In this article [Di Palma et al., 1994: (http://cat.inist.fr/?aModele=afficheN&cpsidt=4093099)], Di Palma et al. (1994) used 90 mg/day of methylfolate to treat depression and discussed research on the use of 50 mg/day of methylfolate [including Guaraldi et al., 1993: (http://www.ncbi.nlm.nih.gov/pubmed/8348200)]. There's more research on the use of 50 mg per day, but I think some are abstracts. Di Palma et al. (1994) also keep repeating that the patients who participated in those trials were "normofolatemic" (i.e. displayed normal serum folate levels). The main issue I would wonder about is the use of supplemental folic acid per se, past a certain dosage. It seems to cause some strange effects, at dosages above 10 or so mg/day, in the long term. It's not that it's really toxic [except in people who have dihydropteridine reductase deficiency, an inherited genetic disorder (http://hardcorephysiologyfun.blogspot.com/2009/05/evidence-that-reduced-folates-can-serve.html)] but that it may compete with methylfolate for entry into the brain (as suggested by the authors of one of those articles on dihydropteridine reductase deficiency) and may compete with tetrahydrobiopterin (BH4) for binding to tyrosine hydroxylase or the nitric oxide synthases. But if one is not taking supplemental folate or has a serum folate value that is within the normal range (due to some dosage of folic acid below 5 mg or something), I don't think the serum folate level is really relevant to the effects of methylfolate. The serum folate range is very small, and a serum folate level within the normal range of values is unlikely, in my opinion, to produce anything close to "saturation" of the intracellular binding sites for the intracellular total folates (the concentration of binding sites, in the liver, is something like 150-200 uM, at least, excluding the binding sites on the pterin biosynthetic enzymes). But one would want to discuss this type of thing with one's doctor, especially if one were taking any medications. In that past posting I linked to, the authors of one of the articles go into all the research on the use of reduced folates (such as methylfolate) and oxidized folates (folic acid) in people who have dihydropteridine reductase deficiency, and the authors provided a lot of evidence that reduced folates tend to actually be safer than folic acid, in terms of their effects on the brain. That seems paradoxical, at first glance, because reduced folates are more potent, from the standpoint of their effects on cell proliferation, etc. But they exert less of a pro-convulsant effect, for example, and don't cause the neurological symptoms that folic acid does in people with dihydropteridine reductase deficiency (DHPRD) and in some forms of phenylketonuria, I think, in which reduced folates have been used instead of BH4 (this was before BH4 was approved to treat BH4 depletion in phenylketonuria). That's probably because of the lack of capacity of folic acid to serve as a BH4 analog, except to the extent that some of it can be reduced (converted into reduced folates intracellularly).
One thing I can think of that would be a downside of high dosages of methylfolate would be the potential to mask vitamin B12 deficiency, and I think there's reason to consider dosages of methylcobalamin in the 1-5 mg/day range, in combination with methylfolate, even assuming that the serum B12 is normal. The other thing is that methylfolate can probably serve as a BH4 analog in humans (it seems to, in my opinion), and, to the extent that it can, that could conceivably cause some sort of abnormal nitrergic effects at high dosages. That doesn't seem to be much of a downside, in my opinion, although a person who had an inflammatory disease or something like multiple sclerosis could experience some sort of mixture of bad and good effects from methylfolate at high dosages, as a result of the BH4 "mimesis" at higher dosages. But the supposed nitrergic effect is also likely to contribute to the dopaminergic/noradrenergic effects of methylfolate, given that, for example, L-arginine releases dopamine in a BH4-dependent manner (although it's more complicated than one might think) [I'm pretty sure it's the Liang et al. (1998) article: (http://scholar.google.com/scholar?hl=en&q=%22L-arginine%22+dopamine+tetrahydrobiopterin)]. So it's not really likely to be a bad effect, up to a certain dosage (I mean that different people might experience differing degrees of nitrergic effects from methylfolate, and those effects might be problematic in some people and not in others, etc.). I tend to think that combining methylfolate with L-arginine might cause undesirable side effects, at high dosages of either one, and I tend to think the nitrergic effects of methylfolate in the brain (the supposed nitrergic effects) are likely to be "better" than those of arginine. L-arginine just seems to produce inconsistent effects or to produce a mixture of mood-elevating and mood-worsening effects. It's not a matter of toxicity, but it just doesn't seem to produce very predictable effects. The research shows that inconsistency.
The main issue, in my opinion, would be to exercise some caution in combining high dosages of methylfolate with noradrenergic or dopaminergic medications, because the BH4-mimicking effect of methylfolate would be expected to augment noradrenergic/dopaminergic effects. It's not that it's really about neurotoxicity, in my opinion, but that methylfolate could just augment the effects of those medications and cause agitation or insomnia or nervousness, etc. That's the main effect of BH4. Its predominant effect is to enhance dopaminergic and noradrenergic transmission in the brain, and methylfolate really seems to begin serving as a BH4 analog at high dosages. For example, they've used BH4 to treat dopa-responsive dystonia [(http://scholar.google.com/scholar?hl=en&q=%22dopa+responsive%22+dystonia+tetrahydrobiopterin+supplement); (http://scholar.google.com/scholar?hl=en&q=%22dopa+responsive%22+dystonia+tetrahydrobiopterin)], and I think that's mainly or always caused by mutations affecting BH4 biosynthesis. I can't say that methylfolate definitely serves as a BH4 analog at higher dosages, and I've never taken BH4 and therefore can't make even a subjective comparison (BH4 has been used to treat depression, in a number of small studies, is available by prescription in the US, and is sold under the generic name of sapropterin dihydrochloride; but it's not available over-the-counter and seems unlikely to be something that would be covered by prescription). L-methylfolate is available by prescription or over-the-counter, as discussed in past postings.
I tend to think that the way methylfolate works is to cause something resembling saturation of the binding sites in the liver (and maybe also the brain or other extrahepatic tissues), at the "lower" range of dosages (I mean that this quasi-saturation might begin to emerge at, say, 15 or 20 mg/day or maybe less), and then begin to serve as a BH4 analog at higher dosages. In my experience, the effects of L-methylfolate are greater at the higher dosage range, but there's some dosage range at which one would experience diminishing returns from further increases in dosages. But Di Palma et al. (1994) found, incidentally (without seeking to find any such effect), that the patients' liver enzymes were decreased by the 90 mg/day dosage. If methylfolate were toxic at that dosage, one wouldn't expect to see a reduction in serum liver enzyme levels (the reductions were significant, and I don't have the article in front of me right now) and might expect to see a worsening of liver function (given that the intracellular total folate levels in the liver would be higher than those in any other tissue). But it basically improved liver function, to some extent, in those patients. It's never been proven to treat liver disease or any other disease, however, but I'm just saying that that suggests that the higher dosages are unlikely to be "toxic." I can't make any definitive statements about safety, however, on an individual basis, and one would want to discuss that type of thing with one's doctor. Di Palma et al. (1994) didn't think 90 mg/day was toxic and mentioned that, but they didn't necessarily have any basis for saying that (other than their clinical experience in psychopharmacology). But anyone with any health condition would obviously want to be extra careful and discuss the matter in more depth with one's doctor. For example, low dosages of reduced folates have sometimes produced anticonvulsant effects in people who have specific, probably-genetic forms of epilepsy due to cerebral folate deficiency, but higher dosages could conceivably lower the seizure threshold in the way that many antidepressants do (as far as I know, antidepressants tend to lower the seizure threshold, almost without exception). In general, in my opinion, L-methylfolate is useful (and much more useful than folic acid).
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