New, Inexpensive CBS Ammonia Fix

[aaron_c]

Hi Everyone

I believe I have a new and inexpensive fix for Ammonia issues due to the CBS C699T polymorphism: Liposomal Malic Acid.

At this point I am the only one I know of who has tried this, but here is, as they say, the story so far:

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.

Later I began taking molybdenum, which at this point is around 1500 mcg per day. This has been helpful with sulfur issues, but not ammonia.

To combat the ammonia, I later settled on BH4 (from lwtinternational.com), which has allowed me to take some amount of B6 without the diarrhea or deep depression that would have accompanied it before (diarrhea from too much ammonia--I think--and depression from depletion of BH4)*. The B6 brought me out of a pervasive, sort of flat-affect depression, so I put up with the one downside: Cost. To take a moderate amount of B6, I was spending $10 on BH4 every day.

So how does liposomal malic acid work? First, some background:

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.
​

If you decide to try what I have tried, please take appropriate cautions.


SIDE EFFECTS:

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

Concentrated malic acid can irritate the skin. You may want to be a little careful when preparing the liposomal solution.


DOSING:

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.

Begin with one drop (not dropper). Add more each day, until insomnia (or other side effects) appear, or until ammonia symptoms totally subside. If the side effects are of the allergic variety then discontinue immediately. Ammonia seems to cause different symptoms for different people, but hopefully these symptoms should subside.

For reference, I take three droppers (three squirts from a dropper from a one ounce bottle, approximately 20 drops per squirt) of the liposomal solution in the morning. I put the solution in the jewelry cleaner and put it through a cycle before using it. I also eat the same food every day, because eating food higher in methionine or cysteine produces higher amounts of ammonia. Perhaps it is possible to learn to take more based on what foods one eats, and of course one could take BH4 to take up extra slack.

Make sure to take some B6 as well, and to take molybdenum as needed.


LIPOSOMAL DIRECTIONS:

Combine and blend (I use a half gallon mason jar with a hand blender):

3 tablespoons Sunflower Lecithin
1 tablespoon Malic Acid Powder
1.5 cups warm water

You may wan to blend the lecithin first, then put it in the refrigerator and wait for two hours. I do not do this.

Potentially, you could blend it for about two minutes and use that. I blend it for less time and then put it in an ultrasonic jewelry cleaner for a total of a half an hour. I got my Ivation cleaner at amazon for I believe $40-50.

There may be some lecithin leavings at the bottom of the ultrasonic cleaner--ignore them and pour off what you can. In the future, some of the solution may become heavier and darker. I shake the bottle before putting it in the jewelry cleaner, and mix the solution a little bit afterwards, and it works fine.


DISCLAIMER:

I am not a doctor of any kind. My intent is to share what has worked for me, in the hopes that others--who are preferably consulting with a health care practitioner--might benefit as well.


INTERESTING NOTES:

In the course of arriving at liposomal malic acid, I tried a few other things. Fumaric acid did not work as well, although I honestly do not remember details well. Carnitine fumarate did a very little to help with ammonia, but even taking three pills a meal was barely noticeable. Once I had stabilized the liposomal fumaric acid I also tried ornithine in order to increase throughput in the urea cycle. It may have worked, but I could not find a way to take enough liposomal malic acid to deal with it while also not having insomnia. Perhaps this fix has its limits, or perhaps it does not play well with ornithine. Or perhaps this fix will not prove useful to most people.

Obviously, I hope otherwise.

Wishing us all the best,

Aaron C

 

[South]

@aaron_c A couple of questions:
Have your read that diarrhea is a common reaction to too much ammonia (in people with the polymorphism that doesn't clear ammonia very well)? I haven't but haven't dug around for info on that connection. The little bit I've read about symptoms of too much ammonia mostly talked about becoming deficient in serotonin and dopamine from the lack of BH4.
Or are you saying that, prior to trying malic acid, you got diarrhea only when you tried taking vitamin B6?

