. Also means I'm needing less Vit C, Ca which I use for anti-histamine, and bicarb for detox. These 3 are the primary reason I use FB rather than oral. I'm using ascorbic acid and Ca Carbonate, wouldn't want either of those in my gut.

 

[Lance S]

@aaron_c

Wow!!! After getting slightly burned playing with my methylation SNPs, I recently have scaled my supplements way back. But I think you take more supplements than I did prior to scaling back. As I get smarter and feel more confident in my understanding of my methylation, I will add things back in. Understanding your ratios is another datapoint as I plot my next experiment. Thanks.

Hi @Lance S

I know, it is a lot. B6 I get entirely from kombucha at this point, but that isn't a general recommendation, just what seems to work for me right now. I take my malic acid in a liposomal form, so the actual malic acid content is very low...maybe 10 mg? I am not sure. Liposomal stuff tends to be more potent, but this seems more than the increase in potency one might get with, say, vitamin c.

Although (regular) malic acid has been used for fibromyalgia, I think you are the first person on this thread to say that regular malic acid is working for your ammonia issues--and it seems like we are only guessing that it helped with ammonia, right?

Sorry I wasn't very clear, but I took some B6 which resulted in "jittery fight or flight" one day. I decided to see if malic acid would help calm those jittery issues. And it did. I am guessed the "fight or flight" issues are caused by too much ammonia, but to your point it is more likely sulfur byproducts. I felt like I could smell the ammonia although only slightly, and have only recently started sufur strips to get a sense of how high I go dependent upon diet. Other times I have taken more B6 I could definitely smell ammonia. If I take too much protein I can also smell the ammonia.

So this was a one-time experiment with malic acid. I would ideally like to experiment with / take methylfolate, some B2, some B6, B12, but felt like malic acid might help with this supplement regimen.

But the next day I decided to take some malic acid and then add in that supplement regimen. After taking malic acid I noticed that my brain fog seemed to clear. I took some B12 and I felt even better. I decided not to mess with the methylfolate at that point.

I took a guess that the malic acid resulted in increased oxaloacetate, which may have helped clear brain fog occurring because of my Ultra Low Carb Ketogenic diet. I haven't confirmed it but it seems to not knock me out of ketosis and seems to consistently help with brain fog issues.

Still haven't experimented with adding in additional B vitamins and methylfolate.

Hi @Lance S

I googled methylfolate and blood pressure, and found a post by Freddd suggesting that a few days after taking both methylfolate and methylcobalamin, the body's need for potassium increases somewhat dramatically, and that insufficient potassium can cause high blood pressure. Too much or too little potassium can kill you, so I would be careful with adding a bunch of potassium. I actually have very little experience with potassium dosing, but Freddd would know more.
Aaron C

Did not know that potassium can become insufficient for those reasons and will keep it in mind as I eventually experiment with methylfolate and associated B vitamins.

I do jog a couple times a week and potassium can often show up then in my calves if I am deficient. Reluctant to take much if any potassium unless I need it.

Hi @Lance S

Hmm. I cannot find a way that low BH4 would cause "fight or flight," but heartfixer has a good bit on sulfates and sulfites. Apparently sulfates (the less toxic variety) can increase your adrenaline and cortisol. Perhaps your high protein diet is contributing to high sulfates, and the whole thing explodes when you take b6 as that is necessary for CBS to function?

I would say low BH4 doesn't cause the fight or flight, but that it occurs as a result of the cycle that ensues when my CBS pathway gets overstimulated with b6 or other. Effects include (and listed below) sulfite and sulfate generation, excess ammonia, hydrogen sulfide, and alpha-keto glutarate generation.

When I take methylfolate, and B2 I end up with more homocysteine and my homozygous CBS pathway is amplified by the B6. I then end up with a cascade of sulfur breakdown products (sulfite and sulfate, which stimulate the stress/cortisol “fight or flight” response), excess ammonia (in the process wasting BH4 which is used up detoxifying ammonia), hydrogen sulfide (producing “brain fog”), and alpha-keto glutarate (leading to “excitotoxicity”). The G6PDH enzyme system may be affected, leading to abnormalities in sugar control.

