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@dbkita may i ask you what youre mutations are? A1298c homo or hetro? And cbs homo or hetro?
I also want to start with l glutamine but i am
Cbs homo and get neuropathy from sulfur/thiols.. Meat is also not a problem but also veggies...
Hoe much glutamine can i take you think? And do i really need to take it witch glycine? Or can it also without?
Thanks for your info
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!
@dbkita may i ask you what youre mutations are? A1298c homo or hetro? And cbs homo or hetro?
I also want to start with l glutamine but i am
Cbs homo and get neuropathy from sulfur/thiols.. Meat is also not a problem but also veggies...
Hoe much glutamine can i take you think? And do i really need to take it witch glycine? Or can it also without?
Thanks for your info
