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CBS revisited

triffid113

Day of the Square Peg
Messages
831
Location
Michigan
I can't search for a CBS thread since the search string excludes it as "too common"??? So here is a new thread.

I have 2 homozygous CBS mutations and despite what Yasko wrote she was dead wroong in that my homocysteine was RAISED, not lowered. The article here says that a large percent of people with CBS mutations are helped by P5P (which I take in 50mg from Country Life). I did verify that 200mg is no more help for me than 50mg so no benefit in taking more. I thought some may be interested in that it says serine and/or glycine can help most who do not respond to P5P. It also says the way to test is exactly how I have been doing: get your homocysteine level tested to look for the problem and the solution...it's the cheapest way to find a solution that works for you: http://ajcn.nutrition.org/content/75/4/616.full.pdf

I'm kindof looking into why I keep getting anemic even though I've has a hysterectomy and wondering if it has something to do with CBS. I find that CBS can cause G6PD deficiency and G6PD deficiency causes hemolytic anemia under stress, virusses, and some drugs (the article I read did not list the drugs - crud!) I think I am reading though that this happens only in men (x chromosome)? Not sure
 

SOC

Senior Member
Messages
7,849
triffid113 We have a member named CBS which may be why the search is "too common". You might try 'genetic' or 'mutations'. I haven't found the search engine here to be very friendly and I'm fairly expert. :(
 

triffid113

Day of the Square Peg
Messages
831
Location
Michigan
Freshveggies, do you also have and AHCY mutations? I have several (3?) of these. I never saw a SAH test offered anywhere?
 

dbkita

Senior Member
Messages
655
I can't search for a CBS thread since the search string excludes it as "too common"??? So here is a new thread.

I have 2 homozygous CBS mutations and despite what Yasko wrote she was dead wroong in that my homocysteine was RAISED, not lowered. The article here says that a large percent of people with CBS mutations are helped by P5P (which I take in 50mg from Country Life). I did verify that 200mg is no more help for me than 50mg so no benefit in taking more. I thought some may be interested in that it says serine and/or glycine can help most who do not respond to P5P. It also says the way to test is exactly how I have been doing: get your homocysteine level tested to look for the problem and the solution...it's the cheapest way to find a solution that works for you: http://ajcn.nutrition.org/content/75/4/616.full.pdf

I'm kindof looking into why I keep getting anemic even though I've has a hysterectomy and wondering if it has something to do with CBS. I find that CBS can cause G6PD deficiency and G6PD deficiency causes hemolytic anemia under stress, virusses, and some drugs (the article I read did not list the drugs - crud!) I think I am reading though that this happens only in men (x chromosome)? Not sure


I am curious which SNP you have for CBS that is homozygote and also what were some of the other key SNPs from your test(s)?

The relevant section of the article you linked is for people with homocystinuria who have a defective down-regulated CBS gene. You can find this on Wikipedia as well as possible treatments that include P5p.

Do you have homocystinuria? What are your homocysteine levels typically? Just curious.

P5p is the cofactor for CBS so it would make sense that CBS could be upregulated by mega doses of P5p. However, the treatment using P5p is only responsive for about 50% of patients. The others go on low methionine and low protein diets and maybe try TMG dosing. Those second class of patients may react badly to methylation protocols depending on their exact guidelines.

But even a person without homocystinuria and CBS mutations that are upregulating will see homocysteine drop by taking P5p usually (as well as TMG). The problem is the activation of and drain of methyl donors down the trans-sulfuration pathway. One simple way to see this is to test your urine sulfates with strips or better yet a 24-hour urine collection.

Dependent on the test results, I think it is hard to say a CBS gene means low homocysteine and not means high. It is much more complicated than that. A person could have a defective BHMT pathway and an upregulated CBS and still have highish homocysteine in general. The situation is even more complicated when we toss MTHF, MTR, etc. into the mix.

I would agree with FreshVeggies that knowing your SAH might be useful also.

In my own case I am waiting for my genetic tests to come back, (though I already have partial info and have a COMT and an MTHFR a1298c mutation). My homocysteine after two years on methylation support is about 8.5-10 as it flucutates. So many on these forums would say no CBS mutation.

But I have a problem with sulfites, have high taurine (normal-high beta alanine), have issues with ammonia, and my urinary sulfates get really high if I either bump up methylation further OR I eat thiol rich foods. So who knows but something doesn't seem right with the trans-sulfuration pathway. Glycine and glutamine are useful to me since it drops my cysteine by making glutathione. The nights my sulfate levels are lower means better sleep, less amped and more dopamine and serotonin (i.e. better mood).

Just food for thought.
 

freshveggies

Senior Member
Messages
196
@ dbkita I have been enjoying your posts. It is making me think more. My homocysteine is 3.0 Range is 4.1-12.4. My SAH is 56.8 range is 38-49. This is from a Methylation panel from Health Diagnostics and Research Institue.

My sulfates were between 1200-1600 when I started testing back in July, now they are down to 800. I am thinking that by what I have read that I need to get them lower in order to start working on the next phase of methylation. Is that how you see it?

I just ordered a UAA to test taurine, ammonia and sulfates.

I am so stressed out about what to eat. Can you give me some suggestions as to how you eat based on the fact that you might have a CBS? I am not getting a variety and not much protein. I worry about glutamates as they seem to bother me. I have chronic insomnia.

I had started taking 25 mg of zinc gluconate at 2:30 pm and noticed that it made me sleepy so eventually I tried it at bed and could not sleep at all so I moved it back to 2:30 and then started to struggle more with sleep. Falling asleep and then waking up 2 1/2 to 3 hours later and not being able to sleep. I put 2 and 2 together and think that it is glutamates being stimulated from zinc. Based off of what I read from Yasko. However, zinc is a double-edged sword since it can also activate glutamate release via the non-NMDA glutamate receptors.

