Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by joe davison, Dec 19, 2012.
I'm currently only taking b12 but I will be getting some methylfolate soon.
You might start slow on the methylfolate. I tried it recently after having hit my head in a fall.
Just taking one as soon as I woke had a bad effect on my sleep. However, many supplements have that effect on me.
This is the brand I took. I might try it again sometime, but just 1/2 a capsule.
B12 and insomnia
Joe -- exactly two years ago, I had similar issues, perhaps even worse, documented on this board. My doc didn't really know what she was doing, and prescribed, or overprescribed an assortment of methylation supplements, including a couple different forms of b12, and several different types of folate.
Within a few weeks, my anxiety went sky-high, I was agitated, couldn't sleep, was exhausted, yet couldn't sit still -- I thought for sure I wouldn't make it. I backed off on the supps, and eventually stopped them for a few months. Later on in 2011, I tried various combinations of methyl-b12 (this time injections) and some occasional methylfolate. Anxiety, restlessness, extreme fatigue was 'better' at times, but not consistently. I eventually stopped the b12 shots, and switched over to hydroxoycobalmin sublinguals, which seemed to help a bit.
Cut to about 3 months ago. I started taking TMG (trimethylglycine) and folinic acid (which is another form of folate that's a precursor to methylfolate), and my anxiety/restlessness/agitation decreased significantly, and my sleep got better as well. In the last month or so I've increased my vitamin D to 5,000ius -- taken in the morning -- and my sleep has improved even more.
(Vitamin D -- or sunshine -- in the morning is said to help increase melatonin production at night).
I take some methyl-b12 every other day or so, and some methylfolate -- both small amounts, but for me, perhaps my genetics(?), the TMG (which is a methyl donor) and the folinic acid, were the best choices, methylation-wise.
Not sure if it would help you, but just throwin' it out there.
Interesting, Dan. Glad you feel better.
The SLEEP part of the equation sounds good to me. I already take 3000 ius of D, but have never tried folinic acid. What brand do you take and how much? And how did you figure this out? Did you do the 23 and ME test? Or was it just all the trial and error?
BTW...Here's what Ray Sahelian has to say about TMG:
"Trimethylglycine supplement by Ray Sahelian, M.D. Trimethylglycine health benefit and dosage
Trimethylglycine TMG (also known as betaine), and dimethylglycine DMG, are methyl donors that help in the production of several brain chemicals and hence improve mood, energy, wellbeing, alertness, concentration, and visual clarity.
Unless your major is college was chemistry, chances are you don’t remember learning about methyl donors. But if you find the field of mind boosting interesting, you will certainly want to learn more about these supplements. A methyl donor is simply any substance that can transfer a methyl group [a carbon atom attached to three hydrogen atoms (CH3)] to another substance. Many important biochemical processes rely on methylation, including the metabolism of lipids and DNA. Scientists suspect that adequate methylation of DNA can prevent the expression of harmful genes, such as cancer genes. It’s quite likely that our body’s ability to methylate declines with age, potentially contributing to the aging process, and therefore supplementation is an interesting idea in terms of health benefits."
Thanks, I just ordered some TMG and metafolin so I will see how I make out with that and I will also look into folinic acid. I've actually come along way from where I was six months ago. I was depressed and suffering from panic attacks which I've never experienced before. Not to mention the VERY uncomfortable feeling once I started taking large amounts of b12, very on edge and anxious. I don't experience any of those symptoms anymore just insomnia.
Your friend in Canada,
I had the yasko testing a year or so ago...I had/have about 12 different polymorphisms, which came a long with a LONG list of supplements, etc., that were suggested for treatment. Couldn't afford that, nor did I want to add another 20 or so supps to my already overstuffed cupboard.
I couldn't figure it out, although I was fortunate to get an analysis of the genetics done by an RN for no charge. Still, since there is considerably controversy regarding the so-called "CBS upregulation" (and it's connection to the transsulfuration pathway), where one is supposed to limit sulfur foods, proteins, and sulfur-based supplements, it was a challenge trying to figure it out. It wasn't until Anne Likes Red talked about how even though she had the CBS issue, she found that sulfur wasn't a problem in the long run (I think she needed molybdenum to help deal with it?).
Also I re-read the study by Jill James where kids with autism improved -- their glutathione levels, etc., normalized -- using TMG and folinic -- plus their CBS issues were also 'decreased' -- without any mention of sulfur issues. The other thing found in these patients were high levels of s-adenosylhomocysteine (SAH), which I also had on my methylation panel...no one seemed to know how to lower that. I almost by accident found a mention of TMG being the only compound that lowers 'SAH' on Dr. Ben Lynch's MTHFR blog...which reminded me of the James study, which confirmed that it worked. Quoting:
"...the intervention with betaine and folinic acid was successful in bringing all the metabolites within the methionine cycle into the normal range and simultaneously improving significantly the metabolites in the transsulfuration pathway."
