Dimethylglycine

[LaurieL]

The other pathway is the betaine homocysteine methionine methyltransferase (BHMT) pathway. It uses betaine (trimethylglycine or TMG) and homocysteine as reactants, and it produces methionine and dimethylglycine (DMG). These two pathways are in parallel, and both are important to humans, especially depending on their current nutritional situation.

When betaine-HCl is used in large dosages to compensate for low stomach acid, which is present in many PWCs, the concern is that the betaine will overdrive the BHMT pathway, taking flow away from the methionine synthase pathway, which is the one we are trying to encourage.

The BHMT pathway does complete the methylation cycle, though, and therefore it does help to produce SAMe, which is in this cycle, and which is needed for methylation reactions. One of the methylation reactions is the methylation of cobalamin (B12). This is necessary to supply new methylcobalamin as a coenzyme for the methionine synthase reaction from time to time. So it's important to have some SAMe on hand, even to support the methionine synthase pathway.

Dr. Amy Yasko has suggested that the BHMT reaction can be encouraged initially, and then, when the supplements are in place to support the methionine synthase reaction (that is, the B12, 5-methyl tetrahydrofolate, and other B vitamins and cofactor minerals), then the flow that is being carried by the BHMT pathway can be shunted to the methionine synthase pathway, by supplementing DMG, thus slowing the BHMT reaction by what is called in chemistry "product inhibition."


http://tinyurl.com/5rwybkw

Question specifically for Rich VanKonyenburg and inviting discussion from forum members.

A little history of my own supplementation. I had been following a detox program from a toxicologist, and this program is so incredibly similar to Dr. Yaskos and your simplified approach. The only aspect missing from this program was direct methylation supplementation. Specifically the seperate forms of Vitamin B's and folics. So essentially, prior to starting Freddds recommendations of the ad B12 and methyl B12 and the methylfolate, I already had in place the supportive supplements and had been already taking them for some time. Some time would denote atleast a couple of years. I initially had made very good progress as his program (Toxicologist) atleast got me on my feet and able to work again. However, I still seemed to suffer from multiple infections and the fatigue was most definately still a factor and still interferred with having any type of "normal" life.

Hence, it led me to this wonderful forum of like sufferers. I notice some here in which have had exposures to mold, which is also in my history, and also Lyme Sufferers, in which I had an argumentative result in my own Western Blot, and was subsequently treated for Lyme by both antibiotics and herbals for a number of years. Again, with identifiable results but no resolution to my overall fatigue and wellness.

Having said all this, I initially chose Freddd's suggestions, to allow me to observe my bodies reactions and I just couldn't afford the nutragenomics testing. Thankfully, I was able to take his suggestions and although I did go through some "herx" like reactions, they weren't anything like I experienced with The Toxicologist's protocol or the lyme protocols. So, things seemed to have progressed rapidly for me with Freddd's supplementations. Even with Freddd's supplementations, I am quite avidly following the suggestions of Dr. Amy Yasko and you, Rich VanK in observations.

Sooooooo, I have recently begun adding DMG. I had already been taking TMG in a short time after starting the ad B12, methyl B12, the Yarrow B right, and the methylfolate. I realize that my ability to take the high doses I have outlined in other posts are not the normal result of most of those here. Is this attributable to the fact I had already been taking the recommended adjuncts? The ad b12 had a very noticable affect and I attribute it to another elevation in my wellness. Clearly identifiable results. The same with the addition of methyl B12, and subsequently the methylfolate.

I also had a noticable reaction to Niacinamide. Only after taking niacinamide was I able to regulate my body temperature and maintain warmth. This after years of not being able to keep warm. My sensitivity to cold is not anywhere near the extreme it used to be. I would say my reaction to cold is now "normal".

I have recently added DMG with again had identifiable reactions. I had read that adding DMG can cause a revved feeling. I went through exactly that and still do from time to time. I had read that the revved feeling could be a positive in that a system is resetting but I panicked and started cutting the dose. When I did this, I went through a reversal and actually felt worse. It was the only thing I changed.

Question: Might this indicate a BHMT polymorphism? Is this what others experience with this type of polymorphism?

I have basically been trying to learn the entire Krebbs cycle including the methylation cycle and have been experimenting with supplementing different points and observing my bodies reactions.

LaurieL

 

[LaurieL]

Taking DMG has been with mixed feelings for me. I definately had a revved up, jazzed effect from it. In fact, after a few weeks, it still does this to me quite often but I am noticing other things that kinda make me worry a bit.