I used to take magnesium glycinate to help me sleep, then it was recommended that I quit it for fear it was activating the glutamates. Now I am re-thinking this as it used to help me sleep. I don't know if something could have changed to not work with me anymore but it might be worth a try as I am low in mg and need to get it higher, but can't take anymore mg citrate.

I have been using gaba, valerian, and kava to help me sleep. Last night I couldn't get to sleep so I took another gaba at 10:15 and slept until 4:00 and was kind of wired. So I took another gaba and kava. It took me one hour to start to feel drowsy again. I might have finally dozed off again.

Any suggestions to any of this that I have written. Thank you.
 

dbkita

Senior Member
Messages
655
@ dbkita I have been enjoying your posts. It is making me think more. My homocysteine is 3.0 Range is 4.1-12.4. My SAH is 56.8 range is 38-49. This is from a Methylation panel from Health Diagnostics and Research Institue.

My sulfates were between 1200-1600 when I started testing back in July, now they are down to 800. I am thinking that by what I have read that I need to get them lower in order to start working on the next phase of methylation. Is that how you see it?

I just ordered a UAA to test taurine, ammonia and sulfates.

I am so stressed out about what to eat. Can you give me some suggestions as to how you eat based on the fact that you might have a CBS? I am not getting a variety and not much protein. I worry about glutamates as they seem to bother me. I have chronic insomnia.

I had started taking 25 mg of zinc gluconate at 2:30 pm and noticed that it made me sleepy so eventually I tried it at bed and could not sleep at all so I moved it back to 2:30 and then started to struggle more with sleep. Falling asleep and then waking up 2 1/2 to 3 hours later and not being able to sleep. I put 2 and 2 together and think that it is glutamates being stimulated from zinc. Based off of what I read from Yasko. However, zinc is a double-edged sword since it can also activate glutamate release via the non-NMDA glutamate receptors.

I used to take magnesium glycinate to help me sleep, then it was recommended that I quit it for fear it was activating the glutamates. Now I am re-thinking this as it used to help me sleep. I don't know if something could have changed to not work with me anymore but it might be worth a try as I am low in mg and need to get it higher, but can't take anymore mg citrate.

I have been using gaba, valerian, and kava to help me sleep. Last night I couldn't get to sleep so I took another gaba at 10:15 and slept until 4:00 and was kind of wired. So I took another gaba and kava. It took me one hour to start to feel drowsy again. I might have finally dozed off again.

Any suggestions to any of this that I have written. Thank you.


Ok there is a lot to cover here. So warning long post incoming.

I am at work (finally over my daughter's cold) so I don't have access to all my bookmarks, papers, etc. so I won't be able to give you particular links right now. Also I am not an M.D. so take this with a grain of salt please.

1) Sulfates can be a big deal. Fortunately you are CBS heterozygote but you also have BHMT SNPs. Clearly your homocysteine is low and your SAH is high so there is something going on there that is transforming homocysteine rapidly so it has a short effect half life. I would certainly worry about sulfite processing and exposure to sulfites given how low your homocysteine is (i.e. what are your molybdenum levels?)

Still your MTRRs and MTHFR mean you probably need methylation support but again they are all hetero so you are not the extreme methylation category that is often discussed on these forums. The issue with CBS / BHMT abnormalities is you can end up draining methyl donors down your trans-sulfuration path, which undercuts what you are trying to do

First there is one caveat, sulfates are not ONLY made down the trans-sulfuration pathway, they are also from the phenolsulfotransferase pathway. However, I am going to assume that is working ok, as often the problems there are with down-regulation and those people (usually kids) are really impacted. I am still learning about that set of pathways currently so I don't have much to comment there.

So I will now return to the trans-sulfuration pathway.

When I was accidentally overmethylating I was running 1600 all the time. When I stepped off the throttle some I was alternating between 600-800 but would some days spike to 1200-1400. Note I take measurements at roughly the same time of night since there are oscillations in excretion and you can't do a 24 hour test all the time.

So my first question was, why the spikes? This was important to me, since the nights I had lower urine excretion usually meant an easier time sleeping; not always but enough correlation to publish a social science paper (sorry inside physics humor).

At first I thought it might be related to the levels of ALA, biotin, molybdenum or even taurine that I would sometimes take. But nothing really correlated over a month of testing. Also my diet is a paleolithic diet with really high protein & fats (else I lose weight and given the catabolic nature of auto-immune disease), so the 200+ grams of protein wasn't the cause since how could I often be around 600?

The answer seemed to be my diet, but my vegetables especially the ones I ate at dinner (there is a temporal lag after all). I tended to eat a lot of thiol-rich vegetables, like 4-5 servings a day of one of the following: broccoli, asparagus, spinach, green beans, peas, etc. The nights I ate 2-3 servings of those at dinner, I spiked. The nights I had 0-1 servings and substituted in say beets, avocado, or potato for the others, I dropped. Couple of nights I hit 400 with nothing else different than my vegetable choices.

This matched some of the reading I had done a la Andy Cutler that the problem foods are those high in thiols not those necessarily high in sulfur containing amino acids. The exception might be huge amounts of cysteine like in eggs, but I tend not to eat those foods (subconscious choices?) and what I do get from animal protein, I probably handle well since I take 800-1000 mg of Mg-glycinate per day (~6-7.5 grams of glycine) along with 3-4 grams of glutamine per day. This combo of glycine + glutamine (some of which converts into glutamate ~ 25% in the periphery) turns into glutathione if cysteine is present and as long as ATP is present (I take d-ribose, creatine pyruvate, b-vitamins, etc.)

