Immunologists and doctors need to know all this, but most are not sufficiently interested in nutrition for vitamin D to be widely understood in their professions
May 18, 2023·edited May 18, 2023Liked by Robin Whittle
I read a study on human participants that showed how high fructose corn syrup can impair conversion of Vit D3. Not sure if it would also apply to regular fructose from fruits or honey.
On the issue of conversion or utilization of Vit D3 to the active and hormonal forms, I've read bout the necessity of Magnesium for this. One suggested to get lots of ot it, as if there's no upper bound, while another study showed that there appears to be a optimal spot. The later case showed Mg below certain level (which most people who are not supplementing) resulted in lower D3 conversion, but too much Magnesium seems to also impair conversion. I will have to go back and find the study to see if it was just observational correlation or direct intervention testing on the subjects.
Also do you know about biotin interference in serum testing for 25-OH D3 levels? I think I will have to get my levels along with numerous other tests redone after I stop biotin supplementation for 4+ days. I had deficient D3 levels several years ago at 16 ng/mL. Then I started supplementing, got more sun exposure when I could, and got my levels up (mid-upper 40's). However, it went back down when retesting twice in the past couple years, though not down to the truly deficient level (at 37 ng/mL a year ago). I seem to have hard bringing it back up despite increasing supplementation a bit.
Thanks for the link to the detailed article regarding biotin and interference with test results. I know nothing about biotin and have bookmarked that page for future reference.
I don't know as much about magnesium as I would like to. It is widely regarded by people whose judgement I trust as being an important nutrient which many people are deficient in. I take a capsule with 200 mg magnesium, as chelate, every day: https://www.naturesway.com.au/nature-s-way-magnesium-chelate-1000mg-100-tablets . Maybe I should take two a day. I was taking magnesium citrate, until someone kindly informed me that this is widely used as a laxative.
As explained in our Brownstone.org article and in greater detail at: https://vitamindstopscovid.info/02-intracrine/#02-nothorm only one of the three vitamin D compounds, 1,25-dihydroxyvitamin D calcitriol, functions as a hormone. There is only one such function. All its functions in the immune system and for other cell types which are not involved in calcium-phosphate-bone metabolism are not related to hormonal signaling.
I doubt that the body would respond differently to fructose from fruit and honey than it does from foods containing high fructose corn syrup. The difference would be in the quantities. Such products are common and widely consumed in the USA, but are much less common here in Australia, where we have plenty of sucrose from sugar cane.
Thanks a lot for those links! Will save for review later.
As for Magnesium, I take the citrate form and for me it's ok, though I know like you mentioned others typically recommend the amino acid chelates. One usually needs to take a ton of the citrate form to get a laxative effect.
I think this was the one I recall reading a summary or second hand citation about:
So the reality is more nuanced and the Mg effect on 25(OH)D3 appears to also concern calcium with some having to high of Ca:Mg ratio as per the paper, which uses the same receptor. Other reports I recall reading about this didn't mention calcium, which also seems to be another variable in influencing levels along with parathormone. The discussion starts from Figure 3. This might be another factor in my D3 levels if not biotin interference.
Edit: the other factor for me, one other change that occurred during that time of drop in D3 levels from a few years ago was suffering a bout of severe GERD and GI issues. Even though I've mostly recovered I've had to change my diet and the way I eat so that also make me wonder about impairment from intestinal absorption.
Which brings up the question: have you tried sublingual supplementation? The marketing states it's supposed to absorb better but then it makes me wonder about the fat solubility requirements of oral D3
On HFCS or corn syrup and how that came to be prominently used the states, that's a sad and illustrative story of government intervention gone wrong, probably worthy of an article on Brownstone Institute's website.
Hi Tom, I guess you mean a higher level of supplemental intake to raise 25-hydroxyvitamin D levels more quickly than a normal long-term intake, in a situation where the person is known to have been ingesting, or producing in their skin, very little vitamin D3.
Prof Wimalawansa's article mentions higher initial intakes. Since 12.5 mg 500,000 IU is regarded as a safe bolus dose for adults in hospital, https://sci-hub.se/10.1016/j.clnu.2018.08.037, one might simply take a month or two's worth of vitamin D3 in the first week or two.