Second question, why the liposomal version of malic acid instead of using ordinary malic acid? you mentioned this is "to avoid digestive upset", but the doses you seem to be taking of malic acid don't seem very high, did those doses as non-liposomal, ordinary malic acid give you digestive upset?

Very interesting post that you wrote, thank you.

 

[aaron_c]

Hi @South

I am not sure if diarrhea is a common reaction to excessive ammonia. In my case, the connection seemed quite clear. Having said that, uh, hold on tight, because this is about to get a little convoluted:

BH4 and B6: When I take too much BH4, I get a headache behind my eyes. It has become how I know how much BH4 to take. And I spent a few weeks working out how much BH4 I need to take per squirt of B6 (I had to put one 100 mg pill into a 1 oz dropper and take droppers of B6 so that I wouldn't take too much). Without taking B6, I could take maybe one(?) pill of BH4 per day before getting a headache. When I took about three droppers of B6, I had to take 8 or so pills of BH4 before reaching tolerance. And those times when I low-balled my BH4, in addition to feeling slightly less chipper, I would also get diarrhea. In any case, the connection there seemed quite direct: Somehow, the BH4 was helping to both prevent diarrhea and depression.

I suppose that the diarrhea could have come from a BH4 deficiency rather than a local ammonia excess, although I believe my shit smells of ammonia. But that might be a bit of a six-of-one-half-dozen-of-the-other thing.

Prior to taking BH4, diarrhea was a periodic issue for me.

In retrospect, I can see two patterns in relation to my diarrhea: The first was that it would flare when I took b6, as I was at the beginning of my illness--and it disappeared once I discontinued B6 (and everything else) in despiration. But that was 8 years ago. The other handful of times I had something with an appreciable b6 content, I honestly cannot remember if I had diarrhea. I think so, but I am not sure.

The second pattern has to do with location: I live in Portland, Oregon in the USA. I think it could be classified as temperate and wet. At least once a year I travel to Crestone CO, which is two miles higher and much much drier than Portland. When I do so, two things happen: The "Portland depression" would leave me, and I would have daily diarrhea. Some people have attributed the diarrhea and the lifting of depression to the stress of travel, but I do not think this is the case, because I travel to a meditation retreat, where I practice, usually for a month, and the diarrhea lasts the entire time.

When I began taking BH4, the "Portland depression" got fixed, in spite of my still living in Portland. The last time upon arriving in Colorado, I got the "too much BH4" headache, and had to stop taking BH4 before it left. The diarrhea, however, started up again. My conclusion is that climate effects the NOS enzyme that uses BH4, either directly or indirectly, to transform citrulline and nitric oxide into arginine and visa versa. My thought is that the relative air pressure and humidity might have an effect on the body's need for nitric oxide. Somehow in Oregon, less nitric oxide is needed.

So that is the link I see between ammonia and diarrhea. I admit it is not entirely direct. But I believe that the fact that malic acid has an effect similar to BH4, in that I have neither depression nor diarrhea, would seem to support my hypothesis.

For what it is worth, if you google "ammonia diarrhea," it seems that it is somewhat common. I suppose that could support or refute my hypothesis.


As for the liposomal version: I think I was playing a hunch and skipping some steps that a good scientist would take. My main concern is that concentrated malic acid can be caustic to the skin, and I see no reason why it would not be equally caustic to the intestines. And since some people can become allergic to it, and I have had a history of food allergies, I decided to play it safe. But perhaps mixing it with some licorice tea would do equally well. I suppose I'll put that at the end of my "to try" list.

 

[South]

Ok, thanks for the clarification.

 

[Tunguska]

This is interesting. I didn't notice too much from magnesium malate giving about 1000mg malic acid/day, but I feel slightly better eating apples. Nothing too notable in apples except fructose, boron and malic acid. I'll try with a higher dose malic acid supplement once it comes. But I'm already eating a ton of fruit as of now so probably won't be drastic.