So I'm guessing that I needed the TMG for the methyl donors (to help lower the SAH), and the folinic perhaps was tolerated better because it requires a step (or 2?) before it's converted to methylfolate.
Methyl-b12 was added 2 or 3 months into the study, and that helped too, but improvements were seen before that, which suggests perhaps that (at least in this study) some may not need b12, and/or the order of supplementation may have helped with tolerating the methylb12.
Here's the study:
Re: Vitamin D: I was taking 1000-2000ius off and on until I read this study:
...which concluded that "Healthy men seem to use 3000-5000 IU cholecalciferol/d, apparently meeting > 80% of their winter cholecalciferol need with cutaneously synthesized accumulations from solar sources during the preceding summer months. Current recommended vitamin D inputs are inadequate to maintain serum 25-hydroxycholecalciferol concentration in the absence of substantial cutaneous production of vitamin D."
Thanks Dan. I am going to investigate this further.
I just sent in my 23&ME test and should have the results in a couple weeks. Then I can figure what to do.
TMG can be very useful for people who have CBS and / or BHMT polymorphisms. It isn't that it is a methyl donor so much as the BHMT is a shunt pathway that directly converts homocysteine to methioine WITHOUT going through MTHFR at all. At the same time it deprives homocysteine from draining down the trans-sulfuration pathway.
But ... there is always a but ... for others TMG can slow down the flow around the full mehtylation cycle (hard to quantifiy, will vary from person to person based on genetics and other factors). Also BHMT stimulation preferentially boosts norepinephrine over dopamine. I don't think anyone knows why, but analysis of the breakdown metabolites (HMVA, VMA, etc) confirm this. For some this might be great. For those of us with inflammatory conditions that is not so good maybe.
Those are really large doses in the first paper. I am wary about studies that are based on treatments for autistic children. Clearly they exhibit some extreme neurochemistry but I am not sure the majority of us have anything like that going on.
I took 800 mcg folapro, 800 mcg folinic acid, 25 mg P5p sublingual, 2500-5000 mcg sublingual methyl b12, 600mg TMG for almost two years. It helped certain things but when I upped my P5p to 50-75 mg, increased my riboflavin, and ran with 5000 mcg of mb12 every day things got much worse (i.e. pain, insomnia, irritability, etc.)
What really convinced me is the days that I would take the folinic acid and methylfolate AWAY from vitamin C or the days I took less niacinamide. Those days were hellish. Those turn out to be clear signs of over-methylation. All that time taking 250-500 mg of b3 niacinamide and 2 grams of vitamin C 4x/day were saving me somewhat from overdrive. But when I upped some of the critical cofactors even that could not hold true anymore.
Btw thanks for the link on vitamin D. That really puts things in perspective especially depending on a person's COMT and VDR polymorphisms. Looks like I need to increase a bit. I suspect that means if you need to boost your 25, hydroxy-D storage form then you need to be at or above that 3-5K IUs per day especially in the winter to make it build. For some of us that can directly affect dopamine production.
Personally I take 2500 mcg sublinugal every day and no other source. In 2009, when first tested my B12 serum was dirt low. I have only used mb12 and more recently adb12 to supplement and for the last almost 3 years my B12 is either off the charts high (beyond detection limit) when I took 5K per day or now on 2500 at the upper end of the normal range. Yes I know the serum tests show all forms of B12 but I never supplement with the inactive forms (I don't even take a b-vitamin to avoid folic acid and cyano-cobalimin, and take everything I want separately).
But then again I can get by with 400 mcg of folapro now, no TMG and no folinic acid since my genotype has no MTHFR defect except A1298c. Go figure all those years I assumed otherwise. Oy ve!
Excellent points DbKita -- thanks for your insights and further explanation re TMG's association with the BHMT pathway.
Great example(s) of why what may work for one person, may not work, or even be harmful for someone else. I obviously need more methyl donors (always did better in the past when I was taking SAMe for example), but cannot tolerate any niacin or niacinamide, apparently because it 'mops up' methyl donors (and I guess vitamin C -- more than 500mgs/day interferes with methylb12). Perhaps I'll be able to tolerate niacin/amide (and also b6/p5p) in the future when methylation is working better.
Good luck witih your 23&me testing DB -- hope you can get some help deciphering it all. It's all so complex.
To my knowledge vitamin C only interferes with absorption / uptake of methylfolate in the gut. So if you wait say 30-60 mins after taking methyfolate before you take the vitamin C, it should not affect your methylation status much. But if you take them in an overlapping fashion then less methylfolate will be taken up by the body. I think the same holds for folinic acid.
Niacin / niacinamide (the latter directly, the former after conversion) quenches methyl donors, and specifically SAMe.
