Hello, maybe I am flogging a dead horse here... But I have never gone into the details of the subject in the title. One fundamental question I have had for quite some time is, how so many people take long term (relatively) high doses of B3 (in the range of at least 250-1500mg) without apparent methylation issues. Dr Lynch briefly discusses the topic in this short podcast: http://www.seekinghealth.com/natural-health-podcasts/podcast-5-niacin-and-its-use-safely.html And provides a link to a study: http://www.ncbi.nlm.nih.gov/pubmed/11895163 where rats were given a dose of (1,000 mg/kg diet) niacin for 3 months which depleted B6 and B12 and caused a raise in homocysteine. (As Lynch proposes, they mechanism is probably the "stealing" of a methyl group to produce methyl-nicotinamide) Also this study: http://www.ncbi.nlm.nih.gov/pubmed/22971213 clearly suggests that high dose niacin/niacinamide cause methyl consumption. Again they tested humongous dosages ( 0,5-2,4g / kg ) on rats. I have no idea how this applies to humans. Even at the lowest dosage they used (500mg/kg) we're talking about 35 grams of B3 for a 70Kg man/woman. It's unthinkable. Bottom line... it seems that niacin/niacinamide could be dosed in the range of 100-500mg, or more when needed, even in people with methylation issues without causing problems. Naturally, people with methylation deficiencies should already be supporting the problem with adequate amounts of methyl donors. Also this is a generalization and it will always miss specific exceptions. I've read several people in here reporting methylation-related issues with relatively low doses of B3. Experimentation is usually required. Personally I have always been "scared" of taking more than 50mg of B3 as it seemed some sort of dangerous threshold. Since early 2015 I have started taking more and it seems to be helping without noticeable downsides. What do you think?