SAMe vs TMG

[arx]

Hi,

I would like to know how these two are different in mechanisms. I have also read that since SAMe is expensive, TMG can be substituted for it. Any truth in this?

 

[triffid113]

Well...I use TMG 2G/day. I would not use SAMe. SAMe scares me because it is one step from homocysteine, a neurotoxin. I feel that if my body is repleted with the vitamins to make its own SAMe then it is more likely to be replete enough to cart away the homocysteine. Whereas if you cannot get your methylation working due to not supplementing correctly then you supply SAMe, you might not be able to drain it away. Now Rich, as quoted by Freddd, said you can use it to jump start your cycle, and it may be true. But that's just a jump, not a steady supply of something you may not be able to clear. TMG, on the other hand, clears homocysteine, so I feel it is safe. At any rate, TMG is required to prevent post meal surges in homocysteine, the neurotoxin. You want to be able to clear it away asap and you need TMG to do that. mB12+mfolate is the slow path.

 

[arx]

In order to drain the homocysteine produced from taking SAMe, it would be correct to supplement B6,Folate and B12 along with the SAMe,right?

So TMG is performing the opposite task as SAMe. SAMe is producing homocysteine whereas TMG is clearing it away. Then why at many places it is said that TMG is a good alternative to SAMe. Considering a methylation cycle such as here: http://babyfoodsteps.files.wordpress.com/2012/05/methylation-cycle.jpg

It can be seen that SAMe when taken directly will convert to homocysteine. TMG when taken directly will help in converting homocysteine to methionine, thereby fulfilling the two purposes: production of methionine(which SAMe also tends to do), and clearing up of homocysteine.

Please tell if my understanding is correct and share your views.
Thanks.

 

[Lotus97]

I thought TMG and Methione contribute to the synthesis of SAMe. Is this different if SAMe is created naturally than taking as a supplement?

 

[Lotus97]

I found a post by Rich about TMG and Betaine HCL which functions the same as TMG. He also mentions DMG which I don't know too much about, but have considered starting. I suppose there are other threads about DMG and I don't want to take it off topic, but if someone could make a quick comment about DMG I would like to know more.

Betaine and TMG are the same substance. Betaine HCl has a hydrochloric acid molecule bound to it. Yes, if you take betaine HCl, you will also have the benefit of TMG. However, note that TMG stimulates the alternative BHMT pathway from homocysteine to methionine in the liver and kidneys. TMG will promote production of SAMe, but it can shunt flow away from the methionine synthase enzyme, which is partially blocked in ME/CFS. It's important to get this enzyme going, because it is linked to the folate metabolism, which is needed to make new DNA and RNA, and also because it regulates the entire sulfur metabolism. In Amy Yasko's protocol, she recommends starting with some TMG, and then after the B12 and folate have been built up some, to add DMG, which will inhibit the BHMT reaction by product inhibition, and that will push more of the homocysteine through the methionine synthase reaction. The benefit of doing TMG first is that it can increase the level of SAMe, and that is needed by the methionine synthase reductase reaction, which rescues the cobalamin coenzyme of methionine synthase when it becomes oxidized, thus restoring it to the +1 oxidation state and giving it a methyl group, so that it is a functional methylcobalamin molecule again. I don't know what dosage of betaine HCl will interfere with the methionine synthase reaction. Some people use the Allergy Research Group's dilute HCl solution to augment their stomach acid, and then there is no TMG (betaine) involved. Others use lemon juice (note that it is important to use a drinking straw and to flush the teeth with water afterward, because the citric acid in lemon juice chelates calcium and can damage the enamel on the teeth over time).

TMG stimulates the BHMT (betaine homocysteine methyltransferase) reaction, as it is a reactant for it. This reaction takes place in the liver and kidneys. It is an alternative pathway for converting homocysteine into methionine, and it will help to produce SAMe in those organs.

There are a couple of ways that it might produce symptoms. One is that it will initially lower the flow of homocysteine into the transsulfuration pathway, so the rate of production of glutathione may drop lower initially. So symptoms could be caused by initially making the glutathione depletion somewhat more severe.

Another possible mechanism is that it can also take homocysteine away from the main methionine synthase pathway initially, and that will impact the folate metabolism, since the conversion of methylfolate to tetrahydrofolate will decrease in the liver and kidneys.