I couldn't tell if ornithine or carnitine fumarate were doing anything good either. 1g molybdenum was noticeable though for whatever reasons (sulfur or uric acid?).

 

[ahmo]

@aaron_c Really interesting. My body seems to prefer malate form of magnesium. I take my aminos and some other supps, like K+ by footbath, so it would be easy to just add this as well. Wow, I wonder if that would eliminate my need for citrulline, arginine, ornithine, lysine??? I don't always self-test + for all of them, and as time and detox have gone on, I'm needing them less frequently. But this might intervene at the right place in the cycle to help even more.

Where are you getting your malic acid? I see iherb has Nature's Life M.A. caps. I also noted from my compounding chemist's site:

It is very important that the L-isomer of Malic acid is used as it is the active form that exists naturally. When synthesised the malic acid produced contains both the D- and L- forms with the D- form being inactive. When extracted from apples only the L-form (active form) is present.
http://www.custommedicine.com.au/health-articles/malic-acid-for-fibromyalgia/

The NL product doesn't specify type of MA. but the reviews are from FMS folk who like it. http://www.iherb.com/Nature-s-Life-Malic-Acid-800-mg-250-Veggie-Caps/24051

 

[aaron_c]

@Tunguska:
I have been told that molybdenum is helpful as a cofactor of the sulfite oxidase enzyme (SUOX). It allows us to turn sulfites into sulfates. Overactive CBS seems to create a lot of sulfites... Perhaps one day I will be able to be more precise. But I'm pretty sure it doesn't help much with ammonia.

@ahmo:
I got mine from purebulk.com. So far, their stuff seems to be trustworthy...I already ran into problems when I tried switching off their biotin to country life's biotin. And for the malic acid, I use the L isomer, not DL, as you noted.

Good read on iherb, I hadn't realized it was already used for fibromyalgia. Maybe I won't need to make it liposomal--I see 2400 mg per day worked for one person.

 

[Tunguska]

@Tunguska:
I have been told that molybdenum is helpful as a cofactor of the sulfite oxidase enzyme (SUOX). It allows us to turn sulfites into sulfates. Overactive CBS seems to create a lot of sulfites... Perhaps one day I will be able to be more precise. But I'm pretty sure it doesn't help much with ammonia.

I figure perhaps sulfur is part of my problems but I haven't gotten this process down enough yet to tell. It's very possible. What's for sure is that 500mcg+ molybdenum daily seems to be a requirement for anything I try to do. I also understand it raises uric acid.

Then there's this lone piece: http://www.detoxpuzzle.com/serotonin.php http://www.detoxpuzzle.com/molybdenum.php

Tryptophan hydroxylase is increased by phosphorylation, especially protein kinase A, which is dependent on cAMP and by calcium and magnesium. BH4 is the cofactor in this reaction. In order to maximize BH4, you need vitamin C, folate and/or niacin, plus molybdenum.

Similarly dietary purines/pyrimidines seem to be part of the equation of what works for me. I don't know quite why the purines but one or two references mention that BH4 can be made from the purine GTP. Which according to that site requires molybdenum to synthesize, at least de novo, but wouldn't know if any relation to dietary. [Also I wonder if the quote is really true]

I finally got some malic acid but been diverted by another experiment for now...

 

[aaron_c]

@Tunguska

Could you say more about purines/pyrimidines and how they effect you? I have also benefited from a nucleotide supplement, but I wouldn't have thought to bring it into this context. What food choices are influenced by your thinking on purines and pyrimidines?

Very interesting about molybdenum and BH4, if it is true...but I also have my doubts. I just tried to contact the person who put up the site, and I will post if she gets back to me. I googled [gtp synthesis molybdenum], and all I could find was that GTP is necessary to produce molybdenum cofactor, which "forms the active site of all eukaryotic molybdenum enzymes." So it seems like GTP is necessary for molybdenum use, but in three pages of google results, I didn't see anything pointing the other direction. Maybe she got it backwards?

