methylation: VERY low, very slow.....results

Freddd · Mar 14, 2013

I am not bringing up anything incorrect about Rich's prtocol. You are free to actually discuss any specific you wish and I will explain why I have said what I have. However, as it is frozen in time and static, as we learn more and have more experience with things and learn additonal things, anything static will fade into irrelevance. Rich knows mostly the old "traditional beliefs" about b12 and he had a lot to learn about MeCbl and AdoCbl. There are all sorts of legitamate disagreements about any protocol without bringing up all past wrong statements and misunderstandings, Those clarify NOTHING, unless one is writing a history of the eveolving hypothesis. Rich lacked the understanding of b12s and was learning. Howver, he never got a chance to complete that. You see the changes. We were actually close to reaching a compromise way of saying things with the SMP being started for 3 months then with the switch to MeCbl and AdoCbl as the next 3 months and optimize from there. As Rich said if it is going to work well enough a person would know it in three months. The major impediment was how committed he was to genetic ideas over practical results.

Anybody who uses "detox" to describe many different things which need many different responses is never going to get my agreement. That's nonsense just like calling FMS/CFS an "imaginary woman's disease" was nonsense when the docs were doing that. A microtitration of both MeCbl and AdoCbl would be far superior to any amount of HyCbl wich is perhaps 1% effective compared to the active cobalamins. If the idamage were linited to 3 months that won't cause too much damage\. For people with neiuological damage the clock is ticking and 3 months could be the difference between reepairable damage and permanent damage. That is the biggest danger of HyCbl, delaying what is really needed. I'm not talking about the people with a partial methylation block here. I'm talking tabout the people that have already started Subacute Combined degneration which Rich never claimed to be addressing and which the SMP is entirely unable to adrress and completely inappropriate. Work out a reasonable unified program that helps guide people to what is most appropriate for them. I am trying to work out just such a sieve that would identify all the various items formerly known as "detox" and what might work best identifying each of the different pathways. The current "detox" lack of understanding is dangerous.[/quote]

ahmo · Mar 14, 2013

Freddd said:

[/quote]

Thank you Freddd. I made this mistake, going to HyCbl, because of the confusing posts at the time I started. I appreciate the clarity you are bringing, and your continued commitment to unraveling these threads. ahmo

Symptomatic · Mar 20, 2013

Freddd said:

I am just getting started, and trying to figure out the best path for me. I've read a bit, but there is a ton of info and it's hard to sift through. I have a partial methylation block (no neuro damage that I know of), lots of +/- but no +/+. Some of my +/- are COMT though.

Not knowing where to start, I am doing a sort of modified SMP (no lipids yet, no Neuro formula as there are too many things in it that would be bad for me). I assumed that due to my COMT, I'd be better off starting with HyCbl. Based on a suggestion from Caledonia, I am rotating methyl donors, so instead of taking small quantities of each per day, I'm taking full quantities of one per day (TMG, folinic acid, 5-MTHF, HyCbl; also taking Mo and will add Se this week). I'd love to hear your thoughts (or a link to any prior post you may have already made that addresses major highlights/considerations, so you don't have to repeat yourself). Thanks for your time.

Lotus97 · Mar 22, 2013

Symptomatic said:

If you're trying to get advice from Freddd about how proceed in regards to the SMP (Rich's Simplified Methylation Protocol) I'm afraid you're barking up the wrong tree. On numerous occasions Freddd has lobbed all sorts of criticisms at Rich and his methods. Most of the criticisms are not supported by the facts.

While it's true that some people need higher doses (and Rich addressed this issue in his most recent revision), some people need a slower approach. No matter how much Freddd huffs and puffs, both Rich and I have heard from many people who have had a hard time with methylation and needed lower doses. My health has gotten significantly worse from early attempts at methylation where I took too high of a dose.

If you have any questions about the SMP, feel free to ask them here or in Rich's most recent methylation protocol thread.
http://forums.phoenixrising.me/inde...ation-protocol-august-25-2012-revision.19050/
You can also send me a private message (start a conversation) as my health is gotten to the point where I have a limited time to check all of my watched threads. I only participate in the methylation forums so I can help others. Since Rich is gone, I feel my presence is needed more than ever.

