The authors of this article [Hathcock et al., 2007: (http://www.ajcn.org/cgi/content/full/85/1/6)(http://www.ncbi.nlm.nih.gov/pubmed/17209171?dopt=Abstract)] reviewed a number of clinical trials in which researchers had used dosages of vitamin D ranging from 2,000-100,000 IU/day of vitamin D3, and the research generally shows that hypercalciuria hardly ever occurs at dosages of vitamin D3 of 2,000-4,000 IU/day. Hypercalcemia hardly occurred at any of the reasonable dosages and didn't even occur at 100,000 IU/day. There probably isn't a dose of vitamin D3 that has zero potential to elevate urinary calcium, and the slight elevations in serum calcium that oral vitamin D3, in particular, tends to cause (in my opinion) have the potential to exacerbate thrombogenic conditions, as discussed in past postings (http://hardcorephysiologyfun.blogspot.com/2009/01/calcium-magnesium-serum-calcium-vitamin.html).
Sayer et al. (2004) [Sayer, 2004: (http://cs.portlandpress.com/cs/106/0549/1060549.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/15027893)] analyzed a lot of research on the mechanisms underlying nephrocalcinosis, which technically refers to an increase in the calcium contents of the kidneys but is generally taken to mean calcification, meaning the deposition of calcium phosphate (usually in the form of apatite), in parts of the kidneys, and Sayer et al. (2004) basically argued that hypercalciuria is the factor that seems to be associated with nephrocalcinosis. Even relatively small increases in the intake of phosphate have generally decreased the rate of urinary calcium excretion, and phosphate (from sodium or potassium phosphate) at something like 1,000 mg/day has been used to prevent kidney stones in recent decades. Then I guess everyone decided that phosphate is a "vice" or something and had to be removed from the diets of everyone. The research that I've discussed in recent postings indicates that taking very high dosages of phosphate (generally supplemental phosphate at greater than 70-100 mg/kg/day), along with hormonal vitamin D at dosages that cause intermittent hypercalcemia and hypercalciuria, creates the conditions that can cause nephrocalcinosis. But vitamin D itself generally does not cause either hypercalciuria or hypercalcemia, and there's some moderate dosage (i.e. 2,000-4,000 IU/day, as a conservative dosage) that could help keep the parathyroid hormone levels low but could do so without elevating urinary calcium unnecessarily. There's likely to be some middle ground, in my opinion.
One approach would be to use adequate dosages of magnesium (the research is really disorganized in magnesium, and that's the reason I keep avoiding citing all the articles I have on it), given that magnesium has the potential to help prevent nephrocalcinosis (http://scholar.google.com/scholar?hl=en&q=magnesium+nephrocalcinosis), in my opinion, and avoid calcium supplements and get calcium from milk or something like that. (There's some research claiming to show that magnesium decreases apatite formation but increases amorphous calcium phosphate formation, which is not really dangerous, but the research in actual animals generally shows that urinary magnesium wasting, from any number of causes, and decreases in magnesium status/intakes can increase the risk of calcification, in the kidneys and other sites.) I don't take supplemental calcium anymore and get enough calcium from milk that I use to "eat cereal." But anyway, the dosage range of magnesium is large, and I don't really feel like getting into a discussion of it and then have to "wade" through the research. The research on magnesium is not reader-friendly, really, and is surprisingly complex. Magnesium oxide (MgO) is absorbed relatively slowly, throughout much of the small intestine, and chelated magnesium aspartate (MgAsp) or MgAsp HCl (they're not the same) are absorbed more rapidly and are probably absorbed through either the amino acid or dipeptide transporters or by passive diffusion. Magnesium from magnesium oxide is likely to be absorbed by divalent metal transporters or by passive diffusion and the solvent drag mechanisms that enhance the absorption of some cations by passive diffusion. Some people report in the literature that the bioavailability of chelated MgAsp is basically too high for some people to be able to tolerate, and there might be something to that. If it enters the brain too rapidly, it can cause sort of drowsiness or mental sluggishness. The last time I tried chelated MgAsp, I experienced that sort of problem with it and went back to MgO. Some people can't tolerate MgO, however, at higher dosages, given the nausea and GI effects that it can cause. In that case, MgAsp might be preferable. Magnesium orotate would potentially be problematic, in my opinion, because of the orotate, as I discussed, indirectly, in one of my old papers (http://hardcorephysiologyfun.blogspot.com/2009/08/some-more-old-papers-of-mine.html).