So for foods you might want to search google for a list of high and low thiol foods. I myself am making some adjustments now diet-wise, though I see no reason to kill my protein intake.

I do think I would do well to stop taurine (sad since it helped deal with high glutamate but probably re-routed sulfur down the sulfite / sulfate production path) and probably lower my ALA.as well.

2) Glutamates in food are generally only bad if they are free glutamates.There are lists out there that discuss foods low or high in free glutamates. Like did you know natural folates in plants are all packaged in poly-glutamates? Many on here are confused and think plant folates are folinic acid. That is incorrect. Folinic acid is a formyl derivative and a drug. But I won't waste more time on that, one battle at a time :)

There is a lot of recent stuff about free vs bound glutamates since at first alternative medicine doctors cut people off protein entirely. Some of us need protein or we simply do not replenish the body. I think Rich Vank was right in that these are people for whom some sort of deficit or block in the Krebs Cycle makes carbohydrate and unattractive option. The danger for you of high protein intake may be not the glutamates bound in the animal protein but the increased ammonia production.

Glutamates are excitatory but they are also necessary. The question is glutamate vs GABA balance. Zinc helps this balance. So does B6 / P5p (take it only in the morning, never at night). If depleted lithium orotate in small doses can help. Some find pyncogenol / grapeseed extract to be helpful. Manganese seems to increase glutamate in neurons in certain parts of the brain, but is also a necessary co-factor with biotin for glutamine synthetase which is a major mechanism to convert and shuttle glutamate out of the brain. Some push l-theanine, but I would be a bit leery there since that affects glutamate transport and eventually the body develops tolerance.

GABA is only useful if you have a leaky blood brain barrier. To test this take 500 mg of pharmaceutical grade GABA (only) in the middle of the day and see what happens. Do it a second day and see what happens. On day three take 2x500 mg. If the first two days you feel more calm or relaxed or even a bit tired, then you have a leaky BBB, otherwise the GABA will do virtually nada. If you have a leaky BBB then on Day 3 the 2x500 mg is going to probably kick you *bleep* and you will want to sleep or feel drowsy. If it doesn't then you probably have only limited problems with the BBB.

What might or might now work for you will depend on your mineral and vitamin status, your hormones and the state of your gut since the immune system mostly resides there.

You mention sleep issues, but do you have lots of pain or intense periods of mental over-focusing? Mood swings? Night sweats? Racing thoughts? Heart palpitations? There are multiple things that can hit sleep. The biggest enemy is usually norepinephrine. Next is high cortisol at night. Then probably glutamate-gaba imbalance. In others it is sugar metabolic issues. Others it is pain. Overmethylation can do it too. There are many ways to end up at a "wired, but tired" state.Even hyperthyroid will keep you up. The list can be very long. I have probably missed about a dozen other somewhat common causes. A lot it comes down to hormones or neurotransmitters. Of course that is true of many things.

3) ZInc increases inflammation.

So first question is what are you zinc levels in serum, urine and / or hair? If you are depleted then you need some. If not then your diet is fine.

If you have chronic inflammation, then zinc can be a problem if too large a dose taken.I have an autoimmune disease that I take corticosteroids for, so the high levels that are often pushed on these forums are not for me.

I won't even touch the copper balance (too controversial and complicated), except to say that Molybdenum will strengthen the zinc-copper ratio in favor of zinc.

That being said what most people do not know is their is a natural daily cycle to inflammation in the body. One of the major triggers to allow someone to sleep is to have some level of inflammation that peaks at night via immune system activity. This is why people who overdose on corticosteroids or people who have abnormally high cortisol at night cannot sleep. Their inflammation is too low and they cannot sleep. Melatonin is a serotonin-derived hormone that helps start the circadian signaling but it is just the start.

So actually for most people taking zinc in the late afternoon or evening is the best option.

Magnesium is an allosteric reversible inhibitor of NMDA glutamate receptor. The trick is that zinc also affects the NMDA receptors gating them and down-regulating their glutamate binding activation (whereas glycine is a co-agonist). So I don't know where you read that zinc increases glutamate. The problem is some people take much too high levels of zinc and though they down regulate NMDA glutamate receptors they will up regulate some other non-NMDA receptors that are also stimulating. Ergo high zinc supplementation can be a "double-edged sword". Though the 25 mg you are taking is not high so I don't think that is relevant for you.

The fact zinc makes you tired in the afternoon may mean it is increasing inflammation and maybe at a time when your cortisol is dipping (not uncommon for many chronic disorders) but at night it is not enough to overcome whatever else is taking place at a hormonal or neurotransmitter level.

4) There is a lot of disagreement about the role of glycine supplementation whether with Mg or free form and sleep and glutamate activity at the NMDA glutamate receptors

What is not in dispute is that glycine is a co-agonist of the NMDA glutamate receptors.

If you check out some other posts I made (I forget where atm) I noted that there is some recent studies that show that unless super-saturated the control of the occupancy of glycine at the relevant NMDA receptor sites is controlled and modulated by the neuronal firing pattern of neighboring neurons on the common dendritic branch. However, there are implications that if ambient glycine levels rise high enough they could override this control. At baseline, many receptor sites are not occupied by glycine.

That being said some people may not respond well to glycine as it also is involved in protein synthesis and (weakly) in ATP generation (side branch?). It is however, the #1 (or #2?) most abundant amino acid in the body. So if you take glycine whether as Mg glycinate or glycine powder while you will increase your intake, your body still makes 100's of grams a day. So there is a vast reservoir already.

In a typical 200 mg Mg glycinate pill there is about 1.3-1.5 grams of glycine though bio-availability may differ across manufacturers. Compare this to 100's of grams. This should not lead to super-saturation.