My understanding is that niacinamide is converted to 1-methylnictonamide via Nictonamide N-methyltranferase with the reactions S-adenosyl-L-methionine + nicotinamide = S-adenosyl-L-homocysteine + 1-methylnicotinamide.
I take 500 mg of niacinamide a day for energy + other reactions. For a long time before that I took 250 mg. On days I tried 250 and then later 250 I always felt worse (as if I only took 250). My suspicion is I was unintentionally throttling methylation but this is back when my methylation was much, much more on over-drive.
I am still trying to find the precise balance. 400 mcg folapro with no vitamin C gives me good energy, but a bit too much overstimulation (12.5-25 mg sublingual P5p, no TMG, 500 mg niacinamide, 2500 mcg mb12, 2.5 mg adb12 in two dose daily, no folinic acid, 100 mg riboflavin (none r5p)). Usually the overstimulation becomes a problem after 3 days continuous. Also my urine sulfates go up quite a bit. But ... if I take the exact same set up but purt the 400 mcg folapro with 2 g vitamin C, it reverses, energy declines (mental and physical) but stimulaton drops and sleep improves and pain gets much less (again after 2-3 days) and urine sulfates drop.
So who knows what is the precise balance. Maybe less B3, maybe more folapro with vitamin C or probably better would be less folapro without vitamin C. It is tricky since I am COMT+/-, VDR -/- and MTHFR A1298c +/-. What I really need to learn is about my BHMT and CBS mutations to complete the loop.
Lastly I think a lot of people underestimate the importance of ribolflavin-5-phosphate as a regulator of production of L-5MTHF. Everyone focuses on P5p but R5p is the gatekeeper from the methylene intermediate to methylfolate.
When I was on 50 mg riboflavin and 50 mg r5p-sodium, I got ripped apart without realizing why. Now I know.
If you find yourself very intolerant of P5p even at smaller doses I would think the CBS pathway is a problem as it drains your homocysteine into the trans-sulfuration pathway. Unfortunately treating CBS is indirect at best and quite a mess from what I understand. On the other hand TMG may be critical to you to bleed that homocysteine off into the BHMT shunt to spare your sulfites and sulfates.
Good luck to you too. (Yes, CBS is an issue for me...that's what drew me to that study I posted earlier, with TMG and folinic.)
Just curious ... how much TMG, P5p, folinic acid, and L5mthf do you take?
I take basically what they used in the Jill James study (re the TMG and folinic). Methylfolate...usually around 400mcgs a day, split in two, and no P5P currently. Will try in a couple of weeks to add a low dose b-complex...and see what happens.
Here's the doses used in the study:
I take it they must mean 1000 mg for TMG? Otherwise they would take only 1 mg twice daily.
I don't know about autistic children but a TMG intake of 2x 1000 mg is nothing to sneeze at ... that will make a fair amount for norepinephrine relative to dopamine. The level of inflammation that it in itself would generate in someone like me with an autoimmune disease would not be a happy thought. On the other hand it may be needed for those with the homozygote SNPs on the CBS gene who otherwise are not burdened by high inflammation.
Hi dbkita--SO I gave it a go with the TMG--750 mg/day for just 2 days. IT made me feel so much more mentally clear, helped my mood, and my energy. The first night it seemed like my sleep was a little better, but last night I felt a bit revved up. I was hoping it would be beneficial for my sleep, but it doesn't look like it's a good option, at least not for now.
I will have to wait to see my 23&ME results in 2 weeks. Darn. Until then my brain will be its usual wired tired self.
Why not just try a lower dose, say 250mg? 750mg is quite a lot. Are you taking other methyl donors?
adreno--Maybe I could do that in a few days. Right now I think its best to not take any at all.
Like Adreno said 750 mg is quite a bit of TMG. Again the posted study involved autistic children. I myself found 500 mg to be stimulating but that was on top of a lot of other methylation supplements. What other relevant methyl donors are you taking?
That being said while TMG may be a useful part of your protocol going forward, dependent on your SNP profile, it by itself seems unlikely to help you actually sleep unless you are CBS homozygote. It might improve your moods to handle limited sleep better (it does for me) but it will also increase norepinephrine levels. Some people need more norepinephrine (i.e. depression disorders) but TMG increases it at the cost of less relative dopamine which is a mixed blessing at best.
Note with methylation effects they can tend to pile up over several days until they saturate. For me the typical time frame is about 3-4 days to reach the full effect of whatever change I make when it comes to methylfolate, P5p, etc. In other words I might make an increase, feel more energy and more inspired but by the 3rd day I am more stimulated, have more pain and sleep poorer. If I decrease, the first day may calm my nervous system a bit, but by the 3rd or 4th day I am dragging myself around the house and have a poor mood.
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