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Cobalamins are vit.B12 compounds which differ for the cobalt-linked ligand: methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) are the biochemical active compounds. Vit.B12 is present in the plasma as MeCbl, 5kdeoxyAdoCbl, and hydroxoCbl. The actions of vit.B12 are several, some still unknown. HydroxoCbl has clear scavenging properties against nitric oxide (NO) (1). Such scavenging properties led Van der Kuy and coworkers to embark on an open trial of hydroxoCbl in the prevention of migraine (2). HydroxoCbl administered intranasally in 19 patients with migraine gave a reduction of at least half of the migraine attacks in 53% of the patients. No serious adverse effects were observed and compliance was controlled by monitoring Cbl serum levels. The study had limitations, the most obvious being that it was not controlled, the next being the short duration of the run-in and treatment periods. However, the magnitude of the effect was such as to suggest that it could not be due to placebo and to warrant a full double-blind vs. placebo study. Of course we must accept the Authors' words of caution and wait for a fully controlled study: migraine and neuropathic pain are indeed conditions marked by striking placebo effects, and the placebo effect, which is not absence of medication and is now being elucidated by functional neuroimaging (3), implicates brain regions hypothesized to be involved in the migraine attack cascade (4). Placebo might alone explain the effects encountered in this study. Remarkably however, vit.B12 is another vitamin proposed in migraine prophylaxis: vit.B2 (riboflavin) was found effective both in a pilot (5) and in a double-blind placebo-controlled trial (6), and coenzyme Q10 showed efficacy in an open label trial (7). Use of the latter compounds was based on the hypothesis that a decreased energy state characterizes the migraineur's brain (8), while hydroxoCbl was adopted because of its scavenging properties against NO. There is apparently no common ground to these two mechanistic hypotheses. However, there are intriguing links between the actions of riboflavin, which markedly improves ATP production through the mito-chondrial chain (9), and NO scavengers such as hydroxoCbl. NO at nanomolar concentrations rapidly inhibits the mitochondrial respiration by binding to complex III and cytochrome c oxidase, in particular at low O 2 tensions (10, 11). In brain nerve terminals, this results in rapid glutamate release. NO donors also inhibit complex I and catalase, stimulating the production of NO derivative peroxynitrite, which in turn inhibits complexes I, …