However, glycine is an inhibitory neurotransmitter and whereas GABA is the ruling inhibitory neurotransmitter in the brain, glycine holds court in the spine and related CNS components. So glycine tends to have a calming effect (at least at first) to many people. Couple that with Mg that blockades NMDA glutamate receptors and you have a useful tool potentially. Some people can't handle the spine inhibition. In my case my spine is trying to rip out of body due to my autoimmune disease if I do not use corticosteroids and glycine, etc. So people's mileage may differ.

Personally I take a large amount of free form glycine (~16 g) at bed and it knocks me out for min of four hours. I have some utility for 5htp and I take melatonin to start the process but make no mistake the glycine is the hammer to go to sleep. Evening zinc does not do much for me since I have low inflammation mediated by immune-suppressants that have long half lives, so my situation is not usual.

However, I would be willing to bet that the free form glycine at the amount I take is part of why I wake up often after the four hour mark. So on nights I am more tired anyways I am starting to see if I can reduce the amount. I will have to get back to you on that. I would love to replace the 5htp with tryptophan but the lower BH4 from my MTHFR a1298c SNP probably precludes this and will continue to do until I can further lower ammonia and maybe eventually supplement biopterin (which will also increase dopamine and norepinephrine --- another "double edged sword". So yeah it is complicated.

I also take 1000 mg of Mg glycinate a day. It is possible that is too much and it hampers spine strength and is a bit too inhibitory but ... I am usually less amped when I do that amount. I have tried Mg taurate but then my high taurine and potential CBS dysregulation factors in. Mg malate is an option but you can't get to 1000 mg that way. Mg citrate is an option but my upper GI tract does not like it. For many people Mg citrate will be rate limiting do to how it hits the bowels.

Whatever you decide, go for a significant Mg intake, up to a level your bowels can handle so your Mg:Ca intake is maybe 1:1 as about to the traditional 1:2 the FDA pushes. That is my advice at least. If Mg glycinate worked for you then screw the theory and use it based on your clinical personal experience.

Unless you are desperate I would not suggest high glycine free form at night. That might have opposite effects. It does for some people For me I am pretty sure it is inhibiting the sympathetic nervous system enough for me to sleep regardless of impact on the NMDA receptors. On days I take less glycine at night I may sleep longer, but I usually hurt more. Maybe that is just me.

One benefit of Mg glycinate + low dose glutamine (or not if glutamate in periphery is already high) is to make glutathione and drop cysteine levels. In 2010 my glutathione whole blood was one of the lowest Rich Vank had ever seen. This was after several months of hideous glutathione IVs that made me feel awful (maybe glutamate decomposition or raising cysteine levels). I followed his advice and jacked up vitamin C but I also amped Mg glycinate + glycine at bed time and added l-glutamine (originally for the gut) and added ATP support (creatine pyruvate and d-ribose) and BAM in less than one year my glutathione on the Genova test increased by 2.5 x near the top of the normal range. Meanwhile my glutamate levels normalized and my cysteine was low normal (i.e. the glutathione "drain") was back in business.

5) Valerian root and kava give me insomnia. Go figure. GABA works for me in that I have a very leaky blood brain barrier (how my antibodies got into my CNS likely in the first place) but I cannot control it and it can either be too little or way too much. Also GABA receptors are notorious for their alterations in sensitivity and so tolerance is a problem for many of the GABA mimetics.

If a large dose of GABA is not putting you out then either your BBB is intact or you have too much norepinephrine. I would not mix Valerian and kava or passion flower or any of the *bleep* together with GABA if it can get into the brain since they all affect the benzodiazapene receptors and a whole host of other (not a clean target profile though maybe not as bad as aspirin that lights up the proteome like a Christmas tree)

One possibility is to try niacin / niacinamide at bedtime (not before and with niacin not too much or the flush might get you). I have used this several times when I am overmethylated (a real threat given the MTHFR a1298c and COMT mutations I have). 250 mg or so of niacin can just crush the methylation and tip you over. The sleep might not be a bit odd, but at least you get some. I am not sure I would do that on a regular basis but whatever gets you by sometimes right? I am even considering using niacin low dose to help me reduce glycine to see if sleep improves and see what happens. Who knows how it will turn out :)

One possibility to consider is if you have high cortisol at night (24 hour saliva test), high ammonia in general, or high norepinephrine. Glutamate is always a suspect but don't lock in on blaming only one when others may be the real issue.

God bless and good luck!
 

freshveggies

Senior Member
Messages
196
Ok there is a lot to cover here. So warning long post incoming.

I am at work (finally over my daughter's cold) so I don't have access to all my bookmarks, papers, etc. so I won't be able to give you particular links right now. Also I am not an M.D. so take this with a grain of salt please.

1) Sulfates can be a big deal. Fortunately you are CBS heterozygote but you also have BHMT SNPs. Clearly your homocysteine is low and your SAH is high so there is something going on there that is transforming homocysteine rapidly so it has a short effect half life. I would certainly worry about sulfite processing and exposure to sulfites given how low your homocysteine is (i.e. what are your molybdenum levels?) My moly was just about low normal on a hair test, but still on the low side. I take 500 in the am.

Still your MTRRs and MTHFR mean you probably need methylation support but again they are all hetero so you are not the extreme methylation category that is often discussed on these forums. The issue with CBS / BHMT abnormalities is you can end up draining methyl donors down your trans-sulfuration path, which undercuts what you are trying to do

First there is one caveat, sulfates are not ONLY made down the trans-sulfuration pathway, they are also from the phenolsulfotransferase pathway. However, I am going to assume that is working ok, as often the problems there are with down-regulation and those people (usually kids) are really impacted. I am still learning about that set of pathways currently so I don't have much to comment there.

So I will now return to the trans-sulfuration pathway.

