I can't immediately find an article that documents when this began, but I was remembering that the FDA prevents manufacturers from selling over-the-counter (OTC) folic acid supplements in dosage forms larger than 800 ug (micrograms) per pill. This started in either the 1980's or 1990's, and I can't remember the timing of it. I'm sure that that decision had a major impact on both the perceptions people have about dosage ranges and the dosage ranges chosen for research.
The rationale for limiting the amount of folic acid in a single dose was that a certain number of people with pernicious anemia (produced by vitamin B12 deficiency) could conceivably take high-dose supplements of folic acid and thereby mask the clinical signs (megaloblastic anemia) of their vitamin B12 deficiencies. The vitamin B12 deficiency could then, in theory, progress past the point of only causing anemia and produce irreversible neurological damage (subacute combined degeneration of the brain and spinal cord). This is sort of rational, from a public health standpoint. But the hematological and neurological effects of vitamin B12 deficiency tend to be almost inversely related to each other, meaning that many people who have neurological symptoms do not have megaloblastic anemia [Reynolds, 2006: (http://www.ncbi.nlm.nih.gov/pubmed/17052662)]. Vitamin B12 deficiency can produce a variety of severe hematological and neurological disorders, including hemolytic anemia in 10 percent or more of cases [Andres et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/17145235)] and thrombogenic disorders such as "thrombotic microangiopathy" (meaning thrombogenicity in microvessels, etc.) (Andres et al., 2006) and pseudotumor cerebri (a.k.a. idiopathic intracranial hypertension, which is an elevation of intracranial pressure that can result from venous sinus thrombosis, etc.) [Yetgin et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16326411)]. Those problems don't necessarily have anything to do with megaloblastic anemia, although they might result from it. But a person could have those conditions as a result of vitamin B12 deficiency in the absence of megaloblastic anemia, and some of those problems might result from the inhibition of methylmalonyl-CoA mutase activity in the context of B12 deficiency. If that were the case, the effect would be purely a result of B12 deficiency and wouldn't be affected by folic acid at all. But the entire premise underlying the FDA's dose-limiting rule is that no one would ever be screened for anything but the mean corpuscular volume, apparently, because folic acid supplementation wouldn't mask a decrease in serum B12. The masking of pernicious anemia by an "excess" of folic acid would only be an issue, from the standpoint of public health, if no one ever received a serum B12 test, but I'm not sure why getting a serum B12 test would be so much more difficult than getting a MCV test as part of a hematological panel. In a person whose vitamin B12 status can be monitored, the 1,000-ug upper limit, set by the FDA, for the safe intake of folic acid (and the separate, 800-ug limit for OTC dosage forms) is not a rationally-chosen limit. No one would design a clinical trial to test 1-2 mg of thiamine, for any purpose, and expect any meaningful results, and yet the absence of major results from tiny doses of a fully-oxidized folate, folic acid, is viewed as evidence of the absence of physiological effects of folates in general.
The FDA has to consider things from a public health standpoint, but there seems to have been a psychological effect that has resulted from that 800-ug limit on single-unit dosages in OTC supplements. If the limit of 800 ug per dose had not been set, I don't doubt that there would be 10,000 or even 30,000 ug (20-30 mg) dosage forms being sold OTC now. Those dosages or higher dosages would probably be used in most research. Prescription L-methylfolate is sold in a 7,500-ug dosage form. There can be a tendency to think of the higher dosage ranges [the highest dosages I've ever seen used in clinical trials in adults are 50 mg/d and 90 mg/d of racemic methylfolate, used to treat depression in elderly people or in people with past alcoholism] as being supraphysiological, but, when viewed in the context of the elevations in the cerebrospinal fluid MTHF concentrations produced by 15-30 mg dosage forms in people with "cerebral folate deficiency," these types of higher dosages may be required to elevate the CSF MTHF concentrations meaningfully.
I was thinking about some of the mechanisms by which methylfolate might exert its effects in the brain, and some of the short-term effects could be due to either increases in extracellular adenosine or increases in the activities of methyltransferase enzymes. I don't think the direct, extracellular effects on NMDA receptors would really occur at the kinds of doses that are being used in trials, mainly because the intracellular total folate levels are normally so low. But more importantly, even 15 mg/d of folinic acid, a reduced folate, only elevated the CSF MTHF concentration from 34.4 nM to 127.1 nM [Kurenai Tanji et al., 2000: (http://www.ncbi.nlm.nih.gov/pubmed/11018246)] in an 8-14-year-old person with cerebral folate deficiency. One could argue that a person who has cerebral folate deficiency has, by the very definition of the disorder, some pathological process that limits the accumulation of CSF MTHF. But 127.1 nM was higher than the CSF MTHF levels in the controls, and so the accumulation of CSF MTHF wasn't limited all that much. The dosage range in cerebral folate deficiency, which can be a "cause-unspecified" condition, is 0.5-1.0 mg of a reduced folate/kg (35-70 mg/d for a 70-kg adult). But even 127 nM is not a very high extracellular MTHF concentration, and the intracellular total folates would not be expected to be "saturated" (with all the active sites and allosteric sites occupied by different folates) at that extracellular (interstitial fluid) concentration.
