57 replies to this topic

[OneScrewLoose]

A while back I was taking SAM-E 400mg for a while and it helped, but it was hurting my stomach. I stopped taking it and I haven't felt quite the same since. I had also heard about some people having a defect (about 8-9%) with MTHFR which methylates folate to methylfolate. I figured that, seeing this diagram,

http://www.ds-health...bst/folate2.jpg

if I do have this genetic problem, then there is a good chance that I would have elevated levels of homocysteine since there is not enough methylfolate to go with it. So I got my homocysteine levels checked and I found out that they indeed are elevated. Ordered l-methylfolate today and am gonna have my levels rechecked a week or so after. Will update.

[PiMZ]

MTHFR might not be an issue, the topic was addressed here:

http://www.imminst.o...o...st&p=243509

Somewhere there was a comment where it was noted that some increased risks are seen only in populations in where there is no widespread riboflavin fortification (that is, outside of US). Couldn't t find the reference, however....

For example, 23andme covers the relevant polymorphisms for MTHFR, in particular, the following SNP:

http://www.snpedia.c...x.php/Rs1801133

(I have this 70% reduction in activity but homocysteine is 5.9 umol/L.)

A while back I was taking SAM-E 400mg for a while and it helped, but it was hurting my stomach. I stopped taking it and I haven't felt quite the same since. I had also heard about some people having a defect (about 8-9%) with MTHFR which methylates folate to methylfolate. I figured that, seeing this diagram,

http://www.ds-health...bst/folate2.jpg

if I do have this genetic problem, then there is a good chance that I would have elevated levels of homocysteine since there is not enough methylfolate to go with it. So I got my homocysteine levels checked and I found out that they indeed are elevated. Ordered l-methylfolate today and am gonna have my levels rechecked a week or so after. Will update.

[spacetime]

If homocysteine is a concern then methylcobalamin would be another option. But I wonder if they are all hydrolyzed before uptake.

[OneScrewLoose]

If homocysteine is a concern then methylcobalamin would be another option. But I wonder if they are all hydrolyzed before uptake.

It's not the homocysteine itself that I was concerned about but that if there's enough methylfolate to go with it in order to make the methionine and then SAM-E.

[4eva]

It's not the homocysteine itself that I was concerned about but that if there's enough methylfolate to go with it in order to make the methionine and then SAM-E.

I don't think your body can make methionine. That's an essential amino acid. I believe SAMe comes from recycling HCY (if you don't supplement it).

But those with MTHFr SNP need either methionine or SAMe too because those are the main methyl donors. Methylfolate and methyl B12 are important but are not considered as important a methyl donor as SAMe.

I think the addtion of TMG can help when HCY is high.

I think retesting in a week may not be enough time to see any change; but your doctor will probably recommend a time frame for you.

[OneScrewLoose]

It's not the homocysteine itself that I was concerned about but that if there's enough methylfolate to go with it in order to make the methionine and then SAM-E.

I don't think your body can make methionine. That's an essential amino acid. I believe SAMe comes from recycling HCY (if you don't supplement it).

But those with MTHFr SNP need either methionine or SAMe too because those are the main methyl donors. Methylfolate and methyl B12 are important but are not considered as important a methyl donor as SAMe.

I think the addtion of TMG can help when HCY is high.

I think retesting in a week may not be enough time to see any change; but your doctor will probably recommend a time frame for you.

Am I misunderstanding the diagram of the folate cycle I linked to? It shows methylfolate combining with/using HCY plus a few other things to make methionine. Can someone link to/describe in greater detail how this works?

[4eva]

You need methylfolate and SAMe or methionine with some other things (besides B6, B12).

You were only taking SAMe but not methylfolate. Using only one of those is incomplete supplementing.

People pay good money to supplement SAMe I don't think you found a way around buying that supplement if you undermethylate.

Undermethylation means there is not enough methyl donors. TMG and SAMe are methyl donors. And UM effects folate status; and that's why methylfolate is also needed.

SAMe is basically the same as methionine an essential amino. Your body can't make essential aminos.

Here is some basic info from wikipedia entry on methionine.
As an essential amino acid, methionine is not synthesized in humans, hence we must ingest methionine or methionine-containing proteins.

There are two fates of homocysteine: it can be used to regenerate methionine, or to form cysteine.

Methionine can be regenerated from homocysteine via (4) methionine synthase. It can also be remethylated using glycine betaine (NNN-trimethyl glycine) to methionine via the enzyme Betaine-homocysteine methyltransferase (E.C.2.1.1.5, BHMT).

http://en.wikipedia....wiki/Methionine

[stephen_b]

It seems to me that the last thing people with high homocysteine would want to do is supplement methionine. It will just drive their levels higher. It's easy to get plenty methionine without trying; methionine is a hard thing to avoid. There are even low protein diets out there for people with high homocysteine.