I've never seen a report of true toxicity from magnesium at anything resembling a reasonable dosage (even 1500-2000 mg/day have been used in some research), and the occasional reports of hypermagnesemia have generally occurred in people taking 2500-3000 mg/day or more. The intravenous magnesium dosages used in various therapeutic contexts produce really high serum magnesium levels, but any excess is likely to mainly end up being excreted in the urine almost immediately. There could be some problems with fasting blood glucose levels decreasing in diabetics, in response to Mg supplementation, and it can transiently lower blood pressure and elevate serum potassium (and decrease urinary sodium reabsorption). The changes in sodium and potassium excretion might produce the acute decreases in blood pressure, but, supposedly, the low-level calcium channel blocking effect can reduce blood pressure a little bit. But the blood pressure changes seem to not really persist to as great a degree as one might think. In people who are hypertensive, there might be more of a lasting effect, but I don't know that I'd expect much in that area. The research is sort of mixed on that, but there can be a transient decrease in blood pressure that does not last longer than a day or two, after any increase in the dosage. Obviously, one would want to talk about these things with one's doctor. Magnesium, like many things, could cause side effects (such as electrolyte abnormalities, etc.) that could be detrimental, in conjunction with the effects of medications, for example, but that would not really constitute toxicity, in my opinion, at reasonable dosages. Even in the cases of supposed death by magnesium dosages of 15,000-30,000 mg per day, the person had been drinking the whole bottle of the OTC magnesium supplement for a long time, in one case. And it wasn't clear to me that the existing kidney failure, not the bizarrely high dosages of magnesium, hadn't actually been the cause of death. Magnesium could conceivably increase phosphate turnover or the dietary phosphate requirement, either by binding to phosphate in the GI tract, thereby potentially increasing the requirement, or by increasing the activities of glycolytic enzymes. Reporting on the research on magnesium is like pulling teeth, though, because of the variable qualities of the bioavailabilities and even percent absorption of different magnesium salts or chelated forms. The only other thing I can think of to say is that magnesium aspartate may not mean chelated magnesium aspartate, depending on the manufacturer's labeling practices. Chelated MgAsp is not the same thing as MgAsp as a salt. In MgAsp, the Asp(2-) and Mg2+ are ionized. In chelated MgAsp, the Mg is bound to the aspartate by coordinate covalent bonds. A chelate tends to be absorbed (a significant percentage of a dosage) intact and transported by dipeptide or amino acid transporters or by passive diffusion, but a salt (an ionic pair in crystalline form that dissociates upon entry into solution) dissociates in water.
I should mention that I don't take a multivitamin, because of all of the potentially problematic "ingredients" in it. The only "minerals" or metals I take in supplemental form are selenium, from sodium selenite, at about 150 ug/day, 150 ug of iodine (from potassium iodide), magnesium, and a low dose of molybdenum. Iodine can basically shut down thyroid function at dosages slightly higher than the RDA of 150 ug/day, especially some people, and selenium can also decrease thyroid hormone levels (and cause obesity or something and decrease serum IGF-1 levels, etc.) at dosages of even 200-300 ug/day, according to some research [(http://scholar.google.com/scholar?q=selenium+thyroid+adverse&hl=en); Hawkes et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18565425)]. I can't get the articles showing IGF-1 decreases to show up, but one has to ask oneself what the mechanism would be for that. It doesn't sound like a good effect to me and doesn't sound like a great way of supposedly preventing cancer, but the decreases in IGF-1 may (or may not) only occur at the higher dosage range. But overt selenium deficiency (it's probably uncommon) can also decrease thyroid hormone formation. The function of selenium, in my opinion, is to serve as a cofactor of thioredoxin reductase enzyme complexes, glutaredoxin reductase enzyme(s), glutathione peroxidase enzymes, etc. (and ribonucleotide reductase). It seems like it can have relatively significant effects on antioxidant enzymes, but I'd suggest watching out for those adverse effects. The dosage that causes those effects in one person might be lower than the dosage that causes them in another person. One approach would be to stick to the low end of the range or evaluate how much selenium one gets from his or her diet Manganese is abundant in foods and has been shown to cause psychiatric and neurological derangements, when given in excess, in supplemental form. So I definitely don't supplement with that. Copper and zinc are very problematic in supplemental form, in my view, and are abundant in foods, and I don't take those. And then there's all the potentially neurotoxic or "choroid-plexus-epithelial-cell-toxic" vitamin A and beta-carotene in some multivitamins. I take a small amount of iron protein succinylate, because I work out like a @#$%&%$ madman. That's an exaggeration, but it's a bare-bones approach. In any case, I can't advise anyone on these more boring topics, even, or on any other topics. One would want to talk with one's doctor about these things.