I copied some of that last sentence from here:
http://www.heartfixer.com/AMRI-Nutrigenomics.htm#CBS: Cystathionine Beta Synthase

Hi @Lance S

EDIT: I realized this theory doesn't explain why the malic acid would help bring you down from the fight of flight. So to state the obvious, it would seem that either 1) You are right, and BH4 deficiency causes the fight or flight in some way we do not know; 2) I am right, and sulfates are pumping you full of adrenaline, and malic acid helps alleviate this somehow; 3) My theory might also pan out if the malic acid-adrenaline connection was just a coincidence. Sorry I couldn't be of more help. Pretty cool thing to chew on, although I am sure it doesn't feel so hot to go through. END EDIT

My thought was that the malic acid if it neutralizes your B6 issues, and increases your ability to take in b6, it might do the same for me. That might mean less sulfur byproducts, less ammonia, more BH4, etc... all the things from your original post.

I agree that malic acid adrenaline is probably not a direct connection, but if malic acid can stop my CBS / B6 cascade it might be very useful (4 me). But maybe I misunderstood your use of B6 and malic acid from your first post... I'll have to go back and reread. I thought it was related to displacing BH4 supplements (which enabled you to take B6, which I assumed because of your homozygous CBS SNP would cause all the same issues discussed here) with malic acid.

Sorry I probably made my original post more complicated than it should have been by putting in the low carb stuff.

Hi @Lance S
Have you considered taking a multi-b vitamin? I admit, I am not sure how they might all fit with your picture, but I imagine taking only some b vitamins could easily cause some kind of imbalance.

One final question: Do you have chronic fatigue or fibromyalgia? My whole reasoning about malic acid only holds for people experiencing mitochondrial dysfunction as seen in CFS/FM and maybe autism.

Best of luck, Lance!

Aaron C

I was taking a multi but it had lots of stuff I shouldn't be taking. I should contemplate finding one like Yasko's just to see if it helps.

No CFS/FM. Just a bunch of brain fog resulting from low carb. And an interest to see what might happen if I supplemented by homozygous 677 MTHFR with methyfolate. Learned a hard lesson about how my homozygous CBS pathway needs to be in control first.

But thanks for your posts, been very informative and I still occasionally take malic acid and B12 for low carb brain fog. Seems to work pretty well.

Sorry for my delayed response. Need to learn how to operate these forums better and get the e-mail tracking running.

Best wishes and good luck!

 

[dannybex]

Hmm. I cannot find a way that low BH4 would cause "fight or flight," but heartfixer has a good bit on sulfates and sulfites. Apparently sulfates (the less toxic variety) can increase your adrenaline and cortisol.

Hi @aaron_c ,

This discussion on sulfites vs. sulfates and/or whether or not sulfates are even remotely toxic has been going on for years now. It seems like Yasko and the 'Heartfixer' doc are the only ones making the claim that sulfate is toxic, or stimulates adrenalin and cortisol.

I'm not saying it doesn't, but have you been able to find any independent studies or confirmation that sulfates do indeed increase adrenalin or cortisol?


Also, a couple more questions if you don't mind. It seems like you're taking quite a bit of yucca -- isn't that supposed to quench ammonia? And lastly, have you had any testing done to show your ammonia levels have come down?


Thanks in advance Aaron.

 

[aaron_c]

Thanks @dannybex . Sigh. I wasn't aware that the whole "toxic sulfate" thing was part of the yasko speculation zone. I googled around a little bit and found this review of catecholamine metabolism, but I think it was implying the opposite of what heartfixer guy was saying: That sulfate conjugation of catecholamines leads to their excretion. Perhaps they saw high sulfates together with high excretion of catecholamines and assumed it meant more catecholamines in general--which from my limited vantage right now, appears likely to be wrong. So as you say, I'm not saying it doesn't, but... it does look that way. Thanks again for taking the time to show that to me. I'll be more cautious with heartfixer in the future.