 

[Tunguska]

@Tunguska

Could you say more about purines/pyrimidines and how they effect you? I have also benefited from a nucleotide supplement, but I wouldn't have thought to bring it into this context. What food choices are influenced by your thinking on purines and pyrimidines?

It goes back to uridine (UMP) again. I had a great effect from it but it definitely doesn't work alone and I'm still trying to get it down. Looking back, the days it worked was always on days I had high purine foods beforehand - sardines, kidney beans. But also molybdenum. (I thought it was protein, but adding tons of glutamine and whey doesn't help)

Very interesting about molybdenum and BH4, if it is true...but I also have my doubts. I just tried to contact the person who put up the site, and I will post if she gets back to me. I googled [gtp synthesis molybdenum], and all I could find was that GTP is necessary to produce molybdenum cofactor, which "forms the active site of all eukaryotic molybdenum enzymes." So it seems like GTP is necessary for molybdenum use, but in three pages of google results, I didn't see anything pointing the other direction. Maybe she got it backwards?

I couldn't find anything to support the molybdenum-BH4 (or molybdenum-GTP) link except the same claim made in some Dr. Yasko PDF.

The GTP-BH4 link is mentioned in a few places including here: http://www.ncbi.nlm.nih.gov/pubmed/15509890

BH4 is synthesized via de novo and salvage pathways from guanosine 5'-triphosphate (GTP) and 7,8-dihydrobiopterin, respectively, in animal cells.

There's something to purines, but molybdenum... ?

 

[Tunguska]

Oh and the sardines especially seem to be high in guanine (GTP): http://jn.nutrition.org/content/106/3/435.full.pdf (table on page 440)

 

[Tunguska]

I have to point out that aspartate is necessary for both purine (isonine, GTP) and pyrimidine (uridine) synthesis too.

This didn't click before but one of the reasons I figured I needed a protein source in http://forums.phoenixrising.me/inde...e-biosynthesis-ump-uridine.32018/#post-493905 was because aspartate is needed for UMP synthesis. I'm slow so I didn't make the connection with what you wrote here.

On top of that the UMP synthesis generates NADH (http://www.namrata.co/wp-content/uploads/2013/02/steps-of-de-novo-pyrimidine-biosynthesis.png - sorry I can't seem to upload), which in turn helps BH4 according to http://snpedia.com/index.php/Tetrahydrobiopterin and other threads on here.

I don't think large doses of malic acid alone are triggering huge changes for me (folate and R5P have much more immediate effects; note I haven't tried liposomal; it would be nice though since 2400mg at once was a little hard on the stomach) but I figure it probably contributes so I'll keep taking it. It seems smart and I have to cut back on fruit. It might be an advantage over extra protein in that it won't produce new ammonia. Though probably still need glutamine in some capacity.

 

[Tunguska]

I had another question: is there a difference in the amount of sunlight you get between Portland and Colorado?

I ask because in my case none of this works without at least 30-60mins of sunlight exposure beforehand (Vitamin D supplement doesn't seem to make up even at 6000IU; afraid to try higher).

 

[aaron_c]

I think I see what Yasko was talking about. If you check out this book on page 127-128, you'll see that molybdopterin is necessary for xanthine oxidase to convert hypoxanthine to xanthine. Without molybdopterin, the only way to get to get from xanthine, hypoxanthine, or inosine monophosphate (IMP) to xanthine monophosphate (XMP)--and then to guanosine monophosphate (GMP)--is via IMP dehydrogenase, which requires reduced glutathione (GSH). As you probably know, most of us with chronic fatigue (and autism) have low GSH--at least unless we take supplements to change this, and are lucky enough for them to work.

The purine synthesis diagrams I have seen say that synthesis does not normally move through xanthine or hypoxanthine, but rather synthesizes IMP from elsewhere, and then uses IMP dehydrogenase to create XMP, from which GMP is made. With low GSH, the diagram seems to indicate this flow would be diminished, and an alternate route would be necessary in order for our bodies to make enough GMP to balance the adenosine monophosphate (AMP). The alternate route would be through hypoxanthine, then xanthine, then to XMP using xanthine oxidase, which as you will recall, needs molybdopterin.