Overall, vitamin D researchers in general, and immunologists and doctors in particular, should have done a much better job with vitamin D and the immune system.
You are reading the efforts of two people who are outside these fields - though Simon has a PhD in biotechnology - trying to make up for what is missing.
I would very much like to do all this research and get on top of it. However, I have some understandably frustrated musical instrument customers who I need to look after. I don't promise to ever do this to the standards I would like to achieve.
Simon and I cite research which we argue constitutes overwhelmingly strong arguments for attaining at least 50 ng/mL circulating 25(OH)D. However, it is a huge task - beyond what Simon and I can do properly - to reliably determine what ill effects might be expected to to reaching 50 to 100 ng/mL, or occasionally more, in some people, with the body-weight ratio based arrangements we think are generally best.
It is impractical and undesirable for every human on Earth to have their 25(OH)D levels tested and monitored by doctors. The body weight ratios system, with higher ratios for those suffering from obesity, is the only way of generally attaining sufficient 25(OH)D levels for the immune system to work properly.
Even with testing, this would result in some negative outcomes for some people, in ways that generally could not be predicted. At present, I can't even roughly quantify this. However, I expect that the overall level of health of the population would be vastly improved if everyone followed these arrangements.
We don't give car occupants a long lecture about all the hideous ways they might be injured or killed in a car crash *because* they were wearing a seat belt. Generally, they will be very much safer wearing a seat belt - but not always.
In a perfect world, all these concerns about higher 25(OH)D levels would be well researched, known by doctors and by anyone else who took an interest in them.
We are not in that world. One person every 3 seconds dies, hideously, from sepsis. I expect that the global burden of ill-health would be very approximately halved if everyone attained at least 50 ng/mL circulating 25(OH)D. There is no way of achieving this without some people having significantly more than this, and some people suffering health consequences which they would not have suffered if they had remained at the levels which are now common without proper supplementation: most frequently 15 to 25 ng/mL, with lower levels for those with dark skin and/or sun-avoidant lifestyles, and occasionally higher levels for those who get significant UV-B from sunlight and have white skin.
Burt et al 2020 report on the Calgary vitamin D study: https://sci-hub.se/10.1002/jbmr.4152 that post-menopausal women, but not men of the same age, who take substantial amounts of vitamin D3 (5000 or 10,000 IU a day) have a somewhat, but statistically significant, lower level of bone mineral density than those who took 800 IU / day. This impact was in a pattern of general decline in bone mineral density as both men and women age. However, careful computer analysis of the 3D structure of the bone did not predict that there was any loss of strength in the bones of those who took the higher amounts of vitamin D3.
This was a very carefully conducted study, which is unlikely to be repeated, if only due to ethical concerns based on these results. They used exactly the same X-ray scanners, on exactly the same part of the same bone in all these subjects. A world expert in bone scanning, Dick Mazess (who invented some of these scanners) dismissed the significance of this study. There has been very little discussion of it in the peer-reviewed literature. I do not discount it.
How can anyone really, fully, evaluate all these matters?
There are general, widely held, assumptions which turn out not to be true, or at least are subject to credible criticism. For instance the widespread belief that in sarcoidosis and other granulomatous disorders, it is best to reduce 25(OH)D levels. In these conditions, diseased immune cells convert a lot of 25(OH)D into excess calcitriol which enters circulation and acts as a hormone, disrupting the parathyroid gland and the kidneys' efforts to control blood calcium levels (which must be held within very narrow bounds, close to saturation) that 25(OH)D levels should be reduced, to reduce this pathological production of circulating calcitriol. Yet Kamphius et al. 2014: https://sci-hub.se/https://doi.org/10.1002/jbmr.2262 argue that patients with these disorders do better with higher 25(OH)D levels. This does not surprise me. The most likely reason, I think, for these immune cells behaving so wrongly is lack of proper 25(OH)D, at least in that part of the body, for immune cells in general, including those which regulate the errant cells, to work properly.
High blood calcium levels can lead to calcification of the arteries and heart valves. This is a serious concern among doctors who monitor patients following the very high 25(OH)D Coimbra protocol for suppressing many autoimmune inflammatory disorders: https://vitamindstopscovid.info/06-adv/#02-helminths
High calcium levels, at least in some people, can disrupt the mechanisms which trigger the heart's muscle contraction.
