Methylation Panel: Low SAMe,

kyzcreig

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Seems like there's a block going from Met -> SAM.




I found this thread which had a lot of good info by @DREBS
http://forums.phoenixrising.me/inde...thionine-yet-blocked-methylation-cycle.23785/

Apparently ATP and magnesium are the cofactors for Met -> SAM. I take loads of magnesium glycinate, it helps all my symptoms and helps my sleep so I don't think that's the problem.

I did Genova's Nutreval and my krebs wasn't in great shape, so that might corroborate a low ATP hypothesis.
http://imgur.com/pQLGBw2
http://imgur.com/uJmmBK6
Genova has an awesome interpretation guide for that and I've been following its suggestions.
https://www.gdx.net/core/interpretive-guides/Organix-IG.pdf

Does anyone have any other ideas, as to what might be the problem here?
 

PeterPositive

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I remember seeing I had high serum folate and high b12. I take both regularly.
It would be helpful to have a breakdown of the folate levels. I myself had very high "folic acid" in my standard labs but the lab itself doesn't say exactly which type of folate they measure under such label.

I then did a full methylation panel (such as the one recommended by RichVanK) and it showed I had pretty high synthetic folic acid, sufficient folinic acid, barely sufficient 5-MTHF and insufficient THF.

This in turn suggested that my B12 wasn't sufficient and was barely spinning the methylation cycle. Pushing more methyl-B12 has significantly improved the situation and provided some relief in a number of departments (mood, pain, energy)

If you have more details about your folate status and a breakdown of the various forms it could help. Also serum B12 alone won't say much, unfortunately, although your low homocysteine suggests that B12 is working fine.
 

kyzcreig

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That makes sense. Would this test be adequate: http://www.hdri-usa.com/tests/methylation/

Perhaps it would be better to wait before doing another methylation panel (albeit more thorough with HDRI). I'm planning to supplement with SAMe but maybe that would be counterproductive. I know Yasko recommends supplementation if you're low but I want to address the root problem too.

Looking at GDX's interpration guide: https://www.gdx.net/core/interpretive-guides/Amino-Acids-Interp-Guide.pdf
Elevated (or normal) homocysteine, with elevated or low methionine & low cystathionine (suggestive of low Sadenosylmethionine, low taurine, low B6)
And they recommend
Supplement with appropriate amino acids, magnesium, vitamin B6
Which of course I'm doing.

Here's what the interpretation from DD said:

S-adenosylmethionine (SAM), the first direct metabolite of normal methionine metabolism, is lower than expected. Up to half of daily methionine uptake is enzymatically converted in the liver to SAM by methionineadenosyl transferase in the presence of ATP and magnesium. Therefore SAM may be low due to (1) low availability of methionine (check plasma methionine ) (2) magnesium deficiency (check whole blood or red blood cell magnesium levels), (3) inhibition of methionine synthase activity, or (4) genetic or chemical inhibition of methionine adenosyltransferase activity. In the latter case, severe depletion of SAM can be associated with DNA hypomethylation and demyelination in the central nervous system. When dietary methionine and choline are insufficient, the folate-dependent pathway for regeneration of methionine from homocysteine is upregulated increasing the cellular requirement for folate. A potential consequence of the diversion of folate 1-carbon methyl groups towards regeneration of methionine (and SAM) may be functional depletion of folate methyl groups for DNA metabolism and integrity with potential for genetically significant consequences (e.g . genomic DNA hypomethylation). It is uncertain whether physiological decreases in SAM alone induced by nutritional deficiencies are causally related to cellular hypomethylation (J Biol Chem 2000;275:29318-23).

Google pulled up these studies:
http://ajcn.nutrition.org/content/76/5/1177S.full
http://www.ncbi.nlm.nih.gov/pubmed/26722840\
Which state ROS (reactive oxygen species) and NOS (nitric oxide) deactivate methionine adenosyltransferase while reduced-glutathione reactivates it.

For years I've had test results saying I'm low in Glutathione, this seems like another. Since the methylation cycle is what raises your glutathione levels, I'm not sure what I should do. Taking SAMe will probably raise the methionine levels further. I wonder if it's practical to take a lot of Acetyl Glutathione. I emailed the guys that supply Allergy Research and they would sell a kilogram for 1500 euros.
 

PeterPositive

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That makes sense. Would this test be adequate: http://www.hdri-usa.com/tests/methylation/
Yes, that's the one I did. Sorry I didn't have a link at hand.

Perhaps it would be better to wait before doing another methylation panel (albeit more thorough with HDRI). I'm planning to supplement with SAMe but maybe that would be counterproductive. I know Yasko recommends supplementation if you're low but I want to address the root problem too.
You're probably right. I tried supplementing SAMe but it didn't tolerate it very well and it didn't make any difference.