I've you're not taking the Neurological Health Formula I'd recommend taking some basic vitamins and minerals instead. I can make some suggestions if you're not sure what to take.

I'm curious why you're taking TMG. I'd recommend taking lecithin instead of TMG. The reason why I say "instead" rather than "both" is because lecithin has choline in it which is also a methyl donor. Both TMG and choline stimulate the BHMT pathway, but you don't want it overstimulated. Rich has said that the phospholipids in lecithin are critical to healing the mitochondria. Some people do need extra methyl donors, but Rich seemed to think most people didn't need TMG. Here's what he said in regards to lecithin and also TMG and other methyl donors that stimulate the BHMT pathway such as TMG, choline, phosphatidylserine, betaine HCL (same as TMG), and Seriphos (similar to phosphatidylserine, but more potent).

sregan · Mar 22, 2013

Lotus97 said:

Lotus, is that correct? It looks like Choline might indirectly stimulate by helping produce Betaine (TMG). But you're not saying other methyl donors contribute to BHMT? I had problems years ago with a digestiive enzyme I was taking regularly. I found that it contained Betaine HCL and assumed it was messing with methylation.

http://jn.nutrition.org/content/132/8/2367S/F1.large.jpg

Lotus97 · Mar 23, 2013

sregan said:

But you're not saying other methyl donors contribute to BHMT?
I'm not sure I understand your question unless that was a typo because I listed several other methyl donors that also stimulate the BHMT pathway. According the quote from Rich, TMG could be useful for some people at least in the beginning, but later it would either either need to be removed or you could continue taking TMG and add DMG to divert the flow away from the BHMT pathway. Rich doesn't have TMG in his protocol though unless you count the 50 mg in the NHF. Betaine HCL is the same as TMG except it also has HCL so 100 mg of betaine HCL would be less potent as 100 mg of TMG.

In the quote Rich said that TMG would produce SAMe which is useful in recycling B12, but too many methyl donors and/or too high of a dose could overdrive the methylation cycle which Rich says could cause a drop in glutathione. Among many other things, glutathione is also useful for recycling B12 so it seems there might be a trade-off or at least a balancing act.

Another thing I'm concerned about for myself is that dbkita told me if the BHMT pathway is overstimulated you're going to convert a greater amount of dopamine into norepinephrine. I believe I need more dopamine and less norepinephrine.

Something else that's kind of tricky about choline is its effect on acetylcholine. It seems with CFS it a complicated situation. I haven't had a chance to read the whole thread, but I would recommend checking it out especially if you're taking supplements to boost acetylcholine (many supplements to improved cognitive function/brain fog raise acetylcholine).
http://forums.phoenixrising.me/inde...acetylcholine-toxicity-the-cause-of-cfs.9757/

I was actually just looking at a very similar diagram about choline metabolism. I'm not sure what either means, but I'll post it (along with yours) in case someone wants to check it out

I found out recently that beets, spinach, wheat bran, and quinoa are quite high in TMG.
http://en.wikipedia.org/wiki/Trimethylglycine
And choline is in a lot of foods. This site has a list of foods high in choline (per 100 grams). You can also filter the list into just certain categories and you can also search for individual foods, but they don't list choline content for some foods in the database.
http://nutritiondata.self.com/foods-000144000000000000000-w.html
There's also this chart from wikipedia. I just noticed soy lecithin has twice as much choline as sunflower lecithin according the chart.

sregan · Mar 24, 2013

Lotus97 said:

According to all the images I can find on google the only thing that can DIRECTLY stimulate BHMT is TMG/Betaine. It looks like from your diagram that oxidized choline will become TMG so it's INDIRECTLY involved based on whatever mechanism/enzyme does the oxidizing. If Rich said other methyl donors are involved, INDIRECTLY is the assumption, I'd like to read that.

Lotus97 said:

Also very good to know and IMO (unless you know exactly what to take to counter that... maybe whey protein to build glutathione during that time who knows?), supports the slow and steady path. The drop on glutathione should be less severe and more tolerable.

That's good, from my experience the two have a very different effect. When I dopamine is up (once taking Mucuna Pruriens or when starting Bupropion on the 3rd or 4th day.) Is an wonderful feeling of being calm and at peace. I feel like the mountain standing firm, peaceful with no place I need to be. NE for me is alertness with some anxiety. I feel like I hardly ever have enough Dopamine but too much NE.