There are variety of potential concerns. Your question is simple and valid. However, answering it reliably is a lot of work, and one should not take the word of a single researcher or doctor on any of this.
After 100 years of research, Professor Wimalawansa's article https://www.mdpi.com/2072-6643/14/14/2997 provides a proper answer to the simple, vital, question: "How much vitamin D to take?". Ideally there would be a consensus article to this effect. At present, there is just his.
Yet his article is hard to read and I know of no justification for his lower ratios for underweight people, so Simon and I put the underweight in the same category as normal and overweight people in the table we *adapted* from Prof. W's article.
The question of marginal problems due to 25-hydroxyvitamin D levels, or occasional serious problems, is important.
This has not been properly covered in peer reviewed research, and like many other aspects of science it is a huge task to find, read and assess the various peer-reviewed articles which might be pertinent.
I hope to be able to do a reasonable job of that, in the fullness of time, but please remember I am a computer programmer and electronic technician, and that all the work I have put into raising awareness of vitamin D in the last three years has involved very high personal financial costs and great frustration among musical instrument customers, some of whom are still waiting for me to finish modifying their instruments which have been here since the start of the pandemic.
Overall, it is my impression that many doctors have an overly fearful view of vitamin D3 toxicity. However, that does not mean that there are no negative consequences, for some people, in attaining what for most people are perfectly healthy levels such as 50 to 100 ng/mL (125 to 25 nmol/L) circulating 25-hydroxyvitamin D.
I can't do a proper job of all this now.
If health authorities had been taking a proper interest in nutrition and vitamin D3 in particular, all this would be very well researched and widely known.
The fact that it falls to Simon Goddek - a PhD biotechnologist - and me (with no formal qualifications in any field) to write a proper account of the need for 50 ng/mL or more 25-hydroxyvitamin D shows you that the medical industry, immunologists, and most occasional and full-time vitamin D researchers should have been making greater efforts. Prof. Wimalawansa is one of the few researchers who takes special actions in response to the current crisis. Most doctors and immunologists generally have no real interest in vitamin D and the immune system.
It is widely believed by doctors that high 25(OH)D (25-hydroxyvitamin D) levels - whatever "high" might mean - increases the risk of kidney stones. However, my initial look at the research indicates that this is not very clearly established. I intend to find out more, but it will take months, at least.
I know of two people who reported heart palpitations when taking what I consider to be a proper amount of vitamin D3, to attain, generally, at least 50 ng/mL 25(OH)D after a few months.
Neither of these are in peer-reviewed journals, but they seem credible to me, especially since a good friend reported arrythmias recently from taking 5000 IU vitamin D3 a day for a few weeks, which went away in cessation after a few days, and returned within a day or so of starting again.
High circulating 25(OH)D will lead to higher levels inside cells in general. 25(OH)D binds to the vitamin D receptor molecule (VDR), but much more weakly than 1,25-hydroxyvitamin D calcitriol. Hormonal calcitriol levels in the bloodstream are very low, below 0.1 ng/mL, so "high" 25(OH)D levels, may affect the VDR and so disrupt the hormonal control of calcium levels, in some people, in some circumstances.
The VDR molecule is not the same in all people, due to genetic differences. Likewise the enzyme which degrades both 25-hydroxyvitamin D and 1,25-hydroxyvitamin D by adding an OH hydroxyl group to the 24th carbon. Howles et al. 2019 https://www.nature.com/articles/s41467-019-13145-x report genetic variants of this enzyme, CYP24A1, which are associated with kidney stones. These variants do not significantly raise circulating 25(OH)D levels, but they would presumably reduce the relatively rapid degradation of both 25(OH)D and 1,25-dihydroxyvitamin D inside cells, where the VDR molecules bind to them.
"'We found that even in those with high levels of vitamin D over 50 ng/mL, there was not an increased risk of hypercalcemia, or elevated serum calcium, with increasing levels of vitamin D,' stated Dr Thacher."