Showing posts with label Iron. Show all posts
Showing posts with label Iron. Show all posts
Thursday, September 3, 2009
Thursday, July 2, 2009
Iron in Psychiatric Disorders
There's quite a bit of research suggesting that low serum iron or iron deficiency can contribute to symptoms of attention-deficit disorder and can derange the responses to dopaminergic drugs or drugs that indirectly influence dopaminergic transmission, including antidepressants (http://scholar.google.com/scholar?q=iron+%22attention+deficit%22+OR+antidepressant&hl=en&lr=) (Yeragani et al., 1989, in search results). The main idea is that brain iron depletion can reduce D2 dopamine receptor (D2R) density and perhaps also D2 receptor sensitivity, etc. I'm not sure if one can really explain it in terms of agonist-antagonist effects. I mean that one can't necessarily say that the adequate delivery of iron to dopaminergic neurons will increases tonic or phasic D2 dopamine receptor activation, given that an increase in the activation of presynaptic D2 dopamine receptors can decrease the firing rates of dopaminergic neurons and potentially decrease postsynaptic or presynaptic D2 receptor activation. But iron does seem to behave as if it's "weakly-D2-agonist-like."
The no observed adverse effect level (NOAEL) for iron intake, in the long term, is 40 mg or thereabouts (depending on the source of the analysis). That's for nonheme iron, and, in my opinion, iron protein succinylate is superior to the other forms. I don't have any financial stake in anything I've ever discussed or will ever discuss, and my reason for mentioning that form is that it doesn't provide massive amounts of glycine and has been shown to not produce as much GI irritation as other forms. In any case, there's also an article citing some obscure research on the use of iron in treatment resistant depression. Although the research is obscure and in a foreign language journal (I don't have time to cite the article right now), the use of low-dose iron supplementation in ADHD would suggest that the applicability to other psychiatric symptoms, in an adjunctive capacity, might have some validity. In any case, iron supplementation is potentially dangerous, and one would want to discuss it with one's doctor.
The heme iron supplied by a diet high in meat was shown to be equivalent to 50 mg of nonheme iron in at least one study, but I don't know that long-term iron intakes of 30-40 mg would necessarily be "safe" (despite the fact that they're less than the NOAEL). There's research in which researchers have used very large amounts of oral or intravenous iron to treat restless legs syndrome, but I really don't think that's safe in the long term or even short term. Most of that has been done in the short term, and I don't know how that's much of a strategy for treating restless legs syndrome (the high dose approach, if one can only use the approach in the short term). Resistance exercise can put a dramatic strain on iron stores in the long term, and there's research showing that [see Deruisseau et al., 2004, in search results: (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=resistance+exercise+iron)]. The effect of resistance exercise is even greater than the effect of endurance exercise (in terms of potentially accelerating iron turnover), and that study I cited only followed the people for 3 months. So one might want to adjust one's iron intake according to one's activity level.
That said, having a high serum ferritin level is not desirable, in my opinion. When the serum ferritin is higher than something like 100 mcg/L (= 100 ng/mL) or is just high (there's disagreement about the target level, but even 50 mg/day of nonheme iron has generally barely even elevated serum ferritin, over a few weeks, in small trials), the serum transferrin levels start to decrease. That's really bad and tends to increase the fraction of nontransferrin-bound iron, with damaging consequences. When the serum ferritin level is reasonable and not pathologically low and also not high, the delivery of iron by transferrin has the potential to be the most efficient (much more efficient than at high serum ferritin levels, especially). The whole iron transport system falls apart at high serum ferritin levels. Also, iron-loaded ferritin can't bind as much zinc, and zinc binding to tissue ferritin proteins probably serves to buffer intracellular zinc levels and prevent zinc neurotoxicity or hematological toxicity [see Price et al., 1982 and others, in this results list: (http://scholar.google.com/scholar?q=ferritin+zinc&hl=en&lr=)]. The relevant function, in my view, would be the "zinc detoxicant" function of tissue/intracellular ferritin polypeptide chains. I think a lot of people are in no danger of being low in zinc, but that's just my opinion.