An acute increase in methionine synthase activity in neurons or astrocytes could increase the interstitial fluid (extracellular) adenosine concentraion acutely or increase melatonin biosynthesis by acutely increasing the activity of hydroxyindole O-methyltransferase (HIOMT), the enzyme that converts N-acetylserotonin into melatonin in pinealocytes in the brain. Methylfolate would be expected to increase methionine synthase activity acutely, and methionine synthase is expressed in a lot of different cell types in the brain and elsewhere. This would reduce intracellular homocysteine and increase the hydrolytic activity of S-adenosylhomocysteine hydrolase (SAHH), thereby decreasing the inwardly-directed, transmembrane adenosine gradient and producing an elevation of extracellular adenosine [Chen et al., 2002: (http://circ.ahajournals.org/cgi/content/full/106/10/1275) (http://www.ncbi.nlm.nih.gov/pubmed/12208805?dopt=Abstract)]. Chen et al. (2002) found that, in response to doubling of the serum homocysteine level, the interstitial fluid adenosine concentration was reduced by almost 50 percent in the kidneys. That's the opposite of the type of effect that methylfolate could produce, even though methylfolate wouldn't produce such a large effect in the short term. But there's a strong, equilibrative component to the transmembrane adenosine transport, and the transmembrane gradient favors the inwardly-directed transport, from the extracellular fluid to the cytosol [Dunwiddie and Masino, 2001: (http://www.ncbi.nlm.nih.gov/pubmed/11283304)]. A decrease in intracellular homocysteine would tend to decrease the inwardly-directed influx and prevent homocysteine-induced sequestration of intracellular adenosine as S-adenosylhomocysteine, thereby maintaining or increasing the extracellular adenosine. That or the elevation of HIOMT activity could decrease alertness, particularly if a person had been awake for awhile. The levels of extracellular adenosine tend to increase throughout the day in different parts of the brain, such as the basal forebrain, and bright light may increase alertness, in part, by reducing the extracellular adenosine concentrations in different parts of the brain [Partonen, 2000: (http://www.ncbi.nlm.nih.gov/pubmed/10783463)]. The increases in HIOMT activity or extracellular adenosine could produce different subjective effects, depending on the time of day, for example. An elevation in extracellular adenosine, such as by methylfolate, would probably cause fairly rapid changes in the densities or degrees of responsiveness of different adenosine receptor subtypes, and the initial, subjective effects might be different in the short term and long term. Additionally, HIOMT activity normally follows a circadian rhythm in the pineal gland/pineal body, and the amount of melatonin being synthesized in and released by pinealocytes declines when there is bright ambient light [Cardinali et al., 1972: (http://www.pnas.org/content/69/8/2003.full.pdf+html) (http://www.ncbi.nlm.nih.gov/pubmed/4506068?dopt=Abstract)].
The activity of HIOMT is also sensitive to noradrenergic activity, and the pinealocytes are innervated by noradrenergic neurons whose cell bodies are in the suprachiasmatic nucleus (SCN) (or by noradrenergic neurons that act, polysynaptically, via the SCN) [Wu et al., 2003: (http://jcem.endojournals.org/cgi/reprint/88/12/5898.pdf) (http://www.ncbi.nlm.nih.gov/pubmed/14671188)] or in the superior cervical ganglia (SCG). Folic acid deficiency produced changes in the amygdalar and hippocampal levels of BDNF and noradrenaline that were thought to be consistent with a chronic anxiety state [Kronenberg et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18614692)] and that could be expected to have resulted from increases in the excitability of noradrenergic neurons whose cell bodies are in the locus ceruleus (the amygdala and hippocampus receive noradrenergic inputs from LC neurons). Methylfolate could have some similar effect on noradrenergic neurons whose cell bodies are in the SCG or other sites and could influence the melatonin rhythm by that type of mechanism, even though it would probably occur more in the long term.
Another effect that could rapidly occur could be an increase in the methylation of calmodulin proteins (calcium binding proteins) and modification of the activities of calmodulin-dependent protein kinases in neurons, etc. [Consogno et al., 2001: (http://www.ncbi.nlm.nih.gov/pubmed/11543736)]. There are major issues with the bioavailability of S-adenosylmethionine, but methylfolate could conceivably produce some of that kind of effect. That effect could modify stimulus-evoked neurotransmitter release in a generalized fashion. Phenylethanolamine N-methyltransferase (PEMT) [Evinger et al., 1994: (http://www.jneurosci.org/cgi/content/abstract/14/4/2106)] is also expressed by some of the A1/A2 adrenergic-cell-group neurons that project to the basal forebrain [Hajszan and Zaborszky, 2002: (http://www.ncbi.nlm.nih.gov/pubmed/12115685)], and that could influence cognitive functioning and the generalized level of arousal/alertness. PEMT catalyzes the biosynthesis of adrenaline (epinephrine), and both adrenaline and noradrenaline are used as transmitters in parts of the brain. I'm not really up for exploring those aspects right now, but it's interesting.
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