Introduction Pauling advocated high-dose therapy involving one or more of four vitamins for a variety of diseases. !ese vitamins are ascorbate (vitamin C), niacin, folate and vitamin B12.1,2 Hoffer focused his attention for treatment of schizophrenia and other diseases on high-dose therapy using niacin and to a lesser extent ascorbate.3-5 However there has not been a plausible explanation, in my judgment, for any substantial efficacy for these four agents which requires the use of such high doses. Pauling’s main suggestion for mechaAbstract: Pauling suggested that responses to high-dose vitamin therapy were due primarily to small increases in response due to lack of complete saturation of enzyme targets. He also suggested that they may be due, in part to “local vitamin deficiencies” although the origin of such deficiencies were unclear. Ames suggested that such therapy might be explained by enzyme polymorphisms involving mutants with lowered Michaelis constants, and while this is an explanation in some cases, this mechanism does not explain any effectiveness of in the broader population of diseased patients. Responses to four vitamins advocated by Pauling can be best explained by the effects of these vitamins on lowering the nitric oxide (NO)/peroxynitrite (ONOO-) cycle, a possible generic mechanism for many different chronic inflammatory diseases. Ascorbate lowers three aspects of the central couplet of the cycle, acting as a peroxynitrite scavenger, restoring tetrahydrobiopterin (BH4) by reducing an oxidized form and inducing increased de novo BH4 synthesis. "e nicotinamide form of niacin inhibits poly adenosine diphosphate-ribosylation, thus sparing nicotine adenine dinucleotide (NAD), as well as supplying niacin for synthesis of NAD/NADH, thus helping restore mitochondrial function in NO/ONOOcycle diseases. Folate in the form of 5-methyltetrahydrofolate is a potent peroxynitrite scavenger, thus lowering the NO/ONOOcycle in that way. Vitamin B12 as hydroxocobalamin lowers the cycle by acting as a nitric oxide scavenger. Each of these responses involve mechanisms that are distinct from the classic functions of these vitamins and they all require supraphysiological levels in order to be effective. "us they provide explanations for each of the four high-dose therapy vitamins that Pauling suggested and for Hoffer’s responses to niacin therapy.