In any case, there's a lot of research indicating that low serum iron levels and poor iron uptake into the brain has a lot to do with the excessive release and actions of pro-inflammatory cytokines on the specialized macrophages [the "reticuloendothelial system" (RES) macrophages], in the bone marrow/RES, that export iron and maintain serum iron (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=macrophages+export+iron+TNF+OR+%22IL-6%22); Kemna et al., 2005: (http://bloodjournal.hematologylibrary.org/cgi/content/full/106/5/1864)(http://www.ncbi.nlm.nih.gov/pubmed/15886319?dopt=Abstract)]. Resistance exercise is one example of something that could conceivably reduce pathological pro-inflammatory cytokine production in the long term, even if exercise might tend to worsen it in the short term. Pro-inflammatory cytokines also interfere with iron export and transport in general and with energy metabolism and everything else, essentially.
The no observed adverse effect level (NOAEL) for iron intake, in the long term, is 40 mg or thereabouts (depending on the source of the analysis). That's for nonheme iron, and, in my opinion, iron protein succinylate is superior to the other forms. I don't have any financial stake in anything I've ever discussed or will ever discuss, and my reason for mentioning that form is that it doesn't provide massive amounts of glycine and has been shown to not produce as much GI irritation as other forms. In any case, there's also an article citing some obscure research on the use of iron in treatment resistant depression. Although the research is obscure and in a foreign language journal (I don't have time to cite the article right now), the use of low-dose iron supplementation in ADHD would suggest that the applicability to other psychiatric symptoms, in an adjunctive capacity, might have some validity. In any case, iron supplementation is potentially dangerous, and one would want to discuss it with one's doctor.
The heme iron supplied by a diet high in meat was shown to be equivalent to 50 mg of nonheme iron in at least one study, but I don't know that long-term iron intakes of 30-40 mg would necessarily be "safe" (despite the fact that they're less than the NOAEL). There's research in which researchers have used very large amounts of oral or intravenous iron to treat restless legs syndrome, but I really don't think that's safe in the long term or even short term. Most of that has been done in the short term, and I don't know how that's much of a strategy for treating restless legs syndrome (the high dose approach, if one can only use the approach in the short term). Resistance exercise can put a dramatic strain on iron stores in the long term, and there's research showing that [see Deruisseau et al., 2004, in search results: (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=resistance+exercise+iron)]. The effect of resistance exercise is even greater than the effect of endurance exercise (in terms of potentially accelerating iron turnover), and that study I cited only followed the people for 3 months. So one might want to adjust one's iron intake according to one's activity level.
That said, having a high serum ferritin level is not desirable, in my opinion. When the serum ferritin is higher than something like 100 mcg/L (= 100 ng/mL) or is just high (there's disagreement about the target level, but even 50 mg/day of nonheme iron has generally barely even elevated serum ferritin, over a few weeks, in small trials), the serum transferrin levels start to decrease. That's really bad and tends to increase the fraction of nontransferrin-bound iron, with damaging consequences. When the serum ferritin level is reasonable and not pathologically low and also not high, the delivery of iron by transferrin has the potential to be the most efficient (much more efficient than at high serum ferritin levels, especially). The whole iron transport system falls apart at high serum ferritin levels. Also, iron-loaded ferritin can't bind as much zinc, and zinc binding to tissue ferritin proteins probably serves to buffer intracellular zinc levels and prevent zinc neurotoxicity or hematological toxicity [see Price et al., 1982 and others, in this results list: (http://scholar.google.com/scholar?q=ferritin+zinc&hl=en&lr=)]. The relevant function, in my view, would be the "zinc detoxicant" function of tissue/intracellular ferritin polypeptide chains. I think a lot of people are in no danger of being low in zinc, but that's just my opinion.