Those other things being an odd smell to my urine, although I cannot pin it. Sulfur like? Asparagus like, when you eat asparagus? Can't quite pin the odor down and equate it to anything. Definately not ammonia like. Although I have had that in the past and am concerned about it.

Could someone explain this to me (meaning the pathways and co-enzymes), and is this something others have experienced? I have been searching for days and still haven't come up with anything helpful quite yet.

Laurie

 

[richvank]

Taking DMG has been with mixed feelings for me. I definately had a revved up, jazzed effect from it. In fact, after a few weeks, it still does this to me quite often but I am noticing other things that kinda make me worry a bit.

Those other things being an odd smell to my urine, although I cannot pin it. Sulfur like? Asparagus like, when you eat asparagus? Can't quite pin the odor down and equate it to anything. Definately not ammonia like. Although I have had that in the past and am concerned about it.

Could someone explain this to me (meaning the pathways and co-enzymes), and is this something others have experienced? I have been searching for days and still haven't come up with anything helpful quite yet.

Laurie

Hi, Laurie.

Adding DMG would have the effect of slowing down the flow through the alternate BHMT pathway that is present in the liver and kidneys. Since you already had plenty of folate and B12 in your cells from your supplementation, the result likely would have been to shift the flow of homocysteine more to the methionine synthase reaction and the transsulfuration pathway. The latter would likely have raised the production of glutathione and would also have improved the function of your body's normal detox system. This would likely have increased the rate at which stored toxins are mobilized into the bloodstream, to be dealt with by the liver and kidneys. The changes you have observed in your urine suggest that the kidneys are extracting toxins from the blood at a higher rate, and this would be consistent with the above mechanism.

Others have reported a variety of symptoms when their partial methylation cycle block is lifted and glutathione is restored, and I have attributed them to increased detoxication and in some cases improvement in immune system function as well as a result of raising glutathione, improving methylation, and restoring folate levels inside the cells.

You can read about the experience of others in the article dated July 18, 2007 at www.cfsresearch.org by clicking on CFS/M.E. and then on my name. It's toward the end of the article.

I hope this helps.

Best regards,

Rich

 

[LaurieL]

I hope this helps.

Are you kidding? I absolutely appreciate your input and am very thankful for it. Yep, definately helpful!!

Two

This is kinda exciting for me in that I could possibly be responding according to many others experiences. I am pleased I have been able to integrate both you and Freddd's suggestions. Kinda surreal. It will be interesting to see what comes up in the near future! I have been noticing some things associated with immunity issues, but I wasn't going to mention them as of yet as it is very likely premature.

Very appreciative.

Laurie

 

[FunkOdyssey]

Adding DMG would have the effect of slowing down the flow through the alternate BHMT pathway that is present in the liver and kidneys. Since you already had plenty of folate and B12 in your cells from your supplementation, the result likely would have been to shift the flow of homocysteine more to the methionine synthase reaction and the transsulfuration pathway. The latter would likely have raised the production of glutathione and would also have improved the function of your body's normal detox system.

Would this be desirable then? It seems like it would, but I haven't seen you routinely recommend adding DMG to B12 and Folate protocols. What are the possible consequences? Too little formation of SAMe?

 

[richvank]

Would this be desirable then? It seems like it would, but I haven't seen you routinely recommend adding DMG to B12 and Folate protocols. What are the possible consequences? Too little formation of SAMe?

Hi, Funk.

Use of DMG is part of the full Yasko treatment, from which I extracted the Simplified Treatment Approach. Dr. Yasko recommends building up the supports for the methylation cycle, and then adding DMG if needed to shift the flow from the BHMT pathway to the methionine synthase pathway, which is desirable. In her full treatment program this decision is based on results from repeated urine testing.

The Simplified approach is a compromise. I proposed it to make methylation treatment feasible for more PWMEs/PWCs, by lowering the cost and complexity. Some people, once they have found that the Simplified treatment has helped them, have gone more deeply into the full Yasko program. Others have found that the Simplified approach was enough to give them significant benefit, without the greater cost and complexity.

Last summer I gave an invited talk at the Yasko Protocol Conference, and I explained this tradeoff. Dr. Yasko is very supportive of what I have done, though she herself continues with the more complete program because she believes that the added benefit to be gained from it is worthwhile. In the clinical trial of the Simplified approach that Dr. Nathan and I conducted, after six months of treatment, we asked Dr. Yasko, among others, for advice on follow-on treatment for individual patients. Some were given the additional treatments she recommended, and experienced additional benefits.