Prof. Holick is the world's foremost vitamin D researcher. He was the first person to isolate 25-hydroxyvitamin D from human blood serum, in 1969: https://www.mdpi.com/2072-6643/15/3/593 .
However, see my three part reply, above, to MoreQuestionsThanAnswers. I don't accept any single article, or opinion, as being the definitive answer to a nuanced question such as how some people might have bad reactions to "higher" 25-hydroxvitamin D levels. I want to see for myself - which takes more time than I have to do it properly.
I read a study on human participants that showed how high fructose corn syrup can impair conversion of Vit D3. Not sure if it would also apply to regular fructose from fruits or honey.
On the issue of conversion or utilization of Vit D3 to the active and hormonal forms, I've read bout the necessity of Magnesium for this. One suggested to get lots of ot it, as if there's no upper bound, while another study showed that there appears to be a optimal spot. The later case showed Mg below certain level (which most people who are not supplementing) resulted in lower D3 conversion, but too much Magnesium seems to also impair conversion. I will have to go back and find the study to see if it was just observational correlation or direct intervention testing on the subjects.
Also do you know about biotin interference in serum testing for 25-OH D3 levels? I think I will have to get my levels along with numerous other tests redone after I stop biotin supplementation for 4+ days. I had deficient D3 levels several years ago at 16 ng/mL. Then I started supplementing, got more sun exposure when I could, and got my levels up (mid-upper 40's). However, it went back down when retesting twice in the past couple years, though not down to the truly deficient level (at 37 ng/mL a year ago). I seem to have hard bringing it back up despite increasing supplementation a bit.
My only guess at this point is the biotin interference causing false results in the blood tests because that's what has changed in my regimen since then. See: https://chrismasterjohnphd.substack.com/p/biotin-causes-false-lab-tests
Hi VJ,
Thanks for the link to the detailed article regarding biotin and interference with test results. I know nothing about biotin and have bookmarked that page for future reference.
I don't know as much about magnesium as I would like to. It is widely regarded by people whose judgement I trust as being an important nutrient which many people are deficient in. I take a capsule with 200 mg magnesium, as chelate, every day: https://www.naturesway.com.au/nature-s-way-magnesium-chelate-1000mg-100-tablets . Maybe I should take two a day. I was taking magnesium citrate, until someone kindly informed me that this is widely used as a laxative.
Patrick Chambers MD has a particular interest in magnesium nutrition: https://www.researchgate.net/publication/359772765_Long_Covid_Short_Magnesium, https://www.scirp.org/journal/paperinformation.aspx?paperid=119926 and, from 2003, http://www.mgwater.com/laf.shtml. Also: https://www.cellphysiolbiochem.com/Articles/000603/ (These are not in journals indexed in PubMed: https://www.ncbi.nlm.nih.gov/pmc/journals/ .) Henry Lahore has a lot of material on magnesium at: https://vitamindwiki.com .
As explained in our Brownstone.org article and in greater detail at: https://vitamindstopscovid.info/02-intracrine/#02-nothorm only one of the three vitamin D compounds, 1,25-dihydroxyvitamin D calcitriol, functions as a hormone. There is only one such function. All its functions in the immune system and for other cell types which are not involved in calcium-phosphate-bone metabolism are not related to hormonal signaling.
Fructose is another subject I wish I knew more about. It is a lot of work finding the best research, and all the other stuff, and understanding it sufficiently to evaluate it. Here are some items I bookmarked but have no read: https://academic.oup.com/ajcn/article/115/6/1453/6573846 , https://pubmed.ncbi.nlm.nih.gov/10682873/ , https://www.diagnosisdiet.com/full-article/has-fructose-been-framed , https://vitamindwiki.com/Fructose+%28High+Fructose+Corn+Syrup%29+consumes+2X+more+Magnesium+than+sugar+%E2%80%93+May+2014 and "Chronic High Fructose Intake Reduces Serum 1,25 (OH)2D3 Levels in Calcium-Sufficient Rodents" https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093611.
I doubt that the body would respond differently to fructose from fruit and honey than it does from foods containing high fructose corn syrup. The difference would be in the quantities. Such products are common and widely consumed in the USA, but are much less common here in Australia, where we have plenty of sucrose from sugar cane.