In any case, there's a lot of research indicating that low serum iron levels and poor iron uptake into the brain has a lot to do with the excessive release and actions of pro-inflammatory cytokines on the specialized macrophages [the "reticuloendothelial system" (RES) macrophages], in the bone marrow/RES, that export iron and maintain serum iron (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=macrophages+export+iron+TNF+OR+%22IL-6%22); Kemna et al., 2005: (http://bloodjournal.hematologylibrary.org/cgi/content/full/106/5/1864)(http://www.ncbi.nlm.nih.gov/pubmed/15886319?dopt=Abstract)]. Resistance exercise is one example of something that could conceivably reduce pathological pro-inflammatory cytokine production in the long term, even if exercise might tend to worsen it in the short term. Pro-inflammatory cytokines also interfere with iron export and transport in general and with energy metabolism and everything else, essentially.
Friday, June 5, 2009
Potential Problems Associated With Excessive Zinc and Copper Supplementation
These are some more articles that discuss all of the mechanisms by which an excess of intracellular, free zinc can cause mitochondrial dysfunction and toxic effects on many other cellular processes. The authors of this article [Lemire et al., 2008: (http://oldwebsite.laurentian.ca/chem/vappanna/publications/J.%20Applied%20Toxicology%202008.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/17582580)] discuss the fact that an excess of zinc can inhibit various TCA cycle enzymes, such as aconitase, and other mitochondrial enzymes. Although the authors note that zinc can interfere in a generalized way with enzymes and proteins that contain iron-sulfur clusters, aconitase is known to also utilize nonheme iron (I mean nonheme iron that is also non-iron-sulfur-cluster-bound iron) [see, for example, Lee et al., 1996: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=aconitase+nonheme+iron)]. Zinc can be utilized to form zinc protoporphyrin, and I wonder if zinc isn't actually incorporated into iron-sulfur clusters. But it wouldn't have to be, and zinc could reasonably be expected to displace, with particular ease, nonheme iron (i.e. Fe2+/Fe3+) from its binding sites on enzymes whose catalytic activities or regulatory functions depend on the presence of bound, nonheme iron.
I think neurotoxicity from excessive zinc supplementation is a very serious issue, and, in my opinion, low-level, pathological changes, such as psychiatric symptoms or gradually-progressing neurotoxicity, may result from dosages of zinc that many people would not view as being especially massive. Only a relatively few authors, as far as I can tell, have written articles, over the last few decades, discussing the potential hazards of zinc supplementation at the more commonly-used dosages. Even fewer articles on the nutritional aspects of zinc have considered that problems with zinc supplementation may have nothing to do with copper depletion, even when copper is depleted as a result of the excess zinc. In my opinion, based on the literature, many of the cases of neurotoxicity associated with excessive zinc supplementation (there are many, many case reports in the literature, and I don't feel like listing dozens of them out, right now, in this posting) may have had relatively little to do with copper depletion, and one sees that copper supplementation, in many cases, did not very effectively ameliorate the neurological disorders and demyelination that researchers had found in association with excessive intakes of zinc. [Some of the articles and case reports are scattered throughout the results of this search: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22zinc+supplementation%22+neurotoxic+OR+neurological+OR+demyelinating+OR+demyelination+OR+%22white+matter%22), and this is an "instructive-but-not-comprehensive" list of articles that google scholar classifies as being related to an article on excessive zinc supplementation: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=related:-bvm-ASLfasJ:scholar.google.com/)]. In most cases, the researchers have discontinued the zinc supplementation at the same times they have initiated copper supplementation, and then the researchers have attributed the modest improvements in the neurological conditions or anemia or thrombocytopenia or pancytopenia to the copper repletion. In reality, the absence of zinc may have been the primary and more important factor that led to the improvements.