Yucca is supposed to quench ammonia--and that was why I took and take it. But it has not done very much, if anything, for me. On the other hand, it doesn't seem to have any downside for me.

Unfortunately, mostly in the interest of money, I never had ammonia levels checked in the first place. So it is possible that I am barking up the wrong tree entirely with this. Still, if looks like and duck and quacks like a duck...I'll assume it is a duck for now. Now that I have insurance from the state, I could probably get ammonia levels checked for free, but I'm not sure how helpful it would be without the before picture.

Finally: I have actually stopped the liposomal malic acid in favor of resistant starch. The raw potato starch alone didn't seem to do much, but since I started having cooked and cooled potato starch (along with some raw potato starch, but I don't know how much it matters) not only have I not needed malic acid, but I have been able to eat a higher protein diet and take a moderate amount of B6 without smelly diarrhea or depression (the two symptoms that, taken together when resulting from B6, I assume means I have too much ammonia.) I haven't posted about this before now because I haven't quite found an equilibrium while taking potato starch. The potato starch has thrown a whole lot of my supplement dosages out the window, and I would like to know more before I post further.

 

[dannybex]

Thanks for your kind reply @aaron_c . I'm definitely not an expert at all -- still searching for answers. It's certainly frustrating to read one thing on one site, then completely contradictory info or research on another, so I understand the situation.


It was always my understanding that high ammonia levels lead to anxiety, agitation, and restlessness, but again, I'm not the expert…just throwing in my take on the topic.

 

[heapsreal]

With yucca, a friend put me onto it (for sleep as high ammonia is said to worsen insomnia) and he said that he only took it for 3 nights then took a night off. He found after 3 nights it seemed to stop working but just taking 1 night off helped with this and sleep improved once again after taking only 1 night off. This was also my experience with it. I cant explain why this is.

My friend had ammonia levels tested and this came down after using yucca. Myself, i didnt get ammonia tested. So i cant say if its helped me with ammonia, i guess it has? I also wonder if it works through its anti inflammatory effects as its normally used for arthritis, maybe it has anti inflammatory effects against certain inflammatory cytokines found in many cfsers??

 

[Tunguska]

Thanks @dannybex . Sigh. I wasn't aware that the whole "toxic sulfate" thing was part of the yasko speculation zone. I googled around a little bit and found this review of catecholamine metabolism, but I think it was implying the opposite of what heartfixer guy was saying: That sulfate conjugation of catecholamines leads to their excretion. Perhaps they saw high sulfates together with high excretion of catecholamines and assumed it meant more catecholamines in general--which from my limited vantage right now, appears likely to be wrong. So as you say, I'm not saying it doesn't, but... it does look that way. Thanks again for taking the time to show that to me. I'll be more cautious with heartfixer in the future.

I've had serious doubts sulfates are even remotely a problem for someone like me. I consumed large amounts of sulfur for half a year and things became worse after cutting back (long story now). The test strips showed around 800-1200. Some of the alternative Parkinson's and dopamine-fixing stacks administer 3000-4500mg of L-Cysteine a day to keep the sulfur(-containing amino acids) normal. Reading around acne forums people deliberately increase sulfur all around to help skin issues and claims are we don't get enough in diet. If it increased cortisol it would be a good thing for me anyway.

(The most damning counter-argument is the one of sulfur-containing amino acid restriction increasing lifespan)

 

[juzcat17]

i have the +/+ cbs A360A and -/- CBS C699T. Do i have an ammonia sulfite problem that i need to fix?. read in some places ti the lower level problem. I tried Starting up on freddds B12 but it lasted 2 days and then read on yasko i need to fix CBS first. Any ideas?. Happy thanksgiving for americans

 

[Valentijn]

i have the +/+ cbs A360A and -/- CBS C699T. Do i have an ammonia sulfite problem that i need to fix?.