A little TMG is often helpful when methylfolate and B12 supplementation are started, because it can help to raise SAMe, needed for recycling methyl B12. After these supplements are well underway and methionine synthase is coming up in activity, the TMG can be stopped, or DMG can be added to counter the BHMT pathway, so as to route more of the homocysteine to the methionine synthase pathway and the transsulfuration pathway.

 

[triffid113]

In order to drain the homocysteine produced from taking SAMe, it would be correct to supplement B6,Folate and B12 along with the SAMe,right?

So TMG is performing the opposite task as SAMe. SAMe is producing homocysteine whereas TMG is clearing it away. Then why at many places it is said that TMG is a good alternative to SAMe. Considering a methylation cycle such as here: http://babyfoodsteps.files.wordpress.com/2012/05/methylation-cycle.jpg

It can be seen that SAMe when taken directly will convert to homocysteine. TMG when taken directly will help in converting homocysteine to methionine, thereby fulfilling the two purposes: production of methionine(which SAMe also tends to do), and clearing up of homocysteine.

Please tell if my understanding is correct and share your views.
Thanks.

Yes, you have it. But be careful how you word it. Both SAMe and TMG raise SAMe. And I would never use B6, folate or B12, but only P5P, mfolate, and mB12. In particular, too much B6 causes neuropathy and B6 does not protect the kidneys from glycation, whereas P5P protects the kidneys from glycation, and can be taken in higher doses, in fact I have never heard that one can take too much. P5P also helps the CBS +/+ defect to work correctly in a large percentage of people. Folic acid can block the receptors for mfolate, cB12 can block the receptors for mB12. SAMe cannot lower homocysteine, P5P+mB12+mfolate can lower homocysteine OVER TIME, and only TMG/choline can lower homocysteine immediately so there is no buildup after meals.

What Lotus says in interesting but I have no experience with all that stuff. I take exception to the thought that taking TMG may reduce the transsulfuration pathway and lower glutathione temporarily...firstly homocysteine is a nerve toxin and is never intended to build up and so you NEED TMG to keep it from postprandial buildup in your system because the transsulfuration pathway is SLOW and the mB12+mflate pathway is SLOW. While it is true that if you let homocysteine build up to do its deleterious damage it may eventually process through the transsulfuration pathway but that is not the way to raise glutathione. If you keep homocysteine from building up by recycling, then instead of injuring your nerves while waiting to drain by that path it will be (and is supposed to be) cycled THREE times through the methyl cycle making SAMe for use throughout the body, and THEN it will drain through that pathway to make glutathione (or not) EXACTLY as it would have done anyway but w/o the nerve ad blood vessel damage. It was deermied that the people who ate the most amount of TMG through diet eat 2g/day.

I would NEVER EVER consider taking betaine HCL for anything to do with the methyl cycle. It is stomach acid and you can burn out your stomach with it if you do not need it or even if you do and guess the amount wrong.

She says taking TMG can lower BH4 production but I think this is just theory, I have never seen any such study or even anything remotely like it. From my own observations on me I think the things that slow pathways are more like radical oxygen species and feedback mechanisms and missing cofactors and that you cannot speed these pathways up if you do not have missing "ingredients" and your CRP is low. So for instance taking 50mg P5P vs 200 mg P5P yields the same homocysteine level. I should add that I have genetic defects on every single one of these pathways and all I can do is replete. I can worsen my homocysteine by not being replete but I cannot get it much lower than normal (yes, I can get .02 lower than normal) by taking higher doses or varying doses of cofactors that I observe. Maybe someone with one path with no mutations on it could achieve something different, but the TMG path is ALWAYS the fastest because there is only 1 chemical reaction that must occur there whereas on every other path 2 reactions must occur.

So all I know is that this is what gets my homocysteine perfect:
2/day Thorne Basic B
1 Solgar Metafolin (800 mcg)
50mg P5P
2g TMG (Soloray 1g pills)
I do not take mB12 except as is in the Thorne Basic B.

However note:
I do take 50,000 D/week and D is known to improve the methyl cycle.
The methyl cycle enzymes need both zinc and copper. I have to supplement both.
I take high dose anti-oxidants, as free radicals negatively impact the methyl ccyle.
I take DHEA and studies say the testosterone it makes corrects my CBS defects and the DHEA or something it makes also improves my ability to make or conserve BH4 (so maybe I am saying the same thing because it is CBS +/+ that uses up BH4 so fast, although it could be the MTHFR 1298AC it corrects although I never read that it did so). Beaware that BH4 is also destroyed by oxidative stress, hence the many benefits of antioxidants.

