This article [Bean et al., 1955: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abstract&artid=438858) (http://www.ncbi.nlm.nih.gov/pubmed/14392222)] is really interesting. It's old, but the authors induced pantothenic acid (PA, vitamin B5) deficiency in several people and found that the people, who had displayed sunny dispositions, soon "became quarrelsome, sullen, and petulant," felt sleepy and ended up spending a lot of time in bed, and developed peripheral neuropathy, low plasma cholesterol, and abnormalities of adrenal steroid biosynthesis. Kuo et al. (2007) induced PA deficiency in mice and found that the animals developed remarkably severe neurological symptoms and other abnormalities. The dystonia that the mice developed is consistent with the types of motor abnormalities that one would expect to result from damage to or iron deposition in the globus pallidus or basal ganglia in general, and Kuo et al. (2007) note that iron deposition in the globus pallidus, a group of neurons in the basal ganglia, occurs in humans with Hallervorden-Spatz syndrome (HSS or pantothenate kinase-associated neurodegeneration). HSS is a genetic disorder that reduces coenzyme A (CoA) levels by reducing the activity of pantothenate kinase, the first enzyme in CoA biosynthesis. Smith and Song (1996), cited below, discuss all of the neurological symptoms and hematological abnormalities that occur in animals depleted of PA. Researchers used to say that PA repletion produces more "cholinergic" effects than anything else, given that a major CoA-containing species is acetyl-CoA and that acetylcholine biosynthesis is sensitive to acetyl-CoA availability. But the article by Bean et al. (1955), showing somnolence and irritability, suggests, in conjunction with the dystonia observed in animals and the involvement of the basal ganglia and globus pallidus, more of a dopaminergic effect than a cholinergic effect. Those are somewhat vague and general statements that I'm making, but that's my subjective sense of the effects of PA on the brain (that its effects are probably as much catecholaminergic as cholinergic).
Even though I generally think the use of nucleotides and other approaches produce more potent biological effects than other nutrients, such as PA, it's important to realize that there's really no way to evaluate a person's PA status [Smith and Song, 1996: (http://cat.inist.fr/?aModele=afficheN&cpsidt=3155583)]. It's easy to dismiss articles that use large doses of specific vitamins or nutrients and find therapeutic effects, and I don't claim to know all of the mechanisms that could account for the effects of apparently supraphysiological dosages of various cofactors or cofactor-precursors, such as PA. But the dosages are apparently not supraphysiological, because the effects can be accounted for in terms of the known effects of the cofactor(s). Malabsorption can produce very dramatic decreases in the absorption of some nutrients, and, given the high prevalence of fatty liver disease in the population at large, for example, it is not unreasonable to expect that malabsorption would affect the absorption or enterohepatic recycling of nutrients in certain numbers of people. Heubi et al. (1997) [Heubi et al., 1997: (http://www.ncbi.nlm.nih.gov/pubmed/9285381)] found that, in children with cholestatic liver disease, massive dosages of magnesium were required, for many months, to overcome the intraluminal, unabsorbed free-fatty-acid-mediated (or triacylglycerol-mediated) or bile acid-mediated decreases in the intestinal absorption of magnesium. The mean dosage required was 11 mg/kg, which is 770 mg/d for a 70-kg adult, but some individual children required up to 34 mg/kg/d. That would be 2,380 mg/d for a 70-kg adult. Unabsorbed fatty acids and similar compounds bind to magnesium by ionic interactions, and the effect on magnesium absorption can evidently be really significant. Most people wouldn't need to take that much magnesium under any circumstances, and there's some potential for hypermagnesemia at doses higher than 2,000-3,000 mg/d, mainly but not exclusively in people with kidney disease. But the point is that problems like that can be severe. I was really surprised at the magnitude of that deficit in absorption, and many months were required to correct the overt deficiency states that those children were experiencing. When I used to see articles that mentioned malabsorption, I thought that explanation sounded far-fetched or vague. But it's not necessarily vague at all, and the effects can be significant.
I've just seen that most of the people who dismiss the idea that "expected" physiological responses to cofactors can occur at high doses seem to not have a good understanding of the metabolic functions of the cofactors or the manifestations produced by the depletion of the cofactor(s). When I forget about some of these articles, I tend to develop a dismissive attitude toward things like PA, too. But, for example, one way of explaining the effects of large doses is to recognize that reversing a deficiency may, in the short term, produce pronounced responses to large doses. Bean et al. (1955) used 4,000 mg/d for six days, to replenish the PA stores (the CoA pools), and then used 2,000 mg/d for the subsequent 20 days. Presumably, lower doses could have been used subsequently. One could use a similar explanation to account for the supposed effects of 10,000 mg/d of PA in this article [Leung, 1995: (http://www.ncbi.nlm.nih.gov/pubmed/7476595)].
In one article I have on my computer, the author of a hastily-researched, superficial review article on PA makes the statement, early in the article, that PA deficiency is "rare," but the case may simply be that no one is looking for evidence of PA depletion in anyone. There's no reference to support that statement, by the author of the article, that PA deficiency is rare, but, even aside from the lack of any research to support the statement, how would anyone know the extent to which PA deficiency is either common or rare? No one does any screenings for PA status, and there's no reliable test to evaluate PA status. I'm just saying that it's easy to say something is rare or that there's no good evidence for such-and-such, but those types of statements aren't necessarily true. CoA participates in vast numbers of enzymatic reactions, and, incidentally, that's part of the reason for the difficulty in evaluating PA status.
Also, there can be a tendency to group all nutrients together and make arbitrary dosage choices. For example, there are reasons to think that the dosages for vitamin B2 [given its potential for exacerbating redox cycling reactions and for enhancing clotting factor biosynthesis, by accelerating the cytosolic, "warfarin-insensitive" reductase enzymes that participate in the vitamin K cycle (http://hardcorephysiologyfun.blogspot.com/2009/01/vitamin-b2-riboflavin-and-vitamin-k.html)], vitamin B3 [given the potential for NAD+, which most of a dose of niacinamide is converted into, to enhance PARP activity and causes ATP depletion under certain circumstances (http://hardcorephysiologyfun.blogspot.com/2008/12/nonoxidative-pentose-cycle-prpp-and.html)], and lipoic acid [given that the biosynthesis of the lipoyl- cofactors for different components of the pyruvate dehydrogenase complex occurs after the octanoyl- precursor has become bound to the enzymes and that exogenous lipoic acid can inhibit the pyruvate dehydrogenase complex, rather than activate it (http://hardcorephysiologyfun.blogspot.com/2009/01/inhibition-of-activity-of-pdhc-by-r-or.html)] should arguably be limited under various circumstances, and the full, therapeutic dosage ranges for cofactors with fewer dose-limiting side effects tend to not be widely recognized or known by people.
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