These are some articles that discuss some old research using 25-1,000 mg/d (25,000-1,000,000 ug/d) of folic acid in humans [Boss et al., 1980: (http://www.ncbi.nlm.nih.gov/pubmed/6893465); Zettner et al., 1981: (http://www.ncbi.nlm.nih.gov/pubmed/7325593); McCarty, 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17224245)]. I'm not suggesting anyone would ever want to take such a high dose. The fact that doses that high were well-tolerated and produced no evidence of toxicity tends to make the dosages of 30 mg/d [()] or 50 mg/d [()] or 90 mg/d [()] of reduced folates (methylfolate or L-folinic acid) look less risky or unreasonable, at least from the standpoint of planning clinical trials. There are also many articles [here's one: Nishiyama et al., 2000: (http://ajp.amjpathol.org/cgi/content/full/157/3/815) (http://www.ncbi.nlm.nih.gov/pubmed/10980121?dopt=Abstract)] in which the authors describe the use of intraperitoneal, bolus injections 450 mg folic acid/kg bw, in rats (200-250 g, adult rats), as a way of inducing acute renal failure. That scales to a human dose of more than 9,000 mg [450 mg/kg bw of rat/4.71 = 95.5 mg/kg bw of human = 6,688 mg/d for a 70-kg human; even if one uses the most conservative scaling factor of 10, meant for the high mass-specific metabolic rates and surface-area-to-mass ratios of mice, this ends up being 3,150 mg/d for a 70-kg human (3.15 million micrograms)], and the i.p. injection probably potentiates the effect on the kidneys. That type of dose is 100-200 times the largest dose of a reduced folate that's been used in a serious clinical trial. Even something like phosphate can induce acute renal injuries, and some of the phosphate preparations used to prepare people for colonoscopies have been linked to acute kidney damage ("acute phosphate nephropathy") in some people (http://www.usatoday.com/news/health/2008-12-11-colonoscopy-drugs_N.htm?csp=34).
One of the researchers (Oster) whom McCarty (2007) discussed had been researching folic acid as a xanthine oxidase inhibitor, and folic acid turned out not to be a xanthine oxidase inhibitor. One can say the researchers who were using 80 mg/d of folic acid didn't understand the mechanisms or understand that most of that high of a dose is absorbed as unmetabolized folic acid, but the researchers were using folic acid to treat essentially the same conditions that methylfolate or folinic acid or lower-dose (15 mg/d) folic acid are being researched for the treatment of today (peripheral arterial disease, enhancing nitric oxide-dependent vasodilation, wound healing in people with diabetes). Even though Oster, a researcher discussed in the article by McCarty (2007), didn't know it, his use of higher doses of folates was 20-30 years ahead of the game. It looks like Boss, Zettner, Seegmiller, and colleagues [Boss et al., 1980: (http://www.ncbi.nlm.nih.gov/pubmed/6893465); Zettner et al., 1981: (http://www.ncbi.nlm.nih.gov/pubmed/7325593)] weren't really using high-dose folate clinically, as Oster had been using it, but were just trying to test the hypothesis that folic acid had been producing some of those effects by acting as a xanthine oxidase inhibitor.
I suppose the ends don't necessarily justify the means, but researchers don't have an understanding of the precise mechanisms involved in many treatments. And the dosages being used in clinical trials are still all over the ballpark, today, and are not necessarily any less arbitrary than they used to be. There tends to be maximal reduction in homocysteine in response to 5-15 mg/d of folinic acid, but that's probably just saying that the concentration of intracellular total folates in the liver is at a level that maximizes methionine synthase activity in the liver. It doesn't really say much about the intracellular folate levels in extrahepatic cells, even though a given serum folate level may allow one to predict the concentrations of intracellular folates in a cell outside the liver. There's a great article [Brown et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16469322)] showing that there are growth-related ("trophic") effects of 9.3 uM extracellular folic acid on cultured cells (drastically-different cell morphologies, etc.), and the homocysteine and S-adenosylmethionine + S-adenosylhomocysteine levels and rates of efflux from the cells were the same for the cells in both the high-folate (9.3 uM, or 9,300 nM) and low-folate (20 nM) media. Many cell types have their own methionine synthase enzymes, but the intracellular homocysteine level depends on both the localized, intracellular methionine synthase activity and the very high methionine synthase activity in the liver overall (this indirectly reduces intracellular homocysteine in cells outside the liver by removing homocysteine from the blood). The article just shows the same thing, essentially, that other articles have shown, except the authors measured the SAM-e, SAH, methionine, and homocysteine concentrations and looked at the cytoskeletal and barrier functions [reflecting intercellular (between-cell) interactions] of the cultured endothelial cells. The articles purporting to show "saturation" of body-wide, folate-dependent processes, such as serum homocysteine, at 5-15 mg/d are really only showing a degree of saturation of the liver's capacity to remethylate homocysteine, and it's already known that the concentrations of intracellular total folates are almost always highest in the liver.
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