In the next few days or weeks, I'm going to try to summarize some of the main points from the postings I've made over the last year. In some cases, each summary encompasses hundreds of pages of writing and numbers of articles, articles and pages that I've explored in horrendous, "rock-and-roll-ice-storm" ways over the last year. Here are summaries of some of the groups of postings.
In my opinion, zinc and copper supplementation can be very problematic and inadvisable in many cases, in the absence of medical supervision. There are hundreds of reports of neurotoxicity visible on MRI and degeneration of the brain and spinal cord in humans who have taken excessive supplemental zinc, and the mechanisms that regulate the amount of neurotoxic free zinc and, also, copper are not very reliable, from a physiological standpoint. Copper transport in the blood and even in cells is messy and poorly-regulated, and many foods, including many breakfast cereals, have more than enough copper and also have enough zinc (as well as manganese, for example).
In my opinion, vitamin A or beta-carotene supplementation has the potential to cause serious neurotoxicity, and there are many reports of neurotoxicity or "pure" psychiatric disorders caused by vitamin A or beta-carotene supplementation. One important mechanism is, in my opinion, the toxic effects that retinoids, including vitamin A and beta-carotene as a precursor of vitamin A and retinoic acid, etc., exert on epithelial cells of the choroid plexuses that form cerebrospinal fluid and are crucial in the regulation of other brain functions, such as glutamate efflux, etc. Retinoids, including vitamin A and its precursors, can elevate the intracranial pressure by causing toxic effects on the choroid plexuses at extremely small dosages in some people, and those elevations in the intracranial pressure and associated venous ischemia or venous sinus thrombosis could be important causes of the psychiatric manifestations that vitamin A or beta-carotene supplementation have been associated with. In some cases, people who have done nothing but eat one of the relatively few foods high in preformed vitamin A (i.e., carrots or liver or fish, conceivably, as in fish liver, etc.) have developed severe psychiatric disorders that remitted upon discontinuation of the carrot-eating-induced psychosis or suicidality. The nutrition tables do not differentiate between beta-carotene and preformed vitamin A and only provide information about "retinol equivalents," but even eating a lot of beta-carotene in foods could conceivably produce adverse effects, given that an increase in beta-carotene intake can increase vitamin A (and that elevations in intracranial pressure have been shown to occur across miniscule increments in serum retinol, etc.).
In my opinion, all of the therapeutic effects of oral S-adenosylmethionine, in every disease state it has been used in, could be replicated by oral adenosine monophosphate or adenosine triphosphate. Both of those are sold, and each would be expected to exhibit much higher bioavailability (meaning entry into the brain or other extrahepatic tissues) than many oral SAM-e preparations would, in my view. These disease states include liver disease and osteoarthritis, etc. SAM-e has been researched heavily in many different contexts. The adenosine (and other purine metabolites from it) derived from the SAM-e is likely to be, in my opinion, the only significant mediator of the therapeutic effects of SAM-e. The extreme rapidity with which adenosine is utilized, by any of several pathways, precludes, in my view, a mass-action, inhibitory effect of the extra adenosine or other purines derived from it, on S-adenosylhomocysteine hydrolase activity. Nonetheless, the adenosine derived from SAM-e can increase the intracellular ATP and cAMP levels, and increases in ATP availability can be a determinant of the rate of formation of SAM-e. Increases in the cAMP/AMP ratio or in cAMP levels of cAMP in relation to other purines can influence the activity of S-adenosylhomocysteine hydrolase. One could use a methionine adenosyltransferase inhibitor in an experiment, but the use of that would not allow one to rule out, at all, the contribution of adenosine, derived from SAM-e, to the endogenously-produced SAM-e (via the utilization of adenosine for ATP formation, etc.). Adenosine has been used to treat liver disease in animal models and is thought to enhance hepatic blood flow and to maintain hepatocellular ATP levels and to ameliorate portal venous thrombosis (effects that could account for its therapeutic effects, especially along with pyrimidine nucleotides, in animal models of liver disease), and adenosine is thought to mediate the therapeutic effects of low-dose methotrexate, for example, in rheumatoid arthritis. Thus, there is reason to think that increases in purine availability, in response to exogenous adenosine nucleotides, could influence those conditions by the same mechanisms that SAM-e may influence the conditions. Adenosine could also influence DNA methylation by elevating SAM-e levels (via adenosine-induced increases in ATP levels), and exogenous SAM-e could influence DNA methylation not by increasing the ratio of SAM-e to S-adenosylhomocysteine but by increasing ATP levels (via the conversion of SAM-e to adenosine to AMP, ADP, and then ATP, which is a substrate of methionine adenosyltransferase) or by adenosine receptor signalling, etc.
In my opinion, L-methylfolate has a lot of potential usefulness as an adjunctive antidepressant and as a way of normalizing cognitive functioning or assisting in the treatment of circadian rhythm abnormalities, and its supposed effects in any of those disease states would probably be a result of its enhancement of noradrenergic and dopaminergic activity (via nitrergic mechanisms, secondary to its supposed effects as an analog of tetrahydrobiopterin (BH4), and by the "methylfolate-as-BH4-analog-dependent" increase in tyrosine hydroxylase activity). In my view, as discussed over maybe 150 postings or something, L-methylfolate and other reduced folates are likely to be not toxic or damaging, in theory, at the 30-50 mg/day range, or thereabouts, but I'd advise anyone to obviously use reduced folates under a doctor's supervision. The augmentation or counteracting of the effects of psychiatric medications could be dangerous in some people & could exacerbate the courses of psychiatric disorders. At high dosages, methylfolate and other reduced folates have generally been much safer than folic acid and less neurotoxic. In my view, L-methylfolate, which is available over-the-counter or by Rx, has less potential to produce adverse or unpredictable nitrergic side effects than, for example, L-arginine and is likely to produce more reliable or predictable or consistent effects than something like L-arginine, from the standpoint of effects on the brain.
In my view, creatine supplementation can be problematic at dosages higher than about 1.2 to 1.5 grams/day, over the long term, and low but not high dosages have been used as adjunctive approaches to treating depression in at least two trials (with other trials showing less clearly-defined effects on mood). Obviously, these are all just my opinions.
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