Thanks a lot for those links! Will save for review later.
As for Magnesium, I take the citrate form and for me it's ok, though I know like you mentioned others typically recommend the amino acid chelates. One usually needs to take a ton of the citrate form to get a laxative effect.
I think this was the one I recall reading a summary or second hand citation about:
https://www.scirp.org/journal/paperinformation.aspx?paperid=119926
So the reality is more nuanced and the Mg effect on 25(OH)D3 appears to also concern calcium with some having to high of Ca:Mg ratio as per the paper, which uses the same receptor. Other reports I recall reading about this didn't mention calcium, which also seems to be another variable in influencing levels along with parathormone. The discussion starts from Figure 3. This might be another factor in my D3 levels if not biotin interference.
Edit: the other factor for me, one other change that occurred during that time of drop in D3 levels from a few years ago was suffering a bout of severe GERD and GI issues. Even though I've mostly recovered I've had to change my diet and the way I eat so that also make me wonder about impairment from intestinal absorption.
Which brings up the question: have you tried sublingual supplementation? The marketing states it's supposed to absorb better but then it makes me wonder about the fat solubility requirements of oral D3
On HFCS or corn syrup and how that came to be prominently used the states, that's a sad and illustrative story of government intervention gone wrong, probably worthy of an article on Brownstone Institute's website.
Is there a vit D intake chart that takes elderly hypo-intake into consideration?
Hi Tom, I guess you mean a higher level of supplemental intake to raise 25-hydroxyvitamin D levels more quickly than a normal long-term intake, in a situation where the person is known to have been ingesting, or producing in their skin, very little vitamin D3.
Prof Wimalawansa's article mentions higher initial intakes. Since 12.5 mg 500,000 IU is regarded as a safe bolus dose for adults in hospital, https://sci-hub.se/10.1016/j.clnu.2018.08.037, one might simply take a month or two's worth of vitamin D3 in the first week or two.
What about high levels of vitamin d causing hypercalcemia and therefore heart issues. I heard it's necessary to also take K2 to protect the heart?
Part 3 of a 3 part answer:
Overall, vitamin D researchers in general, and immunologists and doctors in particular, should have done a much better job with vitamin D and the immune system.
You are reading the efforts of two people who are outside these fields - though Simon has a PhD in biotechnology - trying to make up for what is missing.
I would very much like to do all this research and get on top of it. However, I have some understandably frustrated musical instrument customers who I need to look after. I don't promise to ever do this to the standards I would like to achieve.
Simon and I cite research which we argue constitutes overwhelmingly strong arguments for attaining at least 50 ng/mL circulating 25(OH)D. However, it is a huge task - beyond what Simon and I can do properly - to reliably determine what ill effects might be expected to to reaching 50 to 100 ng/mL, or occasionally more, in some people, with the body-weight ratio based arrangements we think are generally best.
It is impractical and undesirable for every human on Earth to have their 25(OH)D levels tested and monitored by doctors. The body weight ratios system, with higher ratios for those suffering from obesity, is the only way of generally attaining sufficient 25(OH)D levels for the immune system to work properly.
Even with testing, this would result in some negative outcomes for some people, in ways that generally could not be predicted. At present, I can't even roughly quantify this. However, I expect that the overall level of health of the population would be vastly improved if everyone followed these arrangements.
We don't give car occupants a long lecture about all the hideous ways they might be injured or killed in a car crash *because* they were wearing a seat belt. Generally, they will be very much safer wearing a seat belt - but not always.
In a perfect world, all these concerns about higher 25(OH)D levels would be well researched, known by doctors and by anyone else who took an interest in them.
We are not in that world. One person every 3 seconds dies, hideously, from sepsis. I expect that the global burden of ill-health would be very approximately halved if everyone attained at least 50 ng/mL circulating 25(OH)D. There is no way of achieving this without some people having significantly more than this, and some people suffering health consequences which they would not have suffered if they had remained at the levels which are now common without proper supplementation: most frequently 15 to 25 ng/mL, with lower levels for those with dark skin and/or sun-avoidant lifestyles, and occasionally higher levels for those who get significant UV-B from sunlight and have white skin.