The BHMT pathway does make SAMe also, but it does not help the folate metabolism, nor does it regulate the balance of the sulfur metabolism, as methioine sulfate does. It can be helpful to encourage the BHMT pathway at first, to build up some SAMe, which is needed to convert oxidized cobalamin back to methylcobalamin, and to convert hydroxocobalamin to methylcobalamin, also. The Simplified approach includes some trimethylglycine (betaine) in the multi, which should help the BHMT pathway.

Best regards,

Rich

 

[FunkOdyssey]

Thanks Rich, very informative.

 

[wciarci]

LaurieL,

Could you list all the supps that you take? Could you suggest a time line for gradual addition? I tried the simplified protocol but had to discontinue due to rashes. I wonder about the sulfur. My family has a history of being allergic to sulfur based meds such as sulfur based antibiotics. Thanks

Wendy

 

[Joopiter76]

Wendy that seems to be suitable. In the general health formula are sulfur containing plants included. so I suggest to take another product without any plants. And be sure it does not contain sulfate in any way. Have a look at your mineral water as well choose one that does not contain much sulfate. Take molybdenum, its only starting to be toxic above 1000g so I take 400g but work up within 2 weeks.

 

[LaurieL]

By Rich VanK

The BHMT pathway does make SAMe also, but it does not help the folate metabolism, nor does it regulate the balance of the sulfur metabolism, as methioine sulfate does. It can be helpful to encourage the BHMT pathway at first, to build up some SAMe, which is needed to convert oxidized cobalamin back to methylcobalamin, and to convert hydroxocobalamin to methylcobalamin, also. The Simplified approach includes some trimethylglycine (betaine) in the multi, which should help the BHMT pathway.

Rich,

The addition of DMG has had a huge impact on my body. Now that I have a few weeks to get settled into this, I would like to tell you my experiences since adding DMG.

Adding DMG would have the effect of slowing down the flow through the alternate BHMT pathway that is present in the liver and kidneys. Since you already had plenty of folate and B12 in your cells from your supplementation, the result likely would have been to shift the flow of homocysteine more to the methionine synthase reaction and the transsulfuration pathway. The latter would likely have raised the production of glutathione and would also have improved the function of your body's normal detox system.

Not only did I experience a jolt in my body's capacity to detox but I also seemed to experience an immune system jolt. After the weird smelling urine thing went away, my body seemed to wake up and finally take note of an infection. The infection was severe enough to be treated with two z-paks back to back. Prior to DMG, I knew it was there, but we couldn't find it. I have been treated many times with many differing antibiotics and it was like taking a placebo pill. Nada.

I realize azithromycin is an immune modulator, and depending on its dosage, can either be bacteriostatic, or bacteriocidal. The dosage was every 12 hours based on bactericidal constant blood levels, with the consideration of half life. I have taken this before, and have never had the response I had this time.

Because of those past failed experiences, I was worried that two Z paks weren't going to be long enough. But it would seem that it was enough for my body to take over and keep healing. I do not seem to be reverting back to the state I was going into prior to its administration.

Is this something similar to what others have experienced with DMG?

Additionally, another question about BHMT and MS. So with DMG, I have slowed down BHMT. But BHMT is responsible for SAMe. Of which I was taking TMG prior to starting DMG. Does one supplement both? Or do I now need to be more specific and finally go to the expense of SAMe? Its about the only suggestion I haven't taken yet.

The dosage of DMG I was taking, was in 100mg increments at five spaced doses a day. How does this compare with others experiences? When taking DMG, what is the half life?

Thanks for your input.

LaurieL,

Could you list all the supps that you take? Could you suggest a time line for gradual addition? I tried the simplified protocol but had to discontinue due to rashes. I wonder about the sulfur. My family has a history of being allergic to sulfur based meds such as sulfur based antibiotics. Thanks

Wendy

I don't have an allergy to sulfur or sulfur based drugs but I also had a rash at the beginning of starting the methylation recommendations. And still healing the last remnants of it still to this day. Although it didn't really get worse or more involved, it sure wasn't healing like it should either.

With the addition of DMG and then the antibiotics just given to me, it finally seems to have rounded a corner.

The supplements. Many of the supportives recommended by Freddd, I had already been taking for quite some time. What I wasn't, I added with little problems.

I used the forms of B12 recommended by Freddd as well as the methylfolate.
I personally chose these, because I wanted the readily available forms, I knew there was a cycle interuption somewhere, and missing enzymes. It was apparent B12 was an issue, and the folate cycle concerned me greatly. I also had the experience of a rash with use of the hydroxy B's. I was concerned with missing enzymes, that I wouldn't be able to effectively convert the hydoxy form and my reaction to hydroxy with the rash cemented my decision.