When I was accidentally overmethylating I was running 1600 all the time. When I stepped off the throttle some I was alternating between 600-800 but would some days spike to 1200-1400. Note I take measurements at roughly the same time of night since there are oscillations in excretion and you can't do a 24 hour test all the time.

So my first question was, why the spikes? This was important to me, since the nights I had lower urine excretion usually meant an easier time sleeping; not always but enough correlation to publish a social science paper (sorry inside physics humor).

At first I thought it might be related to the levels of ALA, biotin, molybdenum or even taurine that I would sometimes take. But nothing really correlated over a month of testing. Also my diet is a paleolithic diet with really high protein & fats (else I lose weight and given the catabolic nature of auto-immune disease), so the 200+ grams of protein wasn't the cause since how could I often be around 600? that is amazing that protein does not cause your sulfates to go up. They are high in sulfates, but low thiols. I think I could eat more than 25 grams of protein a day.

The answer seemed to be my diet, but my vegetables especially the ones I ate at dinner (there is a temporal lag after all). I tended to eat a lot of thiol-rich vegetables, like 4-5 servings a day of one of the following: broccoli, asparagus, spinach, green beans, peas, etc. The nights I ate 2-3 servings of those at dinner, I spiked. The nights I had 0-1 servings and substituted in say beets, avocado, or potato for the others, I dropped. Couple of nights I hit 400 with nothing else different than my vegetable choices.

This matched some of the reading I had done a la Andy Cutler that the problem foods are those high in thiols not those necessarily high in sulfur containing amino acids. The exception might be huge amounts of cysteine like in eggs, but I tend not to eat those foods (subconscious choices?) and what I do get from animal protein, I probably handle well since I take 800-1000 mg of Mg-glycinate per day (~6-7.5 grams of glycine) along with 3-4 grams of glutamine per day. This combo of glycine + glutamine (some of which converts into glutamate ~ 25% in the periphery) turns into glutathione if cysteine is present and as long as ATP is present (I take d-ribose, creatine pyruvate, b-vitamins, etc.)

So for foods you might want to search google for a list of high and low thiol foods. I myself am making some adjustments now diet-wise, though I see no reason to kill my protein intake.

I do think I would do well to stop taurine (sad since it helped deal with high glutamate but probably re-routed sulfur down the sulfite / sulfate production path) and probably lower my ALA.as well.

2) Glutamates in food are generally only bad if they are free glutamates.There are lists out there that discuss foods low or high in free glutamates. Like did you know natural folates in plants are all packaged in poly-glutamates? Many on here are confused and think plant folates are folinic acid. That is incorrect. Folinic acid is a formyl derivative and a drug. But I won't waste more time on that, one battle at a time :)

There is a lot of recent stuff about free vs bound glutamates since at first alternative medicine doctors cut people off protein entirely. Some of us need protein or we simply do not replenish the body. I think Rich Vank was right in that these are people for whom some sort of deficit or block in the Krebs Cycle makes carbohydrate and unattractive option. The danger for you of high protein intake may be not the glutamates bound in the animal protein but the increased ammonia production. Have you hear of taking buytrate for the ammonia? I am wondering if that would be better and yucca?

Glutamates are excitatory but they are also necessary. The question is glutamate vs GABA balance. Zinc helps this balance. So does B6 / P5p (take it only in the morning, never at night). If depleted lithium orotate in small doses can help. Some find pyncogenol / grapeseed extract to be helpful. Manganese seems to increase glutamate in neurons in certain parts of the brain, but is also a necessary co-factor with biotin for glutamine synthetase which is a major mechanism to convert and shuttle glutamate out of the brain. Some push l-theanine, but I would be a bit leery there since that affects glutamate transport and eventually the body develops tolerance.

GABA is only useful if you have a leaky blood brain barrier. To test this take 500 mg of pharmaceutical grade GABA (only) in the middle of the day and see what happens. Do it a second day and see what happens. On day three take 2x500 mg. If the first two days you feel more calm or relaxed or even a bit tired, then you have a leaky BBB, otherwise the GABA will do virtually nada. If you have a leaky BBB then on Day 3 the 2x500 mg is going to probably kick you *bleep* and you will want to sleep or feel drowsy. If it doesn't then you probably have only limited problems with the BBB. I took one gaba last night at 7:30, another at 9:30 and one at 4:00. Still not making me sleep a lot, but I might get a little drowsy. Bad night of sleep.

What might or might now work for you will depend on your mineral and vitamin status, your hormones and the state of your gut since the immune system mostly resides there.

You mention sleep issues, but do you have lots of pain or intense periods of mental over-focusing? Mood swings? Night sweats? Racing thoughts? Heart palpitations? There are multiple things that can hit sleep. The biggest enemy is usually norepinephrine. Next is high cortisol at night. Then probably glutamate-gaba imbalance. In others it is sugar metabolic issues. Others it is pain. Overmethylation can do it too. There are many ways to end up at a "wired, but tired" state.Even hyperthyroid will keep you up. The list can be very long. I have probably missed about a dozen other somewhat common causes. A lot it comes down to hormones or neurotransmitters. Of course that is true of many things. Not too much pain involved, but I do get problems with my shoulders and jaw. No mood swings or racing thought. I sometimes get night sweats and my heart beats faster. I thought it might be estrogen, but then I am not sure about that. I don't feel that wired anymore, It just feels like my brain doesn't know how to sleep.

3) ZInc increases inflammation.

So first question is what are you zinc levels in serum, urine and / or hair? If you are depleted then you need some. If not then your diet is fine. My zinc levels on the hair test were in the normal level.

If you have chronic inflammation, then zinc can be a problem if too large a dose taken.I have an autoimmune disease that I take corticosteroids for, so the high levels that are often pushed on these forums are not for me.