Part 2:
Burt et al 2020 report on the Calgary vitamin D study: https://sci-hub.se/10.1002/jbmr.4152 that post-menopausal women, but not men of the same age, who take substantial amounts of vitamin D3 (5000 or 10,000 IU a day) have a somewhat, but statistically significant, lower level of bone mineral density than those who took 800 IU / day. This impact was in a pattern of general decline in bone mineral density as both men and women age. However, careful computer analysis of the 3D structure of the bone did not predict that there was any loss of strength in the bones of those who took the higher amounts of vitamin D3.
This was a very carefully conducted study, which is unlikely to be repeated, if only due to ethical concerns based on these results. They used exactly the same X-ray scanners, on exactly the same part of the same bone in all these subjects. A world expert in bone scanning, Dick Mazess (who invented some of these scanners) dismissed the significance of this study. There has been very little discussion of it in the peer-reviewed literature. I do not discount it.
How can anyone really, fully, evaluate all these matters?
There are general, widely held, assumptions which turn out not to be true, or at least are subject to credible criticism. For instance the widespread belief that in sarcoidosis and other granulomatous disorders, it is best to reduce 25(OH)D levels. In these conditions, diseased immune cells convert a lot of 25(OH)D into excess calcitriol which enters circulation and acts as a hormone, disrupting the parathyroid gland and the kidneys' efforts to control blood calcium levels (which must be held within very narrow bounds, close to saturation) that 25(OH)D levels should be reduced, to reduce this pathological production of circulating calcitriol. Yet Kamphius et al. 2014: https://sci-hub.se/https://doi.org/10.1002/jbmr.2262 argue that patients with these disorders do better with higher 25(OH)D levels. This does not surprise me. The most likely reason, I think, for these immune cells behaving so wrongly is lack of proper 25(OH)D, at least in that part of the body, for immune cells in general, including those which regulate the errant cells, to work properly.
High blood calcium levels can lead to calcification of the arteries and heart valves. This is a serious concern among doctors who monitor patients following the very high 25(OH)D Coimbra protocol for suppressing many autoimmune inflammatory disorders: https://vitamindstopscovid.info/06-adv/#02-helminths
High calcium levels, at least in some people, can disrupt the mechanisms which trigger the heart's muscle contraction.
There are variety of potential concerns. Your question is simple and valid. However, answering it reliably is a lot of work, and one should not take the word of a single researcher or doctor on any of this.
After 100 years of research, Professor Wimalawansa's article https://www.mdpi.com/2072-6643/14/14/2997 provides a proper answer to the simple, vital, question: "How much vitamin D to take?". Ideally there would be a consensus article to this effect. At present, there is just his.
Yet his article is hard to read and I know of no justification for his lower ratios for underweight people, so Simon and I put the underweight in the same category as normal and overweight people in the table we *adapted* from Prof. W's article.
Part 1 of a 3 part answer:
The question of marginal problems due to 25-hydroxyvitamin D levels, or occasional serious problems, is important.
This has not been properly covered in peer reviewed research, and like many other aspects of science it is a huge task to find, read and assess the various peer-reviewed articles which might be pertinent.
I hope to be able to do a reasonable job of that, in the fullness of time, but please remember I am a computer programmer and electronic technician, and that all the work I have put into raising awareness of vitamin D in the last three years has involved very high personal financial costs and great frustration among musical instrument customers, some of whom are still waiting for me to finish modifying their instruments which have been here since the start of the pandemic.
Overall, it is my impression that many doctors have an overly fearful view of vitamin D3 toxicity. However, that does not mean that there are no negative consequences, for some people, in attaining what for most people are perfectly healthy levels such as 50 to 100 ng/mL (125 to 25 nmol/L) circulating 25-hydroxyvitamin D.
I can't do a proper job of all this now.
If health authorities had been taking a proper interest in nutrition and vitamin D3 in particular, all this would be very well researched and widely known.
The fact that it falls to Simon Goddek - a PhD biotechnologist - and me (with no formal qualifications in any field) to write a proper account of the need for 50 ng/mL or more 25-hydroxyvitamin D shows you that the medical industry, immunologists, and most occasional and full-time vitamin D researchers should have been making greater efforts. Prof. Wimalawansa is one of the few researchers who takes special actions in response to the current crisis. Most doctors and immunologists generally have no real interest in vitamin D and the immune system.