I have had success with small doses of Pregnenolone (supposed to stimulate NMDA) and/or DMAE when I have Brain Fog. At times N-Acetyl Tyrosine has helped as well as cortisol.

Symptomatic · Mar 24, 2013

sregan said:

And that is precisely why I've decided to take TMG/Betaine...I have a BHMT mutation (amongst a raft of others).

Lotus97 · Mar 25, 2013

Symptomatic said:

Understood. I've just began to learn about SNPs and also just sent out a 23andme test kit. If I didn't have some xylitol crystals handy I never would have been able to produce enough saliva

Are there any good places to learn about SNPs? I know there's an entire forum dedicated to SNPs here, but I was hoping for something more introductory because sometimes with the forums you already need to know a little bit to understand what everyone is talking about.

Lotus97 · Mar 25, 2013

sregan said:

Ok. I see what you're saying, but that doesn't mean choline and PS aren't contributing factors. Sometimes
10-20% is enough to push you over the edge, but a lot of this is going to depend on the individual. I've thought I was being careful in the past, but still ended up getting in too deep.

The info about phosphatidylserine/Seriphos is actually from dbkita. I'm not sure why it's not on the chart, but dbkita knows more about methylation than most everyone in these forums.
Low cortisol and high (chronic) NE is the usual pattern. If your cortisol is low and you are not on glucorticoid medications, then PS will decrease cortisol.
Moreover, PS (like TMG) stimulates the BHMT pathway which is great ... IF you need it stimulated.
However, BHMT stimulation is notorious for converting dopamine into NE (everyone seems to ignore this fact on these forums btw). This is a known effect based on scientists measuring the breakdown metabolites of both DA and NE, Unfortunately know one knows for sure WHY this effect occurs. I myself experienced the higher NE when I simultaneously took PS and TMG together.
Most people take PS supplements that quite honestly are not absorbed very well so in that case there is not much effect and they are wasting money. But try something like Seriphos and be prepared ...