I won't even touch the copper balance (too controversial and complicated), except to say that Molybdenum will strengthen the zinc-copper ratio in favor of zinc.

That being said what most people do not know is their is a natural daily cycle to inflammation in the body. One of the major triggers to allow someone to sleep is to have some level of inflammation that peaks at night via immune system activity. This is why people who overdose on corticosteroids or people who have abnormally high cortisol at night cannot sleep. Their inflammation is too low and they cannot sleep. Melatonin is a serotonin-derived hormone that helps start the circadian signaling but it is just the start.

So actually for most people taking zinc in the late afternoon or evening is the best option.

Magnesium is an allosteric reversible inhibitor of NMDA glutamate receptor. The trick is that zinc also affects the NMDA receptors gating them and down-regulating their glutamate binding activation (whereas glycine is a co-agonist). So I don't know where you read that zinc increases glutamate. The problem is some people take much too high levels of zinc and though they down regulate NMDA glutamate receptors they will up regulate some other non-NMDA receptors that are also stimulating. Ergo high zinc supplementation can be a "double-edged sword". Though the 25 mg you are taking is not high so I don't think that is relevant for you.

The fact zinc makes you tired in the afternoon may mean it is increasing inflammation and maybe at a time when your cortisol is dipping (not uncommon for many chronic disorders) but at night it is not enough to overcome whatever else is taking place at a hormonal or neurotransmitter level.

4) There is a lot of disagreement about the role of glycine supplementation whether with Mg or free form and sleep and glutamate activity at the NMDA glutamate receptors

What is not in dispute is that glycine is a co-agonist of the NMDA glutamate receptors.

If you check out some other posts I made (I forget where atm) I noted that there is some recent studies that show that unless super-saturated the control of the occupancy of glycine at the relevant NMDA receptor sites is controlled and modulated by the neuronal firing pattern of neighboring neurons on the common dendritic branch. However, there are implications that if ambient glycine levels rise high enough they could override this control. At baseline, many receptor sites are not occupied by glycine.

That being said some people may not respond well to glycine as it also is involved in protein synthesis and (weakly) in ATP generation (side branch?). It is however, the #1 (or #2?) most abundant amino acid in the body. So if you take glycine whether as Mg glycinate or glycine powder while you will increase your intake, your body still makes 100's of grams a day. So there is a vast reservoir already.

In a typical 200 mg Mg glycinate pill there is about 1.3-1.5 grams of glycine though bio-availability may differ across manufacturers. Compare this to 100's of grams. This should not lead to super-saturation.

However, glycine is an inhibitory neurotransmitter and whereas GABA is the ruling inhibitory neurotransmitter in the brain, glycine holds court in the spine and related CNS components. So glycine tends to have a calming effect (at least at first) to many people. Couple that with Mg that blockades NMDA glutamate receptors and you have a useful tool potentially. Some people can't handle the spine inhibition. In my case my spine is trying to rip out of body due to my autoimmune disease if I do not use corticosteroids and glycine, etc. So people's mileage may differ.

Personally I take a large amount of free form glycine (~16 g) at bed and it knocks me out for min of four hours. I have some utility for 5htp and I take melatonin to start the process but make no mistake the glycine is the hammer to go to sleep. Evening zinc does not do much for me since I have low inflammation mediated by immune-suppressants that have long half lives, so my situation is not usual.

However, I would be willing to bet that the free form glycine at the amount I take is part of why I wake up often after the four hour mark. So on nights I am more tired anyways I am starting to see if I can reduce the amount. I will have to get back to you on that. I would love to replace the 5htp with tryptophan but the lower BH4 from my MTHFR a1298c SNP probably precludes this and will continue to do until I can further lower ammonia and maybe eventually supplement biopterin (which will also increase dopamine and norepinephrine --- another "double edged sword". So yeah it is complicated.

I also take 1000 mg of Mg glycinate a day. It is possible that is too much and it hampers spine strength and is a bit too inhibitory but ... I am usually less amped when I do that amount. I have tried Mg taurate but then my high taurine and potential CBS dysregulation factors in. Mg malate is an option but you can't get to 1000 mg that way. Mg citrate is an option but my upper GI tract does not like it. For many people Mg citrate will be rate limiting do to how it hits the bowels.

Whatever you decide, go for a significant Mg intake, up to a level your bowels can handle so your Mg:Ca intake is maybe 1:1 as about to the traditional 1:2 the FDA pushes. That is my advice at least. If Mg glycinate worked for you then screw the theory and use it based on your clinical personal experience. I think I do need to add this

Unless you are desperate I would not suggest high glycine free form at night. That might have opposite effects. It does for some people For me I am pretty sure it is inhibiting the sympathetic nervous system enough for me to sleep regardless of impact on the NMDA receptors. On days I take less glycine at night I may sleep longer, but I usually hurt more. Maybe that is just me.

One benefit of Mg glycinate + low dose glutamine (or not if glutamate in periphery is already high) is to make glutathione and drop cysteine levels. In 2010 my glutathione whole blood was one of the lowest Rich Vank had ever seen. This was after several months of hideous glutathione IVs that made me feel awful (maybe glutamate decomposition or raising cysteine levels). I followed his advice and jacked up vitamin C but I also amped Mg glycinate + glycine at bed time and added l-glutamine (originally for the gut) and added ATP support (creatine pyruvate and d-ribose) and BAM in less than one year my glutathione on the Genova test increased by 2.5 x near the top of the normal range. Meanwhile my glutamate levels normalized and my cysteine was low normal (i.e. the glutathione "drain") was back in business.