Google pulled up these studies:
http://ajcn.nutrition.org/content/76/5/1177S.full
http://www.ncbi.nlm.nih.gov/pubmed/26722840\
Which state ROS (reactive oxygen species) and NOS (nitric oxide) deactivate methionine adenosyltransferase while reduced-glutathione reactivates it.
Glutathione works for me and it helps with inflammation.
I have tried both normal GSH by Jarrow (500mg) and the super expensive Acetyl-Glutahtione and could not find any difference between the two so I am sticking with regulate GSH, 2x 500mg.

cheers
 

kyzcreig

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interesting, so I don't find oral glutathione makes a huge difference. at least normal GSH. but topical glutathione from kirkman or lee silsby makes my sleep much better and generally relieves symptoms.

the research around acetyl glutathione is compelling but when i tried it before i experienced the same as you. i might try it at much higher doses and see if that's noticeable.
 

PeterPositive

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interesting, so I don't find oral glutathione makes a huge difference. at least normal GSH. but topical glutathione from kirkman or lee silsby makes my sleep much better and generally relieves symptoms.

the research around acetyl glutathione is compelling but when i tried it before i experienced the same as you. i might try it at much higher doses and see if that's noticeable.
Good point. The dosage with Acetyl form is usually lower, the one I bought comes in 100mg capsules and they say to take up to three, so it's 300mg/day.

The Jarrow GSH (and most other brands) comes in 500mg and I've taken up to 3 a day. Even getting to a 1000mg with the Acetyl forms is pretty hard, requiring 10 caps... I've never tried that. I've tried up to 500mg and could not feel any difference. Kept going for a week and then I finished the bottle :) ... but I didn't continue since it is super expensive.
 

kyzcreig

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I agree, but if the alternative is doing 10-20 glutathione IVs, that seems cheap by comparison. I'm probably going to look into doing it wholesale somehow. I wonder if anyone would be interested in a group buy
 

kyzcreig

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Update: I've been taking large doses of acetyl glutathione, I buy directly from a laboratory in Italy (the same one that supplies Allergy Research) and have seen much improvement. You can buy it in bulk here: http://irc.bio/product/acetyl-glutathione/

I'm still not sure what to do about low SAMe. I tried the Niacin-Exercise-Sauna detox protocol and had a huge flare of symptoms. I'm guessing this was because Niacin is metabolized by SAMe and depleted my stores.

What can you do to raise SAMe cost effectively? IV therapy?

I've been reading a whole lot of the research on SAMe and the enzyme family the produces it (MAT: Methionine Adenosyl Synthetase). In adults there's two isozymes for MAT, one in the liver and one in the kidneys. The one in the liver is deactivated by Nitric Oxide (I am a pretty vascular guy so I must have a lot), and oxidative stress. So that might be suppressing it. Scientific literature is sparse. Glutathione is mildly effective at reactivating nitrosylated MAT. They also recommend supplementing with endogenous SAMe. But the bioavailability of SAMe is low and its half life is short so it's not a tenable solution.

I also read a study that demonstrated Glucocorticoids throttle the transcription of hepatic MAT. Another study verified this in humans. So, you could increase the amount of MAT enzymes by using hydrocortisone cream. In my subjective experience it works. But that has its own drawbacks e.g. messing with glucose metabolism.

Still, if I have highly elevated NO (iNOS), that's probably the root issue here. How do I lower it? Mercola on what raises NO:
  • Allergies (histamine)
  • Poor iron status
  • Hypoxia (oxygen deficiency)
  • Carbon monoxide exposure
  • Excess estrogen or 'estrogen dominance'
  • Others
Taking an anti-histamine does help with my MCS. I remember Dr. Rea (of EHCD Dallas) would prescribe histamine antigens, which deactivate histamine, and that helped too. Oxygen therapy via an oxygen concentrator or hyperbaric chamber also helps, but it can raise oxidative stress. Silymarin can help by increasing Glutathione recycling but lowers ferritin.

Of note, TGF-beta lowers NOS expression. I have elevated TGF-beta, so maybe that's the body compensating. Insulin raises NO too. I tend to be insulin sensitive, one naturopath told me he only sees this level of insulin sensitivity in olympic athletes.
 

renski

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There needs to be more information available about this MAT enzyme inhibition, but these are other possible causes:

MAT enzyme inhibition - can be due to inflammation, infection, gut dysbiosis, LPS from streptococcus, etc. Low energy/ATP, low magnesium and low potassium will also slow this enzyme
 
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@kyzcreig

I'm very interested in the points made in the Doctor's Data write up (you quoted some in your opening post). They seem very insightful about SAMe/Adomet. Does DD include different information depending if test results are high as opposed to low?

I hope you see this. I tried to message you but can't work out how to do it!

Thank you.