There's no research indicating that CBS A360A has any impact. Hence I wouldn't worry about it at all.

There's some more discussion on the matter, and more relevant SNPs, at http://forums.phoenixrising.me/index.php?threads/interesting-cbs-variations.24492/

 

[Kimsie]

Hi Everyone
...

After having the genetic testing done and discovering I was C699T +/+, I attempted the yasko protocol to fix this: Mainly, this consisted of a once-a-week charcoal flush. This felt horrible, however, even aside from the diarrhea, which seemed somewhat unhealthy. So I discontinued, and avoided B6 so that CBS wouldn't be able to go into overdrive.
...

To combat the ammonia, I later settled on BH4 ...

The urea cycle works to excrete ammonia from the body in the form of urea. To do so, it requires ammonia and aspartate. Here is a diagram, courtesy of http://www.nature.com/gim/journal/v15/n4/fig_tab/gim2012166f2.html.

As you can see, Oxaloacetate is necessary to produce aspartate, and thus allow citrulline to to become argininosuccinic acid (ASA) et. But both Martin Pall and Rich Van K have suggested that our krebs cycles are stuck further upstream, meaning that we probably aren't making as much succinate, fumarate, malate, or oxaloacetate as we should be. In addition, CBS uses B6, so people with CBS upregulation would theoretically be a bit starved for B6. Aspartate transaminase, the enzyme that shunts oxaloacetate into the urea cycle, requires B6--meaning that CBS upregulation provides a double-whammy to our ability to deal with ammonia by both producing more ammonia and preventing our body from detoxifying it.

I would have used oxaloacetate if it was available, but it is not (perhaps it is not stable, I do not know). Malic acid, however, is quite available. To avoid digestive upset, I made a liposomal preparation, using the same parameters as liposomal vitamin C.

In addition to malic acid, I also take some B6 throughout the day--as much as is found in two bottles of kombucha. Maybe 8mg?

I have used this for four weeks now, and once I found the correct dose to use, I have not had diarrhea or depression, and have been able to go without BH4 entirely.

CAUTIONS:

Some people have allergic reactions to malic acid. It is a common food additive, and naturally occurs in foods like green apples. This is what livestrong has to say about it:

Natural forms of malic acid are found in many common foods, food products and supplements. Malic acid allergies have a low incidence, but for those who are allergic it can cause severe symptoms. Common allergic reactions include itching, hives, trouble breathing, abdominal pain, dizziness and swelling of the throat. In severe allergic reactions, anaphylaxis may occur. Symptoms include swelling of the throat, difficulty breathing, rapid pulse, light-headedness, loss of conciseness and shock. If any of these symptoms occur, seek emergency treatment.​

SIDE EFFECTS:

Since malic acid is a part of the krebs cycle, supplementing it can give you energy. Too much will cause insomnia.

...

Because malic acid is a krebs cycle intermediate, it will give you energy and should be taken in the morning. Like any liposomal solution, it should be taken away from food or drink. I drink something fiveteen minutes before, then wait a half an hour to eat.

I think you are missing the main way that malic acid helps get rid of ammonia. This is something that I have just figured out recently and I did post the following diagram in another post.

Note that the pathway on the left uses NADPH to produce BH4 from BH2. One of the main ways that the body produces NADPH is with the malic enzyme, which changes malate into pyruvate and produces 1 NADPH. It is a sort of loop or shunt in the TCA cycle because the pyruvate can then be changed to oxaloacetate to continue the cycle.

Have you tried mixing baking soda with the malic acid? That's a lot less work than making the liposomal. It takes 1/2 teaspoon per 1 teaspoon of malic acid to mostly neutralize the acid. That's how we take it, but if a person has sodium issues that might not be a good idea.