I've discussed, in past postings, the extraordinarily complex aspects of zinc metabolism and homeostasis, and another issue is that serum copper and ceruloplasmin are not sensitive or very reliable indicators, in my opinion, of the intracellular copper concentrations or of copper status in people who are not grossly copper-deficient. Serum zinc is also not thought to be a reliable measure of zinc status [Fung et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/16215013)], and Fung et al. (2002) found that, even in people who had evidently been deficient in zinc and who had appeared to respond favorably to zinc supplementation, zinc supplementation did not increase serum zinc. These are major obstacles to nutritional research on zinc, in my opinion, and I would seriously question the validities of many descriptions, in the literature, of "zinc deficiency." Here's an article whose author discusses the potential neurotoxicity of zinc supplementation [Levenson, 2005: (http://www.ncbi.nlm.nih.gov/pubmed/15869126)], and here's a remarkable article, from 1989, in which Fosmire (1989) [Fosmire, 1989: (http://journals.lww.com/nutritiontodayonline/pages/articleviewer.aspx?year=1989&issue=05000&article=00005&type=abstract)] displayed remarkable prescience and subjective insight in relation to the potential problems that, in my opinion, could develop with dosages of zinc that many people would not view as being "excessive." I don't think zinc supplementation is a good idea in most cases, but that's just my opinion. I also don't think copper supplementation, above some tiny dosage (such as ~250-500 micrograms of elemental copper, to reach the RDA in combination with one's specific dietary intake), is a good idea, in many cases, but that's also just my opinion. A person would obviously want to discuss these issues with his or her doctor, given that one's unique, individualized nutritional needs are of paramount importance. I also think that the use of supplemental copper to compensate for the copper-depleting effects of zinc supplementation does not make sense and generally just has the potential to cause copper toxicity, but these are just my opinions.
I know this is a disturbing topic, but there's a kind of insanity in the way the different branches of research on zinc remain separated from one another. There's a vast amount of research showing copper-independent neurotoxic effects and extraordinarily complex, dynamic mechanisms of neurotoxicity from excesses of free zinc (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=zinc+neurotoxicity), and then there's the nutritional research on zinc. People seem to think that zinc-induced neurotoxicity is an all-or-nothing phenomenon. The assumption is that high dosages, such as are discussed in the case reports of neurotoxicity or demyelination, can cause problems but that the absence of overt neurological symptoms, in people taking lower doses, is in some way evidence that those lower dosages are not producing any pathological effects in the brain and spinal cord. It makes no sense to me to think that there would be no potential for problems in response to some of these lower dosage ranges, but that's just my opinion. The main reason I think that is that a multitude of factors can influence the amounts of zinc that are being released from intracellular binding sites, and I would expect that both the amounts of intracellular free zinc in neurons and the consequences of that zinc could be drastically different among different individuals with similar serum zinc levels and zinc intakes. The authors of this article discuss the possibility that the therapeutic intake range for zinc may well be small [Maret and Sandstead, 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16632171)], and it's time to face some of these issues, which I feel are serious, relating to zinc and copper supplementation.
I think neurotoxicity from excessive zinc supplementation is a very serious issue, and, in my opinion, low-level, pathological changes, such as psychiatric symptoms or gradually-progressing neurotoxicity, may result from dosages of zinc that many people would not view as being especially massive. Only a relatively few authors, as far as I can tell, have written articles, over the last few decades, discussing the potential hazards of zinc supplementation at the more commonly-used dosages. Even fewer articles on the nutritional aspects of zinc have considered that problems with zinc supplementation may have nothing to do with copper depletion, even when copper is depleted as a result of the excess zinc. In my opinion, based on the literature, many of the cases of neurotoxicity associated with excessive zinc supplementation (there are many, many case reports in the literature, and I don't feel like listing dozens of them out, right now, in this posting) may have had relatively little to do with copper depletion, and one sees that copper supplementation, in many cases, did not very effectively ameliorate the neurological disorders and demyelination that researchers had found in association with excessive intakes of zinc. [Some of the articles and case reports are scattered throughout the results of this search: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22zinc+supplementation%22+neurotoxic+OR+neurological+OR+demyelinating+OR+demyelination+OR+%22white+matter%22), and this is an "instructive-but-not-comprehensive" list of articles that google scholar classifies as being related to an article on excessive zinc supplementation: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=related:-bvm-ASLfasJ:scholar.google.com/)]. In most cases, the researchers have discontinued the zinc supplementation at the same times they have initiated copper supplementation, and then the researchers have attributed the modest improvements in the neurological conditions or anemia or thrombocytopenia or pancytopenia to the copper repletion. In reality, the absence of zinc may have been the primary and more important factor that led to the improvements.
