So we all know that some people are quite sensitive to methyl donors and cannot even tolerate the smallest dose of say, methylfolate, while others can take 5mg from the get-go and feel fine. It's a popular theory that COMT and CBS polymorphisms result in sensitivity to methyl donors because these individuals slowly degrade catecholamines and methyl donors increase said catecholamines, so there's a bottleneck that causes a whole host of issues. I believe this is from Yasko's interpretation of the literature, but I have read a few posts on this forum (some from @alicec) that say that the COMT correlation to methyl donors is just a coincidence and not substantiated in any good data. That being said, what is the root cause to sensitivity to methyl donors? I wonder if trying to associate methyl donor intolerance to some SNP's is too reductionist but I can't think of anything else. Also, does anyone know if caffeine, curcumin and melatonin are methyl donors?