 

[triffid113]

Oh, I forgot, and this may signify...I also take a broccoli supplement (the LEF cruciferous vegetable extract) every day to prevent cancer and that is cysteine. Since I supplement cysteine, I always have a chance to make glutathione, if my biochemistry is going to do so, whether homocysteine builds up waiting to drain away down that path or not.

I do not know how much glutathione I make as it has never been measured, but one test I had measured my taurine and it is high (not excessively so), but if I make more taurine then I probably make less glutathione. Not sure as, supplying extra cysteine means I have more raw material and I may make enough glutathione as well. I read somewhere that glutathione is only made when cysteine is low, which utterly confuses me to the point I am doubtful if that is true. I would be very curious to measure my SAMe...don't know who offers such a test.

 

[dannybex]

And I would never use B6, folate or B12, but only P5P, mfolate, and mB12. In particular, too much B6 causes neuropathy and B6 does not protect the kidneys from glycation, whereas P5P protects the kidneys from glycation, and can be taken in higher doses, in fact I have never heard that one can take too much. P5P also helps the CBS +/+ defect to work correctly in a large percentage of people...

...I take exception to the thought that taking TMG may reduce the transsulfuration pathway and lower glutathione temporarily...firstly homocysteine is a nerve toxin and is never intended to build up and so you NEED TMG to keep it from postprandial buildup in your system because the transsulfuration pathway is SLOW and the mB12+mflate pathway is SLOW. While it is true that if you let homocysteine build up to do its deleterious damage it may eventually process through the transsulfuration pathway but that is not the way to raise glutathione. If you keep homocysteine from building up by recycling, then instead of injuring your nerves while waiting to drain by that path it will be (and is supposed to be) cycled THREE times through the methyl cycle making SAMe for use throughout the body, and THEN it will drain through that pathway to make glutathione (or not) EXACTLY as it would have done anyway but w/o the nerve ad blood vessel damage. It was deermied that the people who ate the most amount of TMG through diet eat 2g/day.

So all I know is that this is what gets my homocysteine perfect:
2/day Thorne Basic B
1 Solgar Metafolin (800 mcg)
50mg P5P
2g TMG (Soloray 1g pills)
I do not take mB12 except as is in the Thorne Basic B.

However note:
I do take 50,000 D/week and D is known to improve the methyl cycle.
The methyl cycle enzymes need both zinc and copper. I have to supplement both.
I take high dose anti-oxidants, as free radicals negatively impact the methyl ccyle.
I take DHEA and studies say the testosterone it makes corrects my CBS defects and the DHEA or something it makes also improves my ability to make or conserve BH4 (so maybe I am saying the same thing because it is CBS +/+ that uses up BH4 so fast, although it could be the MTHFR 1298AC it corrects although I never read that it did so). Beaware that BH4 is also destroyed by oxidative stress, hence the many benefits of antioxidants.

Hi triffid,

Interesting information...thanks for posting. I hadn't heard about homocysteine's effect on nerves...just in the bloodstream. A few questions:

As you know, there is so much conflicting info out there. I've read in several places, that taking p5p, or other 'activated' forms of vitamins, is pointless, because (according to one (old) source: Optimum Sports Nutrition, by Dr. Michael Colgan):

"...every molecule of p5p is broken down in the digestion to plain old pyridoxine, and transported that way through the intestinal well. The body then turns all the pyridoxine into P5P again. So inexpensive pyridoxine is every bit as good as P5P in a vitamin pill."

Knowing of course that I need folinic acid and methylfolate makes me think that perhaps Colgan's info is just way out of date and/or precedes the discoveries of all these genetic polymorphisms. But I'll ask anyway -- what do you think about this argument -- that p5p has to be converted to b6 to be absorbed in the first place?

The reason I ask is because I have the CBS mutations and I haven't been able to tolerate b6 or p5p for the last couple of years, with one exception, when I was taking extra b2 -- then I seemed to tolerate small doses of b6. But p5p...maybe it was due to something else, but it seems like I couldn't tolerate it the last several times I tried -- about a year ago. Would get all tingly and numb in the extremities. (And b2 has worsened my zinc deficiency...so have stopped that for the last six months and am just starting to rebuild zinc.) Sorry...to much info.

2. I also recently heard about methylation needing zinc (I'm too high in copper, so am avoiding that in sups right now). Do you have any citations/links with more information?

3. Same question as #2, except regarding vitamin d and it's connection to methylation. I tested low in both 'd' and zinc via SpectraCell last May. Do you have any links to studies I could show my doctor?

