Here are some thoughts I have. If anyone can show me if and where they are either right or wrong, that would be great. Folate is recycled many times through the methylation cycle, so if you take methyl folate, each molecule only contributes one methyl group to the production of SAMe and then it has to be remethylated before it can be used for that purpose again. I think that the reason taking methyl folate helps has little to do with the fact that it is methylated. I have a theory to propose that I believe applies to other areas in the methylation cycle and could be very helpful. Theory: If the product of an enzyme is lower than needed in the body, then a higher amount of either the substrate (the thing the enzyme works upon, or one or more cofactors is needed. (I am using cofactors loosely to mean anything that the enzyme needs to do its job, even if the thing is a part of the enzyme, such as zinc is a part of methionine synthase). If this is the case then the advantage of taking 5mg of methylfolate for someone who has the MTHFR C677T gene mutation is that because the enzyme is weak, it needs more substrate to work upon, assuming that there are enough methyl groups in the pool to draw from, and folate is the substrate of MTHFR, so giving 5 mg of methylfolate gives a person a lot of folate. I don't see why it makes any difference if the folate is in the form of folinic acid, the form of folate usually found in food, or methylfolate. The tiny amount of methyl groups in 5 mg of methylfolate isn't going to be enough to methylate grams of homocysteine. Where does the pool of methyl groups come from? I have heard that it comes from stomach acid, so you may need to take swedish bitters or something to increase your stomach acid, but I am really not too knowledgeable here. So according to my theory if a person does not have enough SAMe, they need to look at their level of the substrate, homocysteine, and the levels of the cofactors of the methionine cycle. The cofactors here are: folate, zinc, B12, and in some cases perhaps the levels of their methyl pool in the form of stomach acid. I believe that when people take SAMe in large amounts and find that it helps their symptoms of depression or whatever, it is not the SAMe itself that is helping them, but the fact that if you take, say, 1000 mg of SAMe each day, you are adding one gram of the substrate of the methionine cycle. They could get the same effect by taking 1 gram of methionine each day for a lot less money. You may ask: Why would a person be low on this substrate? It could be because they have gut dysbiosis and they no longer are able to digest and absorb the methionine. Or they could have a higher need for SAMe for a variety of reasons, than they can get from their diet. If a person is low on the substrate, taking a large amount of the cofactors can sometimes draw more of the substrate into the cycle, but only temporarily. This is why sometimes taking methylfolate or B12 has a dramatic effect at first, but then stops working as well. If that is the case, you need to get more of the substrate, which for SAMe is methionine. What about people who are sensitive to methyl groups? Why are some people sensitive, and others not? I think this has something to do with COMT and niacin, especially niacin. I will use my son who has schizophrenia as an example. This relates to depression, also. I believe that often low SAMe levels are a result of histamine in the body. High histamine can be caused by allergies or by gut bacteria. My observation is that histamine depresses the levels of dopamine and norepinephrine because high histamine MUST be balanced with epinephrine and the dopamine and norepinephrine levels are drained to be made into epinephrine. High epinephrine also causes a feedback loop to lower the amount of the enzyme that produces dopamine leading to constant low dopamine and norepinephrine. The higher the histamine levels the lower the dopamine and norepinephrine, even enough to cause deep depression in the cases where a person does not have enough tyrosine. Taking tyrosine supplements will help a lot for the deep depression, but the levels of dopamine and norepinephrine will be somewhat low even with lots of tyrosine as long as the epinephrine levels are high because of the feedback loop. I am speaking from experience here. Normally epinephrine levels are high only very briefly, but stress or histamine can keep them high on a continual basis. Since histamine is degraded by SAMe, when the person raises SAMe levels the histamine levels will return to normal and the levels of dopamine and norepinephrine will rise. The COMT enzyme must have SAMe and niacin to work. When we take cofactors and substrates such as folate and B12 to help our methylation cycle we raise the level of SAMe. But even if a person does not have COMT mutations, they will not be able to get rid of dopamine and norepinephrine effectively if they don't have enough niacin. My son who has schizophrenia gets symptoms of overmethylation when he takes folate and B12. He has taken large amount of niacin in the past with no results, but I didn't know at that time that he probably has a mutation that makes it hard for him to absorb folate, so that was probably lowering his SAMe. He even tested low in folate at that time, but we thought that just supplementing the “normal” amount would be sufficient. In order for him to get rid of his excess dopamine (which is believed to be a great problem in schizophrenia) he has to have sufficient levels of both SAMe and niacin, at the same time. I think that what is commonly called overmethylation is really underniacinization; the person for some reason needs more niacin than other people to regulate their levels of catacholamines or they just don't have enough niacin. So with my son what we are trying to do is learn the correct amounts of all the supplements he needs to take to have enough SAMe and enough niacin to keep his dopamine levels in the correct range. It is too early to tell, but it seems to be helping him. You don't want to take huge amounts of niacin, because that will lower your SAMe levels too much because it is a methyl sponge. So for people who are called overmethylators, perhaps the answer is to take whatever amount of folate and B12 and perhaps methionine they need along with some niacin in whatever amount keeps the overmethylation symptoms away. If you try this I would sure like some feedback on how well it works and what amounts of different substrates and cofactors you find works for you.