"Effect of L-methionine supplementation on plasma homocysteine and other free amino acids: a placebo-controlled double-blind cross-over study" (PMID 15870821, involving women with and without urinary tract infections):

...After a methionine-loading test, the volunteers received 500 mg L-methionine or a placebo three times daily for 4 weeks. ... RESULTS: Homocysteine plasma concentrations increased from 9.4+/-2.7 micromol/l (patients) and 8.9+/-1.8 micromol/l (controls) in the placebo period to 11.2+/-4.1 micromol/l (P=0.031) and 11.0+/-2.3 micromol/l (P=0.000), respectively, during L-methionine supplementation. ... CONCLUSIONS: Despite an adequate vitamin status, the supplementation of 1500 mg of L-methionine daily significantly increases homocysteine plasma concentrations by an average of 2.0 micromol/l in patients and in control subjects.

Here's my current anti-homocysteine stack:

• methylfolate: 2400 mcg split into morning and evening doses
• b6 as p5p: 200 mg split into morning and evening doses
• b6 as pyridoxamine: 100 mg at supper
• methyl-b12: 5000 mcg sublingual (actually I wonder if this is too much)
• TMG: 3 g at supper

StephenB

[Chris39]

Can somebody please update me on the status of homocysteine. I talked to my doctor the other day regarding my high value (now >16 umol/L). He told me not to worry, because homocysteine has been removed from the list of relevant markers 2 years ago. He even advised me not to test it anymore and go to a nice restaurant with the money instead.

Half a year ago my homocystein was 14.5 umol/L and therefore I started taking the following:
- Folic Acid 800 mcg
- B6 as p5p: 80 mg
- B6 as pyridoxamine: 50 mg
- Methyl-B12: 1000 mcg sublingual
- TMG: 1 g

The result was an increase of 1.5 umol/L.

[kismet]

Can somebody please update me on the status of homocysteine. I talked to my doctor the other day regarding my high value (now >16 umol/L). He told me not to worry, because homocysteine has been removed from the list of relevant markers 2 years ago.

I'm pretty sure he's wrong. It's not the marker, but it's toxic in vitro, correlates with endpoints in most epidemiologic trials and lowering homocysteine (if you're high to begin with) is benefical (e.g. (1)). The last thing I've read in the literature is that we can't tell yet, because some big RCTs are still under way (but it's definitely less important than we believed it to be).
However, possible risks of high dose folic acid should be taken into account when supplementing to reduce homocysteine. There may be some pretty serious risks for instance: "...prostate cancer [incidence] over a 10-year period was 9.7% (95% confidence interval [CI] = 6.5% to 14.5%) in the folic acid group and 3.3% (95% CI = 1.7% to 6.4%) in the placebo group (age-adjusted hazard ratio = 2.63, 95% CI = 1.23 to 5.65, Wald test P = .01)" (2)
Does anyone remember who warned us of folic acid some time ago?

I don't get why your homocysteine increased? Any ideas?

(1) Stroke. 2009 Mar;40(3):730-6. Epub 2008 Dec 31.
High-dose B vitamin supplementation and progression of subclinical atherosclerosis: a randomized controlled trial.
Hodis HN, Mack WJ, Dustin L, Mahrer PR, Azen SP, Detrano R, Selhub J, Alaupovic P, Liu CR, Liu CH, Hwang J, Wilcox AG, Selzer RH; BVAIT Research Group.
(2) J Natl Cancer Inst. 2009 Mar 18;101(6):432-5. Epub 2009 Mar 10.
Folic acid and risk of prostate cancer: results from a randomized clinical trial.
Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS, Burke CA, McKeown-Eyssen GE, Baron JA.

Edited by kismet, 15 May 2009 - 10:17 AM.

[bgwithadd]

Forsk0lin and TMG, here you come.

[4eva]

Can somebody please update me on the status of homocysteine. I talked to my doctor the other day regarding my high value (now >16 umol/L). He told me not to worry, because homocysteine has been removed from the list of relevant markers 2 years ago. He even advised me not to test it anymore and go to a nice restaurant with the money instead.

Half a year ago my homocystein was 14.5 umol/L and therefore I started taking the following:
- Folic Acid 800 mcg
- B6 as p5p: 80 mg
- B6 as pyridoxamine: 50 mg
- Methyl-B12: 1000 mcg sublingual
- TMG: 1 g

The result was an increase of 1.5 umol/L.

Did you notice any improvement in mood, energy or anything else from this combo?

HCY levels are important. If you see this doctor again just ask him to explain why this is no longer a marker.

My understanding is that high HCY usually indicates undermethylation. Overmethylators may actually have too low HCY. (And too low is possible regardless of lab ranges.)

Folic acid is for overmethylators. TMG is for undermethylators with high HCY.