4. I'd also be curious to learn more about DHEA and the CBS issue...

5. Finally -- did you add the Thorne Basic B after you had the methyl donors, etc., in place? It looks like a pretty decent formulation, but seems to have (like so many), quite high levels of niacinamide/niacin, which as said to act as 'methyl sponges'.

THANKS IN ADVANCE,

Dan

 

[triffid113]

Oh...Dannybex, you know I type so fast that I misspoke...you are right it is homocysteine damaging the blood vessels, but also it feedsback to the methyl cycle, thus affecting it. Properly speaking, homocysteine itself may or may not affect the nerves, but it is a rough indicator that your methyl cycle is screwed up and it is lack of carntine (which methylation is required to produce) that affects the nerves (per lef.org) - you can go there and search for 'polyol pathway' if interested because that is how lack of carnitine affects the nerves. http://www.lef.org/newsletter/2004/2004_12_30.htm (they describe it better in their book).

Danny bex, the link of zinc and copper to methylation is not new. It is part of established biochemistry. Methionine synthase requires zinc as a cofactor. http://enzyme.expasy.org/EC/2.1.1.13
I am afraid I dont have a ref for the copper v- I have found this in several studies but it never made it to ENZYME so science must not be s ure about it yet.

The D reference was from Rich quoted in here somewhere. I tried to find it but he is prolific and it is ctoo hard. Others here know of this tho.

We talked about CBS/DHEA (testosterone) in the past. For ME (I have 2 CBS, one is +/+) DHEA lowers homocysteine. If you really have low homocysteine, this prolly won't help. Sorry!

I cant go into any more detail now - my dad is sick and it is so worrisome.

Trif

 

[triffid113]

Hi triffid,

5. Finally -- did you add the Thorne Basic B after you had the methyl donors, etc., in place? It looks like a pretty decent formulation, but seems to have (like so many), quite high levels of niacinamide/niacin, which as said to act as 'methyl sponges'.

THANKS IN ADVANCE,

Dan

Dan

oddly niacinamide does not bother me, however niacin bothers me very much. Maybe high dose niacinamide would bother me now too, I have not taken it high dose in prolly 20 years. Long ago I tried 100mg niacin and it was like a needle bath that went on for hours, but now I tried again due to that it lowers cholesterol, and it made me numb, as well as flushed and raw ALL day. I felt the niacin reaction was dangerous for me now. Before I felt it was a horrific allergy reaction (when I was young). I tolerate it much less now. The niacin etc. in Thorne doesn't bother me usually...but occasionally it does a bit - like a 5-10 min prckling and flush...but rarely and I always wonder what brought it on....usually it is something like I took unknown vitamins in my pocket and then Thorne as well...maybe thus a higher dose. I am rambling here because I did no scientific test. I just have not found niacinamide or Thorne to be a worry for me SO FAR. In my 30's I used to take 500mg niacinamide and it made me feel good. It made me feel like the sense of touch was a marvelous wonderful thing...I mean all the time, everything I touched felt great, wonderful even. It was a regular part of my protocol.

I have never in my life not been on a B complex. I was so sickly as a kid that my mother read up on nutrition and plied me with vitamins in self-defense. When I was 12 I read Adele Davis' books and Dr. Jarvis' Vermont Folk Medicine and began to take charge of my own health (or lack). I started on B100 complex (any brand that had all 11 B's) and was on that until I met Freddd online and switched to Thorne at 51 or so. I did never ramp up, I just constantly upgraded my protocol as I made new discoveries. I never, ever did this pick and choose only one vitamin or other that many of these young people do as I know biochemistry requires many cofactors to work and I aim to supply them all. It may be because I supplied everything at once that I had no real startup issue or it may be because even the inactive B's helped me somewhat or it may be because I wasn't so bad until my hormones ramped down and I immediately began taking more effective nutrients like active b's before a more serious deficiency could develop. I don't know. I only know that I have a lifelong commitment to (1) antioxidants (2) Complete (and now active) b complex (3) all the basics (I sorta construct my own multi).

Sorry I couldn't be more help
Trif

 

[dannybex]

Thanks for your replies Trif -- I really appreciate them. No need to ever, ever apologize for any reason. Take care of yourself and I hope your dad is feeling better soon.

Dan

 

[dbkita]

I was not aware that DHEA lowers homocysteine. Odd I take 150 mg of DHEA per day and my homocysteine is still ~10.