You inquired about me suggesting a timeline. Please, I am not qualified to make any suggestions at this time, as this is all new water for me too.

What I can offer is an observation about my own experience. In 2006, I started treatments similar to what was included in the helpful supplemental suggestions by Freddd, to have on board prior to starting methylation targeting. As bad off as I was back then, even those suggested supplements, many of which were also on the protocol I was doing then, took time. Some of the reactions I had were severe even with those. These weren't added one at a time either, so I had no pragmatic method to determine which I was reacting to. But react I did. I recognized the detox reaction to the recent addition of DMG because I have been through similar ones in those earlier years.

It took about four hard months to see improvement, and another four to see large steps being taken and from there small incremental positives but without resolution to my problems. This protocol was by an Environmental Toxicologist and did not use Vitamin B12, folates, and a couple of others suggested here. But that protocol included some things not discussed here either.

So the timeline, depending on how long you have been sick, and how many infections you may have accrued due to the immune disruption a methylation block can affect (atleast in my case), may be longer than what any of us prefer. I know by reading my posts here, one would think I am having quick results. But is not the reality of it, so I don't want that to "mislead" anyone.

Laurie

 

[richvank]

***Hi, Laurie.

***My responses are at the asterisks below:


Rich,

The addition of DMG has had a huge impact on my body. Now that I have a few weeks to get settled into this, I would like to tell you my experiences since adding DMG.

***Cool!

Adding DMG would have the effect of slowing down the flow through the alternate BHMT pathway that is present in the liver and kidneys. Since you already had plenty of folate and B12 in your cells from your supplementation, the result likely would have been to shift the flow of homocysteine more to the methionine synthase reaction and the transsulfuration pathway. The latter would likely have raised the production of glutathione and would also have improved the function of your body's normal detox system.
Not only did I experience a jolt in my body's capacity to detox but I also seemed to experience an immune system jolt. After the weird smelling urine thing went away, my body seemed to wake up and finally take note of an infection. The infection was severe enough to be treated with two z-paks back to back. Prior to DMG, I knew it was there, but we couldn't find it. I have been treated many times with many differing antibiotics and it was like taking a placebo pill. Nada.

I realize azithromycin is an immune modulator, and depending on its dosage, can either be bacteriostatic, or bacteriocidal. The dosage was every 12 hours based on bactericidal constant blood levels, with the consideration of half life. I have taken this before, and have never had the response I had this time.

Because of those past failed experiences, I was worried that two Z paks weren't going to be long enough. But it would seem that it was enough for my body to take over and keep healing. I do not seem to be reverting back to the state I was going into prior to its administration.

Is this something similar to what others have experienced with DMG?,

***I don't know whether DMG specifically has has this effect in others, but from a theoretical point of view, getting the methylation cycle going properly, which also normalizes the folate metabolism and glutathione, would be expected to give the immune system a big boost. Methylation silences the expression of retrovirus genes. Folates are necessary to make new DNA for the proliferation of lymphocytes. And glutathione is needed specifically by the T cells and to help counter the effects of oxidative stress that is part of the immune system's inflammation response to infections. So to the extent that DMG would likely have boosted your methylation cycle, it makes sense that it would also have helped your immune system.

Additionally, another question about BHMT and MS. So with DMG, I have slowed down BHMT. But BHMT is responsible for SAMe. Of which I was taking TMG prior to starting DMG. Does one supplement both? Or do I now need to be more specific and finally go to the expense of SAMe? Its about the only suggestion I haven't taken yet.

***When methionine synthase gets going normally, it also completes the methylation cycle, so this produces SAMe also. The BHMT pathway is helpful for startup, but once methionine synthase is working properly, it will pick up the ball and run with it.

The dosage of DMG I was taking, was in 100mg increments at five spaced doses a day. How does this compare with others experiences? When taking DMG, what is the half life?

***Dr. Amy Yasko is not very specific in her book about the dosage of DMG to use. She just says "some." I don't know how much other people have used.

***As far as I know, the half-life of DMG has not been measured. It is converted to sarcosine in the body, and then to glycine. Each of these reactions converts tetrahydrofolate to 5,10 methylene tetrahydrofolate. So there is an interaction between the TMG-BHMT-DMG reaction and the folate metabolism, but it does not replenish tetrahydrofolate, as the methionine synthase reaction does.

Thanks for your input.

***You're welcome.

***Best regards,

***Rich

 

[Joopiter76]

Hi,
Yasko usually suggests 100 to 200mg DMG but not before enough B12 is in place. Ive been taking b12 shots for more then 1,5 years now and when I was very worse DMG was not so good. But now as Im getting better It helped me very well, I take two 100mg tablets a day (starting with one for two weeks).