5) Valerian root and kava give me insomnia. Go figure. GABA works for me in that I have a very leaky blood brain barrier (how my antibodies got into my CNS likely in the first place) but I cannot control it and it can either be too little or way too much. Also GABA receptors are notorious for their alterations in sensitivity and so tolerance is a problem for many of the GABA mimetics. what h

If a large dose of GABA is not putting you out then either your BBB is intact or you have too much norepinephrine. I would not mix Valerian and kava or passion flower or any of the *bleep* together with GABA if it can get into the brain since they all affect the benzodiazapene receptors and a whole host of other (not a clean target profile though maybe not as bad as aspirin that lights up the proteome like a Christmas tree)

One possibility is to try niacin / niacinamide at bedtime (not before and with niacin not too much or the flush might get you). I have used this several times when I am overmethylated (a real threat given the MTHFR a1298c and COMT mutations I have). 250 mg or so of niacin can just crush the methylation and tip you over. The sleep might not be a bit odd, but at least you get some. I am not sure I would do that on a regular basis but whatever gets you by sometimes right? I am even considering using niacin low dose to help me reduce glycine to see if sleep improves and see what happens. Who knows how it will turn out :)

One possibility to consider is if you have high cortisol at night (24 hour saliva test), high ammonia in general, or high norepinephrine. Glutamate is always a suspect but don't lock in on blaming only one when others may be the real issue.

God bless and good luck!
 

freshveggies

Senior Member
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196
I am having problems posting to that post so I will say it here. What happens if you take too much gaba at night? Do you think it just makes for a bad mix and no sleep when I try gaba, valerian and kava together? Would I be better doing mg glyciinate and something else like gaba with that or kava?

Norepinepherine was low on a NT test that I did at 5:00 am. Cortisol not that bad. Not sure about ammonia. I am going to do a UAA test as soon as I get get an am urine. IF i am up at night, then I tend to go to the bathroom.

I was not sleeping before I stated to do the methylation stuff so I think my brain is deprived of nutrients or proper signalling. I am low in iodine. I am having a hard time adding things in and to know if they are helping me because a lot of this affects sleep, but now I am not sleeping worth a darn.

Thank you for your nice post.
 

dbkita

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freshveggies:

My moly was just about low normal on a hair test, but still on the low side. I take 500 in the am.

Fair enough but you might be better off splitting the Mo up during the day. Seems to work better for me.

that is amazing that protein does not cause your sulfates to go up. They are high in sulfates, but low thiols. I think I could eat more than 25 grams of protein a day.

The point here is that thiols are considered more heavy hitting on the trans-sulfuration pathway. I am personally waiting for my 23andme results to verify. I have read elsewhere (can't remember where) that high protein should lead to waves or urine sulfate excretion even with no CBS defect. However, I drink a lot of water, like 100 oz a day beyond some juice, etc. And your body can actually make use of sulfates for various purposes, so it isn't all excreted right away anyways. That being said I need to see a 24 hour urine sulfate test first. I am just finding from personal testing that the thiol rich foods affect my urine sulfates reading much more than my protein intake. I also wonder if this is why 600 mg of ALA would almost knock me out. Weird, eh?

Have you hear of taking buytrate for the ammonia? I am wondering if that would be better and yucca?
Yes and based on recent tests I am about to embark on that odyssey soon. My only issue is high levels of sodium butyrate can affect glucose levels by improving insulin sensitivity. But I have more issues keeping my glucose up than down. Not to mention I am not a big fan of taking sodium at night. We'll see.

I took one gaba last night at 7:30, another at 9:30 and one at 4:00. Still not making me sleep a lot, but I might get a little drowsy. Bad night of sleep.
Imho if three doses are at most making you a little drowsy you are not getting much by the BBB or you have really low sensitivity at your GABA receptors.

Not too much pain involved, but I do get problems with my shoulders and jaw. No mood swings or racing thought. I sometimes get night sweats and my heart beats faster. I thought it might be estrogen, but then I am not sure about that. I don't feel that wired anymore, It just feels like my brain doesn't know how to sleep.

Hmm don't have an easy answer there. I think you said you use melatonin. That makes me think something with serotonin maybe. Have you tried tryptophan at bed time? Or even 5-htp? I will have to mull this over a bit.
You might still be served with say 25 mg of zinc in the evening. There is a spectrum of what is 'normal' for a person.

And yeah bump the magnesium. Low Mg / Ca ratio can wreak havoc.
 

dbkita

Senior Member
Messages
655
I am having problems posting to that post so I will say it here. What happens if you take too much gaba at night? Do you think it just makes for a bad mix and no sleep when I try gaba, valerian and kava together? Would I be better doing mg glyciinate and something else like gaba with that or kava?

Norepinepherine was low on a NT test that I did at 5:00 am. Cortisol not that bad. Not sure about ammonia. I am going to do a UAA test as soon as I get get an am urine. IF i am up at night, then I tend to go to the bathroom.

I was not sleeping before I stated to do the methylation stuff so I think my brain is deprived of nutrients or proper signalling. I am low in iodine. I am having a hard time adding things in and to know if they are helping me because a lot of this affects sleep, but now I am not sleeping worth a darn.

Thank you for your nice post.

If I take too much GABA at night I feel drugged and can't function and it lasts for a long time and I get majorly depressed. My BBB is very leaky and my GABA receptors are very sensitive.

I think valerian and kava and GABA not giving you sleep == you are on the wrong path sorry. I would stick with some melatonin, some Mg glycinate, not take too much calcium (have to be careful since you may have needs for other reasons), and try some gaba and maybe if that doesn't work some tryptophan or 5htp. Also up Mg in general.

If that is not an option or doesn't work then try some niacin. If that works you are over-methylated. Don't underestimate the power of niacin at bed time. Not sure niacinamide but it should work also to quench methyl donors.