It is widely believed by doctors that high 25(OH)D (25-hydroxyvitamin D) levels - whatever "high" might mean - increases the risk of kidney stones. However, my initial look at the research indicates that this is not very clearly established. I intend to find out more, but it will take months, at least.
I know of two people who reported heart palpitations when taking what I consider to be a proper amount of vitamin D3, to attain, generally, at least 50 ng/mL 25(OH)D after a few months.
So far, I have not found peer reviewed research to document this. There was a 2011 conference paper, but it has no proper details: https://www.ahajournals.org/doi/10.1161/circ.124.suppl_21.A14699
This article: https://www.ahajournals.org/doi/10.1161/circ.124.suppl_21.A14699 reports cardiac arrhythmias resulting from *low* 25(OH)D levels.
So far (and I will keep looking) I found only two reports of heart arrhythmias due to high vitamin D3 intakes, and so presumably due to high 25(OH)D levels: https://jeffchen.dev/posts/Vitamin-D-And-Heart-Palpitations/ which cites a report from a doctor about a patient: https://www.devaboone.com/post/vitamin-d-part-2-shannon-s-story .
Neither of these are in peer-reviewed journals, but they seem credible to me, especially since a good friend reported arrythmias recently from taking 5000 IU vitamin D3 a day for a few weeks, which went away in cessation after a few days, and returned within a day or so of starting again.
High circulating 25(OH)D will lead to higher levels inside cells in general. 25(OH)D binds to the vitamin D receptor molecule (VDR), but much more weakly than 1,25-hydroxyvitamin D calcitriol. Hormonal calcitriol levels in the bloodstream are very low, below 0.1 ng/mL, so "high" 25(OH)D levels, may affect the VDR and so disrupt the hormonal control of calcium levels, in some people, in some circumstances.
The VDR molecule is not the same in all people, due to genetic differences. Likewise the enzyme which degrades both 25-hydroxyvitamin D and 1,25-hydroxyvitamin D by adding an OH hydroxyl group to the 24th carbon. Howles et al. 2019 https://www.nature.com/articles/s41467-019-13145-x report genetic variants of this enzyme, CYP24A1, which are associated with kidney stones. These variants do not significantly raise circulating 25(OH)D levels, but they would presumably reduce the relatively rapid degradation of both 25(OH)D and 1,25-dihydroxyvitamin D inside cells, where the VDR molecules bind to them.
Regarding the risk of hypercalcemia, this concern seems to have been overtaken by more recent research: https://www.lifeextension.com/whatshot/2015/5/may-whats-hot-articles#Mayo-Clinic-finds-vitamin-D-toxicity-rare
"'We found that even in those with high levels of vitamin D over 50 ng/mL, there was not an increased risk of hypercalcemia, or elevated serum calcium, with increasing levels of vitamin D,' stated Dr Thacher."
Thanks "Username" for the link, which refers to Michael Holick's 2015 editorial: "Vitamin D Is Not as Toxic as Was Once Thought: A Historical and an Up-to-Date Perspective" https://www.mayoclinicproceedings.org/article/S0025-6196(15)00244-X/fulltext , which cites: Dudenkov et al. 2015: https://www.mayoclinicproceedings.org/article/S0025-6196(15)00185-8/fulltext .
Prof. Holick is the world's foremost vitamin D researcher. He was the first person to isolate 25-hydroxyvitamin D from human blood serum, in 1969: https://www.mdpi.com/2072-6643/15/3/593 .
However, see my three part reply, above, to MoreQuestionsThanAnswers. I don't accept any single article, or opinion, as being the definitive answer to a nuanced question such as how some people might have bad reactions to "higher" 25-hydroxvitamin D levels. I want to see for myself - which takes more time than I have to do it properly.
Life Extension offers a good introductory guide to taking vitamin D: https://www.lifeextension.com/wellness/vitamins/vitamin-d-safe-dosage
Generally speaking, the idea is that risks from taking vitamin D stem mainly from way overdoing it to exaggerated excess (redundancy intended 😀).