I've discussed, in past postings, the extraordinarily complex aspects of zinc metabolism and homeostasis, and another issue is that serum copper and ceruloplasmin are not sensitive or very reliable indicators, in my opinion, of the intracellular copper concentrations or of copper status in people who are not grossly copper-deficient. Serum zinc is also not thought to be a reliable measure of zinc status [Fung et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/16215013)], and Fung et al. (2002) found that, even in people who had evidently been deficient in zinc and who had appeared to respond favorably to zinc supplementation, zinc supplementation did not increase serum zinc. These are major obstacles to nutritional research on zinc, in my opinion, and I would seriously question the validities of many descriptions, in the literature, of "zinc deficiency." Here's an article whose author discusses the potential neurotoxicity of zinc supplementation [Levenson, 2005: (http://www.ncbi.nlm.nih.gov/pubmed/15869126)], and here's a remarkable article, from 1989, in which Fosmire (1989) [Fosmire, 1989: (http://journals.lww.com/nutritiontodayonline/pages/articleviewer.aspx?year=1989&issue=05000&article=00005&type=abstract)] displayed remarkable prescience and subjective insight in relation to the potential problems that, in my opinion, could develop with dosages of zinc that many people would not view as being "excessive." I don't think zinc supplementation is a good idea in most cases, but that's just my opinion. I also don't think copper supplementation, above some tiny dosage (such as ~250-500 micrograms of elemental copper, to reach the RDA in combination with one's specific dietary intake), is a good idea, in many cases, but that's also just my opinion. A person would obviously want to discuss these issues with his or her doctor, given that one's unique, individualized nutritional needs are of paramount importance. I also think that the use of supplemental copper to compensate for the copper-depleting effects of zinc supplementation does not make sense and generally just has the potential to cause copper toxicity, but these are just my opinions.
I know this is a disturbing topic, but there's a kind of insanity in the way the different branches of research on zinc remain separated from one another. There's a vast amount of research showing copper-independent neurotoxic effects and extraordinarily complex, dynamic mechanisms of neurotoxicity from excesses of free zinc (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=zinc+neurotoxicity), and then there's the nutritional research on zinc. People seem to think that zinc-induced neurotoxicity is an all-or-nothing phenomenon. The assumption is that high dosages, such as are discussed in the case reports of neurotoxicity or demyelination, can cause problems but that the absence of overt neurological symptoms, in people taking lower doses, is in some way evidence that those lower dosages are not producing any pathological effects in the brain and spinal cord. It makes no sense to me to think that there would be no potential for problems in response to some of these lower dosage ranges, but that's just my opinion. The main reason I think that is that a multitude of factors can influence the amounts of zinc that are being released from intracellular binding sites, and I would expect that both the amounts of intracellular free zinc in neurons and the consequences of that zinc could be drastically different among different individuals with similar serum zinc levels and zinc intakes. The authors of this article discuss the possibility that the therapeutic intake range for zinc may well be small [Maret and Sandstead, 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16632171)], and it's time to face some of these issues, which I feel are serious, relating to zinc and copper supplementation.
Friday, December 19, 2008
Story on Restless Legs Syndrome
One implication of the NYT story on restless legs syndrome (RLS) (http://well.blogs.nytimes.com/2008/12/17/voices-of-restless-legs-syndrome/) seems, in my opinion, to be that doctors may not be as aware of the existence of RLS, as a clinical entity, as they could or perhaps should be. This may be a valid point, but I think many neurologists and most medical doctors who specialize in the treatment of sleep disorders would be aware of a lot of the research on and atypical manifestations of the condition. I guess the article communicates that. A lot of the research suggests that RLS tends to be a manifestation of very complex neurobiological changes and that these changes include inter-individual differences in gene expression, etc., in neurons in the spinal cord and not just the brainstem. It's my understanding that anything that decreases D2 dopamine receptor density, in the long-term or even in the short-term, and or patterns of D2 dopamine receptor activation (i.e. tonic vs. phasic activation, etc.) could produce the symptoms. This effect could be produced by a large range of drugs. Most of the research on the topic is in sleep-related journals.
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