But you said you have had sleeping problems before methylation so you will have to experiment.

There are far more hormones than estrogen. What was your 24 hour cortisol profile? Have you tried a 24 hour melatonin profile?

Norepinephrine testing is basically useless unless they go into the CNS space which I don't think you want to do. It is next to meaningless, sorry. But if you aren't wired or pulse is not pounding that is not your main issue I would wager.

Beyond that it becomes so complex you need to find the right physician sorry. Too many variables as you pointed out.
 

freshveggies

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196
dbkita, thanks for the reply. I tried 2 mag glycinate last night and it went ok. Not sure if I should try anymore, but I think I used to take 3 at bedtime.
5htp will keep me up all night(probably because I am MAO A), not sure about tryptophan. I have not tried it yet. Zinc will keep me awake the whole night if I take it ab bed. I just am not good taking much at night or even dinner.

It has been a couple of years since I have taken a 24 hour hormone urine test. Where do you get yours.

I did a saliva test for neurtransmitters, but did it at 5:00 am. Was not happy that the test didn't offer 2 samples. One at bed time and then one when you wake early. NeuroScience was the one I used.

I might have to try breaking moly up. I think I could possible use more as I was not very high on it.

I have low DHEA and that can cause sleep issues. I just have a hard time staking it. It can be stimulating for me. And can cause nose bleeds for me. Found out it is some enzyme deficiency per Yasko book. I need to look into that more. Said something about taking NADH and d-ribose.

I took 50mcg's of lithium yesterday to help with glutamate balance and I am on the low side for hair test. It went ok so I am taking it today too.

I was going to take the butyrate in the am as I can't take stuff in the pm---sleep interference.
 

adreno

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dbkitaI took 50mcg's of lithium yesterday to help with glutamate balance and I am on the low side for hair test. It went ok so I am taking it today too.

50mcg? That's basically nothing. You likely get much more than that from food and water. I have seen an estimated RDA of lithium of around 1mg.
 

adreno

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My sleep stack includes:

0.3 mg melatonin (time released)
200 mg magnesium glycinate
200 mg pharmaGABA
15 mg zinc
1 banana
6 g hydrolyzed collagen I&III powder (high in glycine)


This combination almost never fails to make me sleep, and I usually sleep the entire night. Another important thing is electrolytes. If unbalanced, or low in electrolytes, I have tachycardia and racing thoughts and can't sleep. Last night I had this problem. A glass of water with 1/4 teaspoon sea salt and 1/4 potassium citrate put my lights out.
 

freshveggies

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Thanks Adreno. I just added the mg glycinate. Zinc keeps me awake. I would like to look into glycine powder. What brand do you take?
If mg glycinate helps me with sleep, does that mean that glycine will help too?

I do 1000 mg potassium 2 x a day and 1/2 tsp salt 2 x a day. I don't do well taking much of anything past 2:00, but I am looking for things to help sleep.

Yes lithium is low, but I need to go low and slow. My body screams when i add in too high of a dose of anything.

Do you have CBS?
 

adreno

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4,841
Thanks Adreno. I just added the mg glycinate. Zinc keeps me awake. I would like to look into glycine powder. What brand do you take?
If mg glycinate helps me with sleep, does that mean that glycine will help too?

I do 1000 mg potassium 2 x a day and 1/2 tsp salt 2 x a day. I don't do well taking much of anything past 2:00, but I am looking for things to help sleep.

Yes lithium is low, but I need to go low and slow. My body screams when i add in too high of a dose of anything.

Do you have CBS?
Yeah, I have CBS (hetero). The weird thing is when I increase methylation I crave meat like a madman. I am not sure sulfur is a problem or not, I should probably do some testing for that. I take both NAC and R-ALA and P5P. Taurine doesn't make me feel bad, but sometimes spacey or dissociated. On the other hand, MSM is terrible (severe headache, nausea aso).

I do not use free form glycine, but collagen powder (neocell). The free form seems too strong for me. I am one of those persons dbkita mentioned that don't like too much spinal inhibition. I do not like it during the daytime, but I am also sure I couldn't sleep without it. I agree with dbkita that it's the "hammer" for sleep, lol.
 

freshveggies

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Messages
196
Just wondering. I went low protein and then now am rethinking it as their isn't much to eat and we should be able to follow the low thiol foods and meat is on there. I noticed you take turmeric and that raises thiols. Not sure if that would be a problem for you. I will look up that collagen powder. That would be awsesome to be hammered to sleep. I am so needing that.

I looked at the collagen powder and their are so many amino acids? in it. Have you heard of it working for others. I am always afraid of trying something new?
 

adreno

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4,841
dbkita

So inflammation makes you sleepy? This means I shouldn't take any anti-inflammatories (turmeric etc) at night? Could this also why coffee sometimes makes me sleepy? It also happens the few times I've tried methylphenidate. The last time I tried it, just 5mg made me so sleepy I had to go straight to bed. LOL! It's a stimulant drug!

I really should stop the coffee also, I am madly addicted to it (about 2 cups per day). It's terrible for my SNS.
 

adreno

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4,841
Just wondering. I went low protein and then now am rethinking it as their isn't much to eat and we should be able to follow the low thiol foods and meat is on there. I noticed you take turmeric and that raises thiols. Not sure if that would be a problem for you. I will look up that collagen powder. That would be awsesome to be hammered to sleep. I am so needing that.

I looked at the collagen powder and their are so many amino acids? in it. Have you heard of it working for others. I am always afraid of trying something new?
You really need more protein than 25g. That's basically what a 4-year old needs. You are female, right? The recommended minimum for adult females is 46 grams. I probably eat 100-150 grams.

http://www.cdc.gov/nutrition/everyone/basics/protein.html