You should try some SAMe, methylfolate, B6, B12, calcium/magnesium and TMG as a start to lower HCY. There are other supplements but that would be a start to see if this approach helps.

I said usually high HCY is an indication of undermethylation. If your over 50 then that general rule may not apply as much then if your relatively younger.

[Chris39]

Thanks! I am 39 and did not really feel any improvement from taking those supplements. I have also no idea why it might have increased (no change in eating habits etc.).

Those possible risks of high dose folic acid do certainly not sound good. Do they apply to methylfolate as well? If not, I think I will try the methylfolate, the SAMe and increase the TMG to 2000 mg. This should hopefully do the trick.

[4eva]

There are two forms of folate. Not everyone needs the newer methyl form. Those that need methylfolate have MTHFr (or undermethylate). Regular folic acid is not good for them because it can become trapped. Regardless of what dose they take their serum levels can be high because its trapped (not being metabolized properly).

If a study say folate is good or bad I think it needs to be viewed in a context regarding ether genetics or methylation. The different forms can have different effects. Its not one size fits all. You can supplement according to some study that has nothing to do with your genetics or you can supplement according to your own personal needs.

Of course you shouldn't just follow what I say or what anyone else says here; do your research and decide for yourself what's right for you.
I think TMG is good for helping to lower HCY. But SAMe is the best methyl donor. So I think you should be taking both of those until your HCY levels stabilize. Then you may be able to drop the TMG.

Its important to work with a doctor who is willing to do tests to ensure you're on the right path. The wrong supplements can make things worse.

[OneScrewLoose]

If methionine increases HCY, wouldn't SAM-E do the same as well?

[4eva]

Those are considered methyl donors. Undermethylators need methyl donors.

What causes high HCY is faulty methylation. They only use a methionine load test if you have high HCY. Thats becsause the high HCY is reason to believe there is a problem with methylation. And taking methionine only - without the three B vitamins that help methylation (B6, B9, B12) - will indicate if a high HCY person can not metabolize methionine. There is a right way and a wrong way to supplement SAMe or methionine.
I think you supplemented SAMe the wrong way because you didn't taken enough methylating B vitamins (and other augmenting nutrients).

Your were not taking enough B6 I think and your were not taking methyl folate with SAMe.

SAMe (or TMG) alone will not lower HCY. Methylation is a complex process. Those three B vitamins are important. Just about any single nutrient can potentially cause a problem if not supplemented properly, (augmented properly) like calcium, vitamin A, or folic acid without B6 and B12.

http://www.smart-dru...sSouth-SAMe.htm

Edited by 4eva, 15 May 2009 - 09:29 PM.

[spacetime]

Isn't homocysteine reduced or converted to glutathione via transulfuration pathway? Why not target this pathway instead of the remethylation pathway that converts it to methione and them SAME? This would be indesireable because it would severly limit production fo methyl donors? So, then maybe we want to inhibit the transulfation pathway?

[OneScrewLoose]

What would you say is a good dose of L-Methylfolate? Also, I wouldn't have to supp B12 if I am using methylfolate because once its demethylated it's just B12, right?

[4eva]

I've read that you take methylfolate twice a day. (I don't take this myself.)

I would try 800 mcg twice a day to start (if it comes in that dose). Otherwise 400 mcg twice a day. I think Deplin is 2 mg maybe so there are much higher doses available by prescription.

You might wait about a week to increase dose (if you don't take B12).

If I had high HCY I would want to make sure I have all the nutrients that help methylation. I guess you might add in the B12 later. But I don't understand why you don't want to take or think you don't need it.

If methylfolate demethylates to B12 I would think that's really only true if your healthy and don't have any methylation or nutritional problems.

[OneScrewLoose]

I've read that you take methylfolate twice a day. (I don't take this myself.)

I would try 800 mcg twice a day to start (if it comes in that dose). Otherwise 400 mcg twice a day. I think Deplin is 2 mg maybe so there are much higher doses available by prescription.

You might wait about a week to increase dose (if you don't take B12).

If I had high HCY I would want to make sure I have all the nutrients that help methylation. I guess you might add in the B12 later. But I don't understand why you don't want to take or think you don't need it.

If methylfolate demethylates to B12 I would think that's really only true if your healthy and don't have any methylation or nutritional problems.

Well, the methylation problem occurs at MTHFr, right? Being that the case, wouldn't methylfolate be used and quickly demethylated?

[4eva]

You said that SAMe made you feel good. You didn't want to stop taking it you said not that long a go. Since then I assume you had lab results show high HCY. Now you think SAMe is bad and don't take it, based on your interpretation of a methylation diagragm.

Now you seem to think methylfolate is the answer.