I assume you're referring to non-denatured whey because of the cysteine. Rich actually suggest L-Cystine (not L-Cysteine or NAC), but not if you have mercury issues. NAC, cysteine, and cystine can all cause problems if you're mercury toxic. There's more about L-Cystine and methylation in this thread:
http://forums.phoenixrising.me/inde...excitotoxicity-on-methylation-protocol.18721/
How does cystine normally get into the blood? The liver produces glutathione from the constituent amino acids that it receives from the diet via the intestine and the portal vein blood flow. The liver exports some of its glutathione to the circulating blood, and enzymes break down the glutathione into its constituent amino acids. The cysteine is mostly oxidized to cystine, and some of this is taken up from the blood by the brain.
When the methylation protocol is begun, the activity of the methionine synthase enzyme in the liver is increased by supplementing B12 and folate forms. This causes more of the homocysteine to be converted to methionine, so less is available to support synthesis of glutathione. One result of this is that the cystine level in the blood goes down, so that less of it is available to the brain.
At one time Rich had also suggested glutathione for excitotoxicity. I've more or less stopped glutathione recently, but I've noticed when I do take it it calms me down. I take Source Naturals' sublingual (orange flavor is best). More recently, Rich has suggested other supplements
A lot of people experience it when they start this protocol. It's due to too much glutamate in the synapses of the neurons in the brain. The glutamate is supposed to be pumped out and converted to glutamine by the astrocytes, and sent back to the neurons for re-use, but this takes ATP, and when glutathione is low, the mitochondria do not produce ATP as fast as normal. When this protocol is started, I suspect that glutathione initially drops even more, and that is what causes the excitotoxicity. Various things have been recommended by Amy Yasko to counter this, including GABA, theanine, magnesium, Valerian root, grape seed extract, pycnogenol, progesterone cream, and taurine.
Of course, it's better to avoid excitoxicity rather than have to deal with it which is why Rich recommends starting at low doses and doing things slowly.
As you know, I have suggested a somewhat different approach to treating the methylation cycle partial block than Freddd has suggested.
There seem to be more and more people who are exhibiting effects of overdriving the methylation cycle from taking high dosages of methylfolate and methyl B12 together. I do not recommend this approach.
When high dosages of methylfolate and methyl B12 are taken together, the cells are no longer able to control the rate of the methylation cycle, and it becomes overdriven.
One result of this is a rapid buildup of folates in the cells, because of the rapid production of tetrahydrofolate by the methionine synthase reaction.
Tetrahydrofolate is readily converted to the forms of folate needed to support DNA and RNA synthesis, and this releases cells from a block at the S phase of the cell cycle.
They rapidly start dividing, and this produces a strong demand for potassium.
As Alex has noted, it has been shown that the intracellular potassium levels are low in CFS (likely because of an ATP deficit at the membrane ion pumps, due to mito dysfunction, in turn due to primarily to glutathione depletion), so there is no reserve there.
The reason I don't recommend going much higher on methylfolate when it is combined with several milligrams of methyl B12 is that this combination takes control of the rate of the methionine synthase enzyme away from the cells and drives it too fast. The result is that too much of the homocysteine is converted to methionine, and there is not enough left to flow into the transsulfuration pathway to support synthesis of glutathione and other sulfur-containing substances that the cells need.
The result is that the methylation cycle gets going well, but glutathione does not come up, as it needs to do for full recovery. There are excess methyl groups produced because of overdriving the methylation cycle. These are shunted off to the folate metabolism by sarcosine, which is produced by the glycine N-methyltransferase reaction, and then they come back to the methylation cycle via methylfolate. It's sort of like a futile cycle, like a squirrel in a rotating cage.
This is not just based on biochemical theory, though it is supported by that. It is based on lab tests that people who have been on this regimen have sent me.
For most PWMEs, this does not work very well in the long run. In Freddd's own case, because of the genetic variations that he apparently has in the CblC complementation group and in MTHFS (not to be confused with MTHFR), it is necessary for him to use a high dosage of methyl B12 to overcome the CblC problem, and it is necessary for him to use a high dosage of methylfolate to feed his folate metabolism, since he cannot use folinic acid or folic acid. (I'm not sure why he cannot use folic acid. Perhaps he has a polymorphism in the DHFR enzyme, also). Freddd cannot tolerate raising glutathione, because it binds cobalamin to form glutathionylcobalamin, and his version of the CblC complementation group is not able to retrieve cobalamin from glutathionylcobalamin. As far as I can tell, this is a rare genetic variation. Most PWMEs are depleted in glutathione, and this is responsible for a large number of the symptoms.
There may be other PWMEs who have one or more of these genetic issues as well, since Freddd reports that there are some others who respond to these supplements in the same way he does, but most do not seem to have them, based on our clinical study and anecdotal reports from quite a few PWMEs.
Best regards,
Rich

Hmm, I just bought some Mucuna Pruriens/Dopa Mucuna and also pterostilbene to increase dopamine. So have you found that increasing dopamine also increases NE for you?

If you have low cortisol, that could cause high NE. Norepinephrine can lower GABA which would then make NMDA stimulation from excitotoxins worse. As mentioned, methylation can increase glutamate-induced excitotoxicity, but methylation can also cause problems with ammonia
At the same time too much methylation can over-convert histidine into glutamate stimulating the CNS, can lead to too many sulfites, ammonia, and sulfates (which stimulate fight or flight) if you have CBS pathway defects, or to too much neurotransmitter production especially catecholamines.
Ammonia can also be produced via the transsulfuration pathway, which is why Dr. Yasko recommends lowering the B6 intake if a person has an upregulated CBS enzyme. The situation involving B6 is complicated. If a person has a CBS upregulating SNP, it's a good idea not to go too high on B6 until this is dealt with. Later on, it is important to have enough B6 so that the transsulfuration pathway can proceed at a normal rate. Also, B6 is needed to make some of the neurotransmitters, and it's also very important in the metabolism of the amino acids, to name a few. So in the longer term, B6 needs to be brought up, and B2 is needed also, to convert B6 to its active form, P5P.

Isn't stimulating NMDA a bad thing?

Lotus97 · Mar 25, 2013

I forgot to mention in my post above, Rich has said that folinic acid can help with excitoxicity (although I assume that since folinic acid converts to methylfolate for most people it could potentially contribute to excitoxicity)
I actually prefer including both folinic acid and 5-MTHF. 5-MTHF is the form needed by methionine synthase, which is the enzyme with the partial block. Many people's cells are able to convert folinic acid to 5-MTHF well, but many others have inherited genetic polymorphisms that slow this conversion down considerably. The polymorphisms in the MTHFR enzyme are a good example, and these are very prevalent in the population.