Aside from the fact that Yasko is one of the few people out there interested in BH4, I think this is why Yasko is the only one to say that molybdenum is involved in GMP: For people with sufficient GSH, it seems like the impact of deficient molybdenum on GMP levels might me minimal, whereas for those of us with low GSH (as most of her patients probably start with) low molybdenum might very well negatively effect the GMP levels.

As an aside: Some months ago I wondered about yasko's claim that BH4 detoxes ammonia. From the reading I had done, it seemed like it could be necessary for NOS to function, but I could not see any research saying that it was actually used up in the process. And yet my experience matched her assertion: The more ammonia I produced, the more BH4 I needed to take. So I now tend to think that her assertions are worth checking out, even if they seem to contradict what everyone else says. Although I do think she got alpha-keto-glutarate and alpha-keto-butyrate mixed up on her diagram.

@Tunguska, could you say a bit more about what the "great effect" UMP has on you? And also purines+pyrimidines, if that is different? Do you have more energy, or think more clearly, et?

Interesting about the pyrimidine-aspartate connection. I think the question there becomes when does aspartate become the limiting factor in purine synthesis? Because ribose-5-phosphate (R5P) is also necessary, as is ATP, and people with ME/CFS will, as you know, be deficient in both of them. If aspartate were the limiting factor, then the malic acid and B6 should help that out.

As you may know, aspartate is one of the major excitatory neurotransmitters, along with glutamate. Although taking glutamate didn't seem to faze you, so maybe that isn't one of your problems. But Yasko is big on glutamine toxicity and autism, and as you may know, Rich Van Konnynenburg said he thought CFS and autism were essentially the same disease with a different age of onset. So just in case you didn't know, there is reason to be cautious with supplementing those two.

Also, UMP synthesis generates NADH, but going from UMP to TMP uses NADH and ATP, and going from UMP to CTP uses ATP as well. If anything, you are using up NADH and ATP by supplementing UMP, so I doubt that would be how it is helping.

The malic acid does help in recycling NAD to NADH--that's one of the things the krebs cycle does. But I didn't mean it as a substitute for protein or carbs or fat. However if you experience adverse reactions to eating more protein, particularly when taking B6 (the CBS upregulation problem), then it should help. I assumed, but I should probably ask: What makes you think you might have CBS upregulation problems?

Hmm. Perhaps the vitamin D observation could tie it together a little: This abstract says that CTP (from UMP) is used to make CDP-choline (sold as citicoline). CDP-choline, in addition to protecting from excitotoxicity, increases dopamine and noradrenaline, at least in the central nervous system. Perhaps this is why you need sunlight to make the whole thing work? Although, I take CDP choline to help bring down excitotoxicity, and it makes me tired initially. It sounds like this is not the case for you with UMP.

Have you had your vit d tested? Because if sunlight does what 6000 iu of vit D does not, I would wonder about the quality of vit d.

Have you posted somewhere your symptoms and what you are taking? I am beginning to wonder if I am making incorrect assumptions about your situation.

I look forward to hear how your experiments progress.

The very best,

Aaron C

 

[Lou]

Hi Aaron C,

There may be others here like me, interested in the ammonia issue but not versed on all the chemical pathways you're able to so freely navigate.

Although my mthfr mutation is different from yours, excess ammonia is often a problem for us with mthfr 1298c as well. Just wondered if you would comment whether you think BH4 supplements might be helpful for us, too?

I tried biopertin once before without good results, but now wonder if some cofactor deficiency was at fault. Also concerning is spending $72 on supplement and finding myself unable to figure out limiting factor if that occurs.

You seem to write of your supplement as actual BH4, am curious if that is the case? Thanks for any thoughts you may have on all this.