Rich, can you please explain in more detail the reaction DMG >Sarcosine > glycine an how Methylen-THF is generated in this way? I ask this because I have had much profit from formyl-THF which will also be converted to methylen-THF. I am SHMT+ so can this be the reason? It must have something to do with that. If Formyl-THF and DMG helped markly and are all supporting methylen-THF then there must be the link to more improvement. Can you help please??

 

[richvank]

Hi,
Yasko usually suggests 100 to 200mg DMG but not before enough B12 is in place. Ive been taking b12 shots for more then 1,5 years now and when I was very worse DMG was not so good. But now as Im getting better It helped me very well, I take two 100mg tablets a day (starting with one for two weeks).

Rich, can you please explain in more detail the reaction DMG >Sarcosine > glycine an how Methylen-THF is generated in this way? I ask this because I have had much profit from formyl-THF which will also be converted to methylen-THF. I am SHMT+ so can this be the reason? It must have something to do with that. If Formyl-THF and DMG helped markly and are all supporting methylen-THF then there must be the link to more improvement. Can you help please??

Hi, Joopiter76.

Thanks for sharing the dosage information and your own experience with DMG.

I'm glad that the 5-formyl THF has been helpful to you.

Sarcosine is produced in the body in two ways:

1. It is part of the pathway choline-> betaine-> DMG-> sarcosine. The conversion of DMG to sarcosine is catalyzed by the enzyme dimethylglycine dehydrogenase, which requires iron and vitamin B2. This is thought to be the main source of sarcosine normally.

2. It is also produced in the reaction glycine + SAMe -> sarcosine + SAH which is catalyzed by the enzyme glycine N-methyltransferase. This reaction is seen as a mechanism to save methyl groups when they are present in excess (such as after eating a high-protein meal rich in methionine) for times when they are more scarce, such as overnight, and also to limit the ratio of SAMe to SAH. This ratio affects the rates of methylation reactions. In people who I believe have overdriven their methylation cycle by taking high sublingual dosages of methylB12, sarcosine is found to be very high. In people who have a partial methylation cycle block and a high intake of methionine, sarcosine is also high.

Sarcosine delivers its methyl group to THF in a reaction catalyzed by the enzyme sarcosine dehydrogenase, which also requires iron and B2, producing 5,10-methylene THF and glycine. In this way, the methyl group is saved. The 5,10-methylene THF is converted to L5-methyl THF by the MTHFR enzyme, and it then transfers its methyl group to homocysteine via methionine synthase to reform methionine.

So the formation of 5,10-methylene THF from sarcosine does not use the enzyme SHMT, and neither does the formation of 5,10-methylene THF from 5-formyl THF. Thus, if you have a SNP in SHMT that slows its reaction, these other routes to the formation of 5,10-methylene THF may be of help to you.

Best regards,

Rich

 

[Cloud]

Is DMG preferable over TMG?

 

[Joopiter76]

check glycine in the urine. if glycine is high the BHMT shortcut is already supported and you dont need TMG. Yasko works with very little doses of TMG because it can lower the amount of homocystein going around the long way via methionine synthase because it is converted directly to methionine. But wenn SAMe is very low it can be useful to use TMG at the beginning. Im not sure if TMG causes ahir loss or slow groing hair, nails and so on. I wouldntake more than 150mg TMG.

 

[Vegas]

I wanted to weigh in on the DMG-TMG issue

My early experiences with TMG were not favorable. Honestly, I didn't notice much effect from small dosages, but if I would take 1000 mg or so, it seemingly had the opposite effect of what I was aiming for. One thing it did was result in a greater reliance upon catecholamines to function. Assessing the catecholamine response seems to be a reliable indicator of my metabolic production, which I assume, if Rich's hypothesis is correct, relates to cortisol/thyroid output and GSH status.

Taking DMG required some adjustment. Initially, it produced that slightly wired, "fake" energy feeling not unlike some stimulants. I adjusted quickly, and actually find DMG to be one of the very rare supplements (excluding stimulants) that actually increases energy. My only experiences with DMG includes taking it with SAMe. I take 150mg in the am, and 150 mg in the afternoon. I'm not certain if this supplement is right for everyone, I didn't start it until 5 months into the methylation tx. Also, it has to be viewed as one more catalyst to the process, so accelerated detox, with the addition of DMG, can be expected. In other words, don't just throw the kitchen sink at methylation if you are moderately to severely incapacitated or you are likely to regret this decision.