Chris posted he was taking TMG and regular folic acid and his HCY levels went up. Everyone can make mistakes supplementing. The point is to learn from your mistake so you don't repeat that same mistake or same kind of mistake.

Correcting undermethylation requires more than one supplement/nutrient. And it can be a trial and error process getting the right nutrients and right dosages. But I don't think focusing on methylfolate only is the right approach.

If that's what you want to do then good luck with that.

[OneScrewLoose]

If methionine increases HCY, wouldn't SAM-E do the same as well?

This was a question, not a statement. I don't plan to do this with methylfolate alone, but I am trying to get all the info I can.

So, from what I understand, the supps I need so far are:

B6
Methylfolate
B12 (still dont see why I need this if i have methylfolate)
TMG
SAM-E

[PiMZ]

If methionine increases HCY, wouldn't SAM-E do the same as well?

This was a question, not a statement. I don't plan to do this with methylfolate alone, but I am trying to get all the info I can.

So, from what I understand, the supps I need so far are:

B6
Methylfolate
B12 (still dont see why I need this if i have methylfolate)
TMG
SAM-E

and perhaps riboflavin (B2) that was mentioned in the first reply.

[4eva]

If methionine increases HCY, wouldn't SAM-E do the same as well?

This was a question, not a statement. I don't plan to do this with methylfolate alone, but I am trying to get all the info I can.

So, from what I understand, the supps I need so far are:

B6
Methylfolate
B12 (still dont see why I need this if i have methylfolate)
TMG
SAM-E

It is a question based on an assumption; the assumption that methionine increases HCY. That is generally not true.

This link breaksdown all the different parts of the methylation cycle and what supplements are needed for each SNP.

http://www.heartfixe.....hyl Cycle.htm

[stephen_b]

It is a question based on an assumption; the assumption that methionine increases HCY. That is generally not true.

Did you see my post #8 in this thread? That study (PMID 15870821) found that methionine supplementation directly raised homocysteine. Supplementing 500 mg of l-methionine three times daily in 12 healthy women controls raised homocysteine 2.1 micromol/l on average for this group.

One method of detecting hyperhomocysteinemia is the methionine loading test. From this article,

Hyperhomocysteinemia was defined as a fasting homocysteine concentration and/or an increase in homocysteine concentration after methionine loading exceeding the 95th percentile of a healthy control group.

Additionally, "Methionine-loading rapidly impairs endothelial function" (PMID 18838525) and reducing it in the diet promoted longevity in rats.

StephenB

[4eva]

"Despite an adequate vitamin status" is what it says about those who had higher HCY levels from supplemental methionine.

What does adequate vitamin status mean? Were these "healthy" controls given any genetic testing?

If you don't get genetic testing you don't know what specific problems you may have in the methylation cycle.

There is a less precise distinction of under and over methylation. Did that study distingish if those "healthy" subjects were UM or OM?

If you have the right genetics or right kind of faulty methylation (over or under) you can probably get the results you want.

Adequate vitamin status is too vague.

Methionine is a methyl donor and it is a fact that it won't help some people (overmethylators). Women generally speaking tend to be overmethylators. But that is a generalization that is not true 100% of the time. Overmethylators do not need methyl donors because it can have negative results (it speeds up their overmethylation).

I don't see what that study is showing besides the fact that some (vague category) people with adequate vitamin status should not supplement with methionine. That study is useless.

They could get the same results if they used methylfolate although methylafolate is not as significant a methyl donor as methionine or SAMe. Some people do not need methylfolate and should not take it because it can make their overmethylation worse.

[Chris39]

My result from 23andme just arrived. Rs1801133 is AA. Can anybody please translate this?

[stephen_b]

My result from 23andme just arrived. Rs1801133 is AA. Can anybody please translate this?

Rs1801133 is the same as C677T.

From this source,

Part of the MTHFR gene which codes for an enzyme used in Folate metabolism (methylenetetrahydrofolate reductase). The "Normal" encoding is GG at rs1801133 (In literature -CC negative strand). With "AG" at rs1801133, the enzyme is 60% efficient, and with "AA" the enzyme is 30% efficient (compared to "Normal"). Folate and Vitamin B12 are often co-factors (a deficiency in one can be masked by adequate levels of the other). Insufficient levels of Folate and/or B12 can result in higher levels of homocysteine. High levels of Homocysteine are associated with various different health issues.

See also the snpedia entry.

I'd like to get myself tested sometime too, as I suspect I have an impaired folate metabolism.

StephenB

[Chris39]

Thanks! So this finally does explain my high homocysteine level. I better start ordering methylfolate/metafolin and SAMe then.

[OneScrewLoose]

For some reason I thought Folate was B12. It's B9, so that's why I was confused above. Right now for Methylation, I am taking Metanx + TMG. Metanx is a prescription that has P5P, Methylfolate and Methylcobalamin.