 

[Tunguska]

(I'm a little tired so hopefully this holds up)

I think I see what Yasko was talking about. If you check out this book on page 127-128, you'll see that molybdopterin is necessary for xanthine oxidase to convert hypoxanthine to xanthine. Without molybdopterin, the only way to get to get from xanthine, hypoxanthine, or inosine monophosphate (IMP) to xanthine monophosphate (XMP)--and then to guanosine monophosphate (GMP)--is via IMP dehydrogenase, which requires reduced glutathione (GSH). As you probably know, most of us with chronic fatigue (and autism) have low GSH--at least unless we take supplements to change this, and are lucky enough for them to work.

The purine synthesis diagrams I have seen say that synthesis does not normally move through xanthine or hypoxanthine, but rather synthesizes IMP from elsewhere, and then uses IMP dehydrogenase to create XMP, from which GMP is made. With low GSH, the diagram seems to indicate this flow would be diminished, and an alternate route would be necessary in order for our bodies to make enough GMP to balance the adenosine monophosphate (AMP). The alternate route would be through hypoxanthine, then xanthine, then to XMP using xanthine oxidase, which as you will recall, needs molybdopterin.

Aside from the fact that Yasko is one of the few people out there interested in BH4, I think this is why Yasko is the only one to say that molybdenum is involved in GMP: For people with sufficient GSH, it seems like the impact of deficient molybdenum on GMP levels might me minimal, whereas for those of us with low GSH (as most of her patients probably start with) low molybdenum might very well negatively effect the GMP levels.

I hadn't seen anything indicating xanthine would convert to XMP (in that direction). I guess this does it? https://en.wikipedia.org/wiki/Xanthine_phosphoribosyltransferase Couldn't find a reference to the enzyme they wrote on the xanthine-XMP link in the figure from that book.

Anyhow nice detective work, would make sense to me.

@Tunguska, could you say a bit more about what the "great effect" UMP has on you? And also purines+pyrimidines, if that is different? Do you have more energy, or think more clearly, et?

With 250mg UMP sublingual, when it works, produces a strong increase in focus, alertness and motivation in what seems like the front of the brain. Along the lines of the first time I took tyrosine but stronger and more focused. Basically dopamine, exactly where it needs to be. Upping to 500mg sublingual it became a bit robotic. It doesn't seem to be fading but I can't reproduce it 100% consistently yet although some patterns/cofactors are obvious.

Interesting about the pyrimidine-aspartate connection. I think the question there becomes when does aspartate become the limiting factor in purine synthesis? Because ribose-5-phosphate (R5P) is also necessary, as is ATP, and people with ME/CFS will, as you know, be deficient in both of them. If aspartate were the limiting factor, then the malic acid and B6 should help that out.

That's right, I can't imagine in reality what quantities are needed.

As you may know, aspartate is one of the major excitatory neurotransmitters, along with glutamate. Although taking glutamate didn't seem to faze you, so maybe that isn't one of your problems. But Yasko is big on glutamine toxicity and autism, and as you may know, Rich Van Konnynenburg said he thought CFS and autism were essentially the same disease with a different age of onset. So just in case you didn't know, there is reason to be cautious with supplementing those two.

I took a ton of glutamine for gut reasons over months (for which I think it helped) and it probably contributed to brain fog but not immediately. Taking it again now in high doses (5-10g) I don't notice a striking effect but it might be contributing to irritation later in the day. It's not something I wanted to continue but it does seem to be necessary for the pyrimidine stuff. I wonder how much aspartate is too much. Thanks for the warning though.

Also, UMP synthesis generates NADH, but going from UMP to TMP uses NADH and ATP, and going from UMP to CTP uses ATP as well. If anything, you are using up NADH and ATP by supplementing UMP, so I doubt that would be how it is helping.

Ah yeah.