Since the body makes large amounts of malate, I wonder if the reactions some people get are not related to the fact that the malic acid is made from corn, a highly allergenic substance. (I know it is made from corn because I have a granddaughter with a corn allergy.)

I think that B6 is being drained by the SHMT enzyme as you can see above. The folate cycle has an alternate way to make ATP but it can drain B6, NADPH and produce extra ammonia, depending on which parts of the pathways are most functional in an individual person. Taking malic acid should relieve the drain on B6, help produce energy and lessen the ammonia problem.

Another thing that might help in some people is to increase thiamine to push the Pentose Phosphate Pathway, which is the 3rd and most well known producer of NADPH. This alone made my husband's sweat stop smelling of ammonia (he doesn't have CFS), but he has to take about a gram of B1 a day to lower the ammonia, and people with ME/CFS would probably have to work up slowly and some of them may not tolerate it.

I really don't think that the CBS mutation has anything to do with the high ammonia. CBS is regulated by the levels of SAMe and probably other factors, but not by the CBS upregulation. Ammonia is produced when the body uses a lot of glycine decarboxylase (malic enzyme)(edit: that should say glycine cleavage system, not malic enzyme) to produce ATP through the folate cycle or when the body burns amino acids for energy through the TCA cycle.

 

[ahmo]

Rather than making up a liposomal mix, I put the malic powder in my footbath, along w/ my aminos, minerals. Works a charm.

Add: Also, I add it to my H2O enema following my coffee enemas.

 

[aaron_c]

Hi Kimsie,

Thanks again. I really enjoy reading what you have learned about the folate cycle.

The link you shared is pretty fantastic, at least for me. I had not seen a study looking at where most NADPH comes from. It occurs to me (and may have already occured to you) that lower DHFR activity due to lower NADPH, would actually reinforce itself, both causing and being exascerbated by a "methylfolate trap" (when a higher proportion of folates become "stuck" as methylfolate). If this is accurate, then adding a whole lot of B12 to fix the methyltrap would only solve part of the problem.

Ammonia is produced when the body uses a lot of glycine decarboxylase (malic enzyme)to produce ATP through the folate cycle or when the body burns amino acids for energy through the TCA cycle.

I'm confused by this last bit about glycine decarboxylase and malic enzyme being the same thing. I can find a couple of malic enzymes that do what you say--and I think you may be right in that this is one of the ways--maybe the major way--that malic acid is helping with ammonia. But it seems to be different than glycine decarboxylase, and as far as I can tell, only glycine decarboxylase produces ammonia. Am I missing something?

Would you mind sharing your experience with baking soda and malic acid? How much do you take? Did you experience adverse reactions that the baking soda prevented?

I still suspect that if the reaction is "extra energy, inclucing insomnia," then I will suspect that it had do to with suddenly adding something to the krebs cycle, although I agree that the explanation is a bit incomplete.

I wonder if you have any insight into why ammonia is more of an issue for some people than for others?

 

[Kimsie]

Hi Aaron,
I'm glad you enjoyed my post. It's a pleasure to me to read your comments.

Hi Kimsie,

Thanks again. I really enjoy reading what you have learned about the folate cycle.

The link you shared is pretty fantastic, at least for me. I had not seen a study looking at where most NADPH comes from. It occurs to me (and may have already occured to you) that lower DHFR activity due to lower NADPH, would actually reinforce itself, both causing and being exascerbated by a "methylfolate trap" (when a higher proportion of folates become "stuck" as methylfolate). If this is accurate, then adding a whole lot of B12 to fix the methyltrap would only solve part of the problem.

I had not thought of that, but I think you have a very good point. Maybe this could cause a "dihydrofolate trap".

I was so interested in that study that I rented it so that I could look at the body of the study, but pretty much all of the important information is available at the link I gave, especially including the extended data figures and notes at the bottom of the page.