Folinic acid is helpful for a couple of reasons. One is that it is very versatile, in that it can be converted to other forms of folate, which are needed to make DNA, RNA, and purines in general. Another factor is that folinic acid is polyglutamated when it is inside the cells, and this can help to lower the amount of free glutamate, which is an excitotoxin. Excitotoxicity is a problem in CFS, and it is often exacerbated when methylation cycle treatment is entered upon.

Freddd · Mar 25, 2013

sregan said:

Hi Sregan,

Choline has 1 more methyl group than TMG. When it looses that CH4 it becomes TMG.. These are all part of the ordinary food source supply that is used to replenish methyl groups to the active donors, MeCbl, l-methylfolate and SAM-e which pass the methyl group around in it's dance and replenish from the food supply food.. MeCbl generates SAM-e and away they go. Later in the process the MeCbl is regenerated for another time around.

Symptomatic · Mar 26, 2013

Freddd said:

Is it safe to say then that for someone like me (with both COMT and BHMT (and other) mutations including MTHFR, multiple MTRR, VDR, CBS, MAO) - who needs to be careful of methyl donors and wants to try to stimulate the BHMT pathway, that TMG would be a better bet than choline? Not sure I need/want the extra methyl donor.

Lotus97 · Mar 27, 2013

Symptomatic said:

According to that wikipedia chart, sunflower lecithin has half as much choline as soy lecithin so that might be a better choice if you decide to take lecithin and want to limit methyl donors. I'm not sure that wikipedia chart is correct, but I'll leave my comment I guess. I just don't see how they can have different amounts of choline. They both have almost the same amounts of phosphatidylcholine.I can't answer your question, but I will say that sometimes it takes a few days before you realize your dose is too high so that's something to consider when adding things/increasing dosages.

Bluebell · Jul 25, 2013

Lotus97 said:

Lotus97, I think that soy lecithin granules (which is what the Wikipedia chart lists) are different from sunflower lecithin (a pasty oil that comes sealed in gelatin capsules). I've been reading customer reviews of lecithin on other websites, and some people have commented how the lecithin granules have different effects from the lecithin that comes in capsules (and they are talking about capsules of either soy lecithin or sunflower lecithin). Because the two types of lecithin in the Wikipedia chart are of two different delivery forms as well as made from two different plant sources, it could make sense that their choline content per gram may be different.

I have not researched it further because I am avoiding soy and will definitely go with the sunflower kind of lecithin, but people could just do ingredient label comparisons and see how much choline is in each form. (Here is one granules label that I've got up on my browser: http://www.gnc.com/product/index.jsp?productId=2133303)

determined · Sep 24, 2013

update: I have never changed my dose from the initial diluted speck. I actually got a full time job recently and so far am hanging in there. I still firmly believe that my tiny, tiny doses are like inoculations that somehow modulate my immune system.

I'm not cured. I don't have the stamina of a normal person by any means. I remain more chemically sensitive, but this has seemed to be the trade-off. I'm not sure how long I'll be able to keep this job, but for now, I'm managing. Life is good, and I'm still so very grateful to Rich VanK. I think of him often - what a dear man he was/is!

Bluebell · Oct 7, 2013

determined said:

I only learned of Rich after he passed away, but his intelligence, research, hard work, verbal/written clarity, concern, courtesy, kindness, and genuine nature shine through in every one of his huge number of internet contributions.

When I was looking up a health topic a few months ago, I happened across an obituary for him in a newspaper from his region of the country, and reading it brought me to tears.

===

determined said:

That is great!

aaron_c · Jan 5, 2014

Hey Lotus,

Could you point me towards the thread where Rich talked about folinic acid helping with excitotoxicity?

maryb · Jan 6, 2014

@determined
I do hope you have managed to keep doing your job and are feeling okay.

determined · Jan 6, 2014

Thank you, maryb. I've kept my job four months so far. It's hard, but I am still hanging in. We shall see.

methylation: VERY low, very slow.....results

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