The malic acid does help in recycling NAD to NADH--that's one of the things the krebs cycle does. But I didn't mean it as a substitute for protein or carbs or fat. However if you experience adverse reactions to eating more protein, particularly when taking B6 (the CBS upregulation problem), then it should help. I assumed, but I should probably ask: What makes you think you might have CBS upregulation problems?

I'm hetero for one CBS gene, A1298C, and all the BHMTs, but my issue is with ammonia specifically. I've eaten high protein for an extended period because of serious skeletal problems. I don't want to cut back on it (much, except maybe in the morning), but there's a trade-off with it having noticeably affected mental function. I suspect the BH4 is eaten up because a high dose of methylfolate is a requirement for the focus.

Hmm. Perhaps the vitamin D observation could tie it together a little: This abstract says that CTP (from UMP) is used to make CDP-choline (sold as citicoline). CDP-choline, in addition to protecting from excitotoxicity, increases dopamine and noradrenaline, at least in the central nervous system. Perhaps this is why you need sunlight to make the whole thing work?

That's exactly what I had in mind. I'm certain that I need the sunlight specifically for the dopamine-like effect to work. Every day I've had no sunlight the UMP did little to nothing.

Although, I take CDP choline to help bring down excitotoxicity, and it makes me tired initially. It sounds like this is not the case for you with UMP.

I also tried CDP-choline but it was nowhere near UMP in strength. What I read was that citocoline was broken down into choline and cytidine in the stomach (https://en.wikipedia.org/wiki/Citicoline#Medical_uses), and cytidine converted to uridine, so it should be similar to taking a bit of UMP and a choline source. For me too much choline seems to produce a depressant effect too though I don't think CDP-choline had enough to be noticeable. However many months ago I tried a TAU (triacetyluridine) version of uridine and it produced some fatigue at first, so who knows.

Have you had your vit d tested? Because if sunlight does what 6000 iu of vit D does not, I would wonder about the quality of vit d.

I had D levels tested some time ago and was told it was normal but wasn't in a state to ask for a copy. I have noticed a kind of darkening from the Vit D supplement alone, so it has some kind of effect, but you're right that I should try another brand again (this is the... 3rd, but only one I tried with UMP).

Have you posted somewhere your symptoms and what you are taking? I am beginning to wonder if I am making incorrect assumptions about your situation.

Sorry this got all intertwined. What I'm after at the moment is the UMP/dopamine effect, but it surely requires BH4 which I suspect is chronically low because of protein/ammonia, indicated by the necessity for high folate and possibly genetics/history/symptoms. Definitely have low NO symptoms most of the time, zero dopamine/motivation, brain fog, many other things. I take all the vitamins and minerals, basically, I had a link somewhere... but now with uridine and increased folate and fewer end products like CoQ10/NAC. And... malic acid.

If I get it down I'll definitely post about it although it seems to require too many factors so I'm not sure that will happen.

Anyhow this thread is enlightening.

 

[ahmo]

@aaron_c BH4 was something I avoided adding, due to its cost. As I progressed w/ detox and methylation over the last couple years, I didn't seem to have symptoms suggesting the need for it (just to add to the BH4 conversation...nothing about why I'm posting today.Also, I added molybdenum early on, after scoring high on pyroluria questionnaire.

Anyway, I'm here today to thank you for your Excellent Sleuthing to uncover Malic Acid

I was using a combo of ornithine, arginine, citrulline, lysine. I take all my supps by self-testing, have been doing so effectively for these past years. I now need less of these supps since I've been detoxxing. Recently I've tended to need 1/8 tsp citrulline, 1/4 tsp arginine, 1/2 tsp ornithine, lysine. I don't test + for all of these all the time.

Last night was my first trial of malic acid. I used 3 caps Natures' Life 800mg malic acid only, instead of any combo of the others mentioned above. Similar to your liposomal method, I added them to my footbath, which is how I've been taking my aminos and other powders over the last year. This AM i started w/ 3 caps, body asked for more, so I added another 1/2. Happy body. And body signals to me that it prefers this to the others!! Well Done Aaron!