I'm confused by this last bit about glycine decarboxylase and malic enzyme being the same thing. I can find a couple of malic enzymes that do what you say--and I think you may be right in that this is one of the ways--maybe the major way--that malic acid is helping with ammonia. But it seems to be different than glycine decarboxylase, and as far as I can tell, only glycine decarboxylase produces ammonia. Am I missing something?

Oops!, I meant to say glycine decarboxylase, or glycine cleavage system, not the malic enzyme.

Would you mind sharing your experience with baking soda and malic acid? How much do you take? Did you experience adverse reactions that the baking soda prevented?

It's just that malic acid is very acid in the mouth and stomach. My husband can take it plain in capsules, but we take it mixed in water. Some people get upset stomachs from the acidity. We use L-malic acid, not the mixed form, half of the mixed form is probably useless for these biochemical reactions. We are taking about 5 grams 3 times a day, which is about a slightly heaping measuring teaspoon, with about 1/2 teaspoon of baking soda. If someone was not bothered by the acidity or mixed it with enough water they could probably do without the soda, but be careful to clean the teeth afterwards because of the acidity.

I still suspect that if the reaction is "extra energy, inclucing insomnia," then I will suspect that it had do to with suddenly adding something to the krebs cycle, although I agree that the explanation is a bit incomplete.

It does help with energy, but none of us in our family is experiencing any insomnia (but we don't have CFS). By taking malic acid you can increase NADPH and this can affect many metabolic pathways, not just the energy pathway. If someone is having insomnia from malic acid, my suggestion would be to try some niacinamide, if they can, because I suspect that it is because they are producing more adrenaline and having trouble getting rid of it. I have a hypothesis that people with these illnesses need extra niacin of some form.

I wonder if you have any insight into why ammonia is more of an issue for some people than for others?

I think it is because of genetic differences that cause different pathways to be affected to different degrees in each individual. Some people might have a little genetic block in the glycine cleavage pathway or in some aminotransferases, for example, in the case of ammonia. Or maybe they have a problem with the other pathway for BH4, but I can't remember what it is.

I think that the same underlying cause is behind not only ME/CFS, but a fairly wide range of chronic and generally debilitating illnesses, which all involve a messed up pathway for the metabolism of cysteine to sulfate, but have different symptoms because of genetic differences. The one thing that they all have in common is an inhibited electron transport chain and distorted amounts of some of the intermediates of the TCA cycle, but not the same distortion for everyone, except for succinyl-CoA, which is low but which is never measured by itself so there are no tests to prove it.

Kim

 

[Kimsie]

...

Here is some clarification:

In Yasko's reverse direction, MTHFR takes quinoid-dihydrobiopterin (q-BH2) and converts it to BH4. In this reverse direction, methylfolate is used as the reducing agent (producing 5,10-methylenetetrahydrofolate in the process). NADPH can also act as the reducing agent.

However, this reverse reaction has only ever been shown to occur under in vitro conditions - according to the research articles Yasko cites in the pdf reference @aaron_c linked to in an earlier post. The extent to which this reverse reaction occurs under normal physiological conditions in the human body is probably debatable.

This reverse reaction happening in the body seems to just be a theory. Certainly there seem to be no publications showing that A1298C has a greater ability to impair this theoretical in vivo reverse reaction than C677T.*

More importantly, note that in this reverse reaction, MTHFR would be performing the identical transformation of q-BH2 into BH4 that another enzyme in the body already does, i.e., dihydropteridine reductase (DHPR). (Not to be confused with DHFR. The gene that makes DHPR is QDPR.)

I'm not finding any evidence that MTHFR makes BH4 when it runs backwards. Are you sure? I think that when someone takes a lot of methylfolate it can increase all the folate reactions, including DHFR, which does make BH4, and that might be where the confusion comes from. Taking a few milligrams of any particular form of folate rather than another isn't going to make any difference unless the person has difficulty converting the particular form they are taking.

As far as I can tell, DHPR and DHFR (a folate enzyme) are the only two enzymes that can make BH2 into BH4.