Why not only SAM-e?

Most under-methylators are low in "everything" (homocysteine, SAMe, methionine, B6, Calcium, Magnesium, Zinc, Glutathione, Creatine, etc.) and what they need is more methyl. VITAcure Methyl Plus contains "everything" except SAM-e. An exception to this is folate: folate is essential in the methylation cycle*, but under-methylators are often too high in folate, and folate tends to accumulate and trap methyl, so avoid supplementation of high dose (but some is eventually necessary)!

Initially, homocysteine is TOO LOW with under-methylators. That could cause some problems since SAM-e converts from Methionine in our cells, which again converts from homocysteine. When there is not enough homocysteine, there will be problems creating enough methionine, etc. One should however not supplement directly with homocysteine, but start with SAM-e which again converts to homocysteine (therefore it is important to start with SAM-e before, or at the same time as carefully introducing VITAcure Methyl Plus).

There are of course other supplements that are helpful for under-methylators. For instance inositol (may reduce anxiety, promote sleep, critical to signaling, counterbalances choline, supports folates, B6, B12, TMG, and methionine). Tryptophan (serotonin support - helps balance mood and is often depleted). Both of these make you very sleepy, so you are better off taking these before sleep.

You could have problems converting homocysteine back to SAM-e quick enough. Supplementing with SAM-e will solve the initial problem of lacking SAM-e which is the principal methyl (CH3) donor in all cells of the body. The release of methyl increases, which you will notice giving you plenty of advantages if you are low (read: undermethylated). 

SAM-e converts to SAH (S−Adenyl Homocysteine) by giving away a methyl group (CH3). And SAH is quickly transformed into homocysteine (HCY), which is more stable than SAH. Then HCY is converted back to SAM-e via B12/folate/TMG pathways. We all have this cycle in our cells. It takes place more than a billion times per second in the body. That should give you some idea of how important methylation is. If it did not happen, we would not be alive, but the SPEED of this process vary from one individual to another. Higher SPEED results in more methyl (CH3).

You can end up with a higher level of homocysteine if you only supplement with SAMe unless you also provide the cofactors to help conversion back to SAMe. Check the risks (vascular problems etc.)! And you don't want heart attacks, strokes, and even Alzheimer/dementia.

Be aware if you have high homocysteine levels before you try SAMe. Most undermethylated people have low homocysteine (contrary to what many people think) due to a slower methylation cycle, so that should not be a problem for most people. High levels of homocysteine results in narrowing of blood vessels, and small concentrations the opposite.

If the cells convert homocysteine back to methionine or cysteine more efficiently via different pathways, you can avoid the problem of homocysteine buildup, and more SAM-e is produced in your cells, reducing the need of supplementing with SAM-e after a while. And this is where VITAcure® Methyl Plus plays an important role, facilitating all the pathways, and also helping the cells to speed up the methylation cycle.

Some tend to think methylfolate alone will solve the problem. The problem is that folate is usually already high with histadelics (under-methylators), and it can cause symptom flareups, as (along with B12) it can increase the trapping of methyl molecules, so they need to restrict folate (B complexes are often too high in folate).

There are many other cofactors required. However, we will not go into detail explaining everything here. For instance, Magnesium is critical in metabolizing methionine to SAM, and absorbable form is crucial (avoiding aspartate or -glutamate). Calcium releases, and so lowers, histamine. Deficiency can directly cause histamine elevation. Calcium also supports catecholamine release into the synapse and is often depleted with under-methylators. Zinc counters overstimulation and supports homocysteine metabolism to cysteine or methionine, and is often depleted with under-methylators and even more so with pyrolurics. Zinc methionine is one of the two bio-available forms and the best choice for under-methylators and is for instance needed for synthesis of GABA in brain. Glutathione is needed to create homocysteine from SAH, and to methylate B12, so it can turn homocysteine to methionine, and is depleted by oxidative stress. Vitamin B-6 is an essential co-factor in synthesis of serotonin and in metallothionein formation, it also helps metabolize homocysteine to cysteine (we use the active form P5P coenzymated B6). Selenium (antioxidant support) from yeast is the best form of selenium. Vitamin C is an important antioxidant that decreases histamine, moderates stimulation and also antidepressant. Riboflavin 5-Phosphate is the bioactive, tissue ready form of riboflavin, which is an essential cofactor for the formation of other B vitamins, and necessary for methylation pathways in the body. NAD is used in the methylation cycle and is also directly involved in neurotransmitter production.

Creatine is produced naturally in the human body. As much as 70%(1) of the SAMe is used in the creatine synthesis. Creatine is necessary for maintaining both muscle and brain tissue. Careful supplementation of creatine could help you even more with increasing methylation/SAMe, and at the same time give you other benefits both for muscles and your brain where the demand for creatine is high. 








*Methylation cycle (Methionine->SAMe->SAH->Homocysteine->Methionine...):

A concise overview of homocysteine metabolism, with open arrows indicating metabolic fluxes, ovals indicating enzymes and italics indicating vitamins. Homocysteine is the transmethylation (TM) product of the essential sulphur-containing amino acid methionine, with SAMe and SAH as intermediates. Homocysteine can be either remethylated to methionine or degraded by trans-sulphuration (TS). In the folic-acid-dependent remethylation reaction, which is catalyzed by methionine synthase (MS) and uses vitamin B12 as a cofactor, 5-methyltetrahydrofolate (5-MTHF) donates a methyl group to homocysteine. Subsequently, tetrahydrofolate (THF) receives a methylene group from the serine/glycine couple, a reaction that uses vitamin B6 as a cofactor. Tetrahydrofolate can also be generated by reduction of supplemented synthetic folic acid to dihydrofolate (DHF) and subsequently to THF. Next, 5,10-methylenetetrahydrofolate (5,10-MeTHF) is reduced to 5-MTHF, requiring the enzyme methylenetetrahydrofolate reductase (MTHFR). Another folic-acid-independent remethylation reaction, uses betaine (TMG) as a methyl group donor, generating dimethylglycine (DMG). In the irreversible catabolic (trans-sulphuration) pathway, the rate-limiting reaction is catalyzed by cystathionine β-synthase (CBS) and requires the active form of vitamin B6 as a cofactor.



Numbered reference list:
1. https://www.walshinstitute.org/uploads/1/7/9/9/17997321/methylation_epigenetics_and_mental_health_by_william_walsh_phd.pdf [page 21]



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