 

[ahmo]

Re Bh4, Here's some info posted by @Critterina in another thread:

http://forums.phoenixrising.me/index.php?threads/snps-interpretation-guide.32187/#post-497018
...And people with A1298C are inefficient at converting methylfolate back to folinic acid. It didn't seem like that would be important, since they can convert it to methylfolate, and since they are taking the folinic, they will have plenty of that, too. In fact, that was my reasoning that led me to trial it. Here's the rub: The problems associated with A1298C stem from a lack of BH4, which is used for a lot of things, but in particular it makes serotonin and dopamine. The important part is not how much you have, but which way the cycle turns.

BH4 and BH2 are the two forms of biopterin in the biopterin cycle. BH4 turns into BH2 when it makes serotonin and dopamine, when it converts folinic acid to methylfolate, and other things that are important. To recycle it back to BH4 takes one of two enzymes. The first is MTHFR, in the reaction that converts methylfolate to folinic acid. If you're taking folinic acid, the MTHFR enzyme is going to be converting it to methylfolate, not the other way round, not the way you want it to be turning. It's trying to achieve equilibrium and you're pushing the reaction one way, when to make BH4, it needs to go the other.

(The other enzyme is IDHPR. I don't know much about it, whether there are SNPs that affect it's efficiency or not. I assume so, which probably contributes to why some people suffer more from their A1298C SNP than others. Anyway, we're not doing anything about that, so it is what it is.)

So, my "logical" reason to think that the only people who should really be taking folinic acid are those with neither of the above MTHFR SNP, is based on this explanations. I can't dispute that I certainly don't have the whole story, and caledonia's "cautiously trial" recommendation is based on the experience of many people - probably both healthcare practitioners (who may not have access to the patient SNPs) and people writing in this forum (who have a variable level of experience). I don't mean to discount it. I just probably wouldn't recommend folinic to treat these SNPs.

 

[Jarod]

Malic acid is a chelator also.

 

[aaron_c]

Hi @Lou,

I am not too versed in mthfr 1298c, but I have read some Yasko on MTHFR1298c: She says that the mutation is on the SAMe regulatory region, and I hear her implying that it causes problems with SAMe binding. SAMe, she says, would normally cause MTHFR to cycle "backwards," converting 5MTHF to 5,10-methyleneTHF but converting dihydrobiopterin (BH2) to BH4. Unfortunately, the study she seems to be citing in this slide-show on BH4 is not available for free. Perhaps another day I'll make it to my local naturopathic college and use their computers... I mention this partly because although I have read about the whole MTHFR-BH4-BH2 thing before, I seem to recall some amount of uncertainty, and I have yet to see a primary source on the subject--not that they aren't there, but I haven't seen them.

In particular I am unsure about Critterina's comment about the forward reaction of MTHFR using up BH4. Where did you get that from @Critterina?

Also, it seems like there are other (proposed?) methods of BH4 recycling, although the ones shown here both involve NADPH, which we in the CFS/ME family tend to be short on. Rich Van K thought this was because of the low activity in the pentose phosphate pathway, which he said was the main recharger of NADP to NADPH. Also, NADPH is used to recharge glutathione, so it would make sense that it would be exhausted in GSH deficiency.

And now I see another diagram with the same enzymes, but listing NADH as the cofactor...so...*shrug*

Lou, to get back to your question: Yasko certainly recommends BH4 support, although I am not sure all of what she had in mind there. Because your BH4 problems would seem to stem from difficulty regenerating BH4 rather than losing an excessive amount to ammonia, I am unsure how much the malic acid would help. Perhaps somewhat?

I did take actual BH4. I bought it from livingwelltodayinternational, although I see that they are currently limited in their supplies. I have tried taking high doses of 5MTHF to support BH4 as well, and I seem to recall it helped in a BH4 kind of way...but I think it caused an imbalance elsewhere, and I had to abandon the attempt. But it seems to help some people.

Best of luck in finding more of the answers you need.

Aaron C