A little TMG is often helpful when methylfolate and B12 supplementation are started, because it can help to raise SAMe, needed for recycling methyl B12. After these supplements are well underway and methionine synthase is coming up in activity, the TMG can be stopped, or DMG can be added to counter the BHMT pathway, so as to route more of the homocysteine to the methionine synthase pathway and the transsulfuration pathway.
Some people have had good experience with methylcobalamin. It can be especially helpful if a person has a shortage of methyl groups, though that can also be helped by taking some additional trimethylglycine (some of which is in the multi that is part of the simplified treatment). or some SAMe. It's used a lot subcutaneously by the DAN! doctors in autism treatment, and as you probably know, freddd on this forum advocates its use as well. In his case, because of a mutation in the intracellular B12 processing enzymes, his body is not able to utilized hydroxocobalamin readily. But I believe that this is a rare situation, based on the published literature. freddd does not agree that it is rare, based on his experience.
TMG stimulates the BHMT (betaine homocysteine methyltransferase) reaction, as it is a reactant for it. This reaction takes place in the liver and kidneys. It is an alternative pathway for converting homocysteine into methionine, and it will help to produce SAMe in those organs.
There are a couple of ways that it might produce symptoms. One is that it will initially lower the flow of homocysteine into the transsulfuration pathway, so the rate of production of glutathione may drop lower initially. So symptoms could be caused by initially making the glutathione depletion somewhat more severe.
Another possible mechanism is that it can also take homocysteine away from the main methionine synthase pathway initially, and that will impact the folate metabolism, since the conversion of methylfolate to tetrahydrofolate will decrease in the liver and kidneys.
Betaine and TMG are the same substance. Betaine HCl has a hydrochloric acid molecule bound to it. Yes, if you take betaine HCl, you will also have the benefit of TMG. However, note that TMG stimulates the alternative BHMT pathway from homocysteine to methionine in the liver and kidneys. TMG will promote production of SAMe, but it can shunt flow away from the methionine synthase enzyme, which is partially blocked in ME/CFS. It's important to get this enzyme going, because it is linked to the folate metabolism, which is needed to make new DNA and RNA, and also because it regulates the entire sulfur metabolism. In Amy Yasko's protocol, she recommends starting with some TMG, and then after the B12 and folate have been built up some, to add DMG, which will inhibit the BHMT reaction by product inhibition, and that will push more of the homocysteine through the methionine synthase reaction. The benefit of doing TMG first is that it can increase the level of SAMe, and that is needed by the methionine synthase reductase reaction, which rescues the cobalamin coenzyme of methionine synthase when it becomes oxidized, thus restoring it to the +1 oxidation state and giving it a methyl group, so that it is a functional methylcobalamin molecule again. I don't know what dosage of betaine HCl will interfere with the methionine synthase reaction. Some people use the Allergy Research Group's dilute HCl solution to augment their stomach acid, and then there is no TMG (betaine) involved. Others use lemon juice (note that it is important to use a drinking straw and to flush the teeth with water afterward, because the citric acid in lemon juice chelates calcium and can damage the enamel on the teeth over time).