Great article. I followed the same logic and came down on the "benefit is mild and correlated with your skin tone and where you live (I'm in Ohio), and the cost is very low" side, and therefore take 5000 IUs a day.
Every time I see analyses of single chemical (or whatever) interventions like this, I keep thinking "this is what the data would look like there was some other factor that wasn't being controlled for." The part you write about "whoa, it's amazing all the ways that the body creates, interacts with and uses vitamin D" makes me think "well, are we sure we've actually discovered all of them?" I feel like a lot of the outcomes from these studies are exactly what we'd see if there were other moving pieces in the machine, that are affected by (or affect) the whole "vitamin D process" in some way, or in some circumstances, or only in the presence of some other thing, that we don't understand yet.
Oh, I'd think it's unlikely we've discovered all of them. Vitamin D is an interesting case where early on, it seemed like we had mechanistic evidence that vitamin D levels shouldn't matter (because the kidneys only need very low levels of storage vitamin D to regulate active vitamin D) and only later did we learn that things are much more complicated.
It's a little bit unclear what to make of that. You can fall back to the idea that ancestral levels are safer, but ancestral levels aren't always best. It's even conceivable that we could discover some pathway through which vitamin D might be harmful.
right! And even then, since the acute vit D toxicity level seems to be crazy high, it would probably need to be some kind of additional interaction with something else. Which is what I thought of when I read the part where you note that vitamin D is supplemented frequently in margarine. What if, as some do, you believe that margarine isn't good for you? If lots of people's vit D consumption was inextricably linked to margarine consumption across the course of those studies, what would we expect to see?
Ha, yes, good point! Once you start fortifying foods, vitamin D levels become a weak signal for diet patterns that would otherwise be irrelevant.
The fortification of foods seems to be incredibly random. For example, New Zealand doesn't currently make any effort to fortify, but it just so happens that almost all the margarine consumed in New Zealand comes from Australia, where margarine is fortified.
And why fortify margarine in the first place? I guess you could argue that it's replacing natural vitamin D that would be lost if someone substitutes vitamin D for butter. But margarine is fortified WAY beyond the level that's in non-fortified butter...
I wish I had the time to read more about it, but yeah, the whole "fortified foods" (how much, what vitamin, in what cases, alongside what things?) thing seems like a underrated gold mine for bad science and misunderstanding causes and effects.
I had just sufficient levels of Vitamin D. I tried to get the levels higher with a daily tablet followed by a weekly high dose Calciferol tablet. Nothing moved the needle, until a doctor recommended taking daily drops (at about 4000 IU). That worked incredibly well.
I wonder how much of an outlier I am, in that the form of the supplement made a huge difference.
It seems that (all?) the RCTs have done a very poor job in assessing the claim that increasing from the 25th percentile to the 75th percentile decreases overall mortality.
It's hard to say how unusual that is. On average, all the trials seemed successful in raising vitamin D levels regardless of the particular intervention they gave. (https://dynomight.net/vitamin-d/#fn:19) But that might conceal lots of person-to-person variation.
But... yes, I think the trials on the whole didn't do a great job of assessing that claim. Arguably the best single trial on that count is probably RECORD, simply because it happened to be done in a time and place with low baseline levels and it had a pretty big sample. And the results of RECORD are pretty good. But they didn't seem to measure levels at the end, and there were only 5000 people, which isn't enough to detect plausible effects.
You're talking about parathyroid hormone levels rising as vitamin D levels drop from 70 nmol/L to 25 nmol/L? I see no particular reason to be terrified about that. To the best of my knowledge, having a little extra parathyroid hormone floating around isn't obviously bad. It's just a weird thing, suggesting that maybe we don't fully understand even the traditional endocrine view of vitamin D.
No, I'm talking about health science not moving unless "someone notices something" THAT scares me.
I'd like it to move something like a filesystem scans a directory: no questions unasked.
But I realize that's not efficiently possible. Even if one could, we'd drown in unchewable data.
I wish there were a more affirmative process for ASKING, not as big a reliance on serendipity (which has given us some amazing stuff (vaccination, antibiotics), but wow, why weren't we on the hunt for them?)
To the best of my knowledge, there are few if any animal studies studying things like the outcome of vitamin D on mortality over a lifetime. (There are studies, but they are usually short term and/or focused on toxicity.)
I assume the reason is the same we have few animal studies for other nutrition or longevity interventions, namely that that the expense is ungodly. With a modest hazard ratio like 0.95, you'd need many thousands of animals and you'd need to maintain them for years and years. A single day of maintaining a monkey in a research facility is something like $75. Multiply that by a monkey lifetime and then again for thousands of monkeys, and the problem appears.
Oddly, if it's ethical to do an intervention in people, using people is far cheaper than animals, because people keep themselves alive at their own expense!
The other issue is that results of interventions in animals are only weakly correlated with those in humans. This is one reason so many prospective drugs fail in human clinical trials even after "successful" animal trials.
For vitamin D in particular, the effect sizes you show in this article are so small to begin with that I would never trust an animal vitamin D trial's results to transfer to humans.
I think also, if I remember correctly, that the human vitamin-D generation and use process is sufficiently different than most commonly studied animals. Particularly ones totally covered in fur/hair.
Just when I think you can't raise the bar any higher, you go in depth on D3, and compliment other high quality observers, and raise the bar. I'm glad you're here.
If Professor Steve Jones of UCL says anyone living on the same meridian as London or higher should take it....and now dynomight. It must be at least considered.
Thank you! Though from a quick search I fear that Steve Jones and I might arrive at that conclusion from quite a different point of view, in that he seems far less suspicious of correlational evidence than me.
Interestingly, in this letter he seems to suggest it would be better to take storage vitamin D (calcifediol) rather than regular vitamin D:
Nothing crazy about that, since it would presumably be easier to absorb since it doesn't need to be processed by the liver, and people eat storage vitamin D naturally if you eat animal products. But I wonder what the logic is. Apparently, there are some supplements with this form, although not common.
Lovely read, as always!
Excellent article. One of your best. Very readable, and you present the available data with uncommon clarity.
Great article. I followed the same logic and came down on the "benefit is mild and correlated with your skin tone and where you live (I'm in Ohio), and the cost is very low" side, and therefore take 5000 IUs a day.
Every time I see analyses of single chemical (or whatever) interventions like this, I keep thinking "this is what the data would look like there was some other factor that wasn't being controlled for." The part you write about "whoa, it's amazing all the ways that the body creates, interacts with and uses vitamin D" makes me think "well, are we sure we've actually discovered all of them?" I feel like a lot of the outcomes from these studies are exactly what we'd see if there were other moving pieces in the machine, that are affected by (or affect) the whole "vitamin D process" in some way, or in some circumstances, or only in the presence of some other thing, that we don't understand yet.
Oh, I'd think it's unlikely we've discovered all of them. Vitamin D is an interesting case where early on, it seemed like we had mechanistic evidence that vitamin D levels shouldn't matter (because the kidneys only need very low levels of storage vitamin D to regulate active vitamin D) and only later did we learn that things are much more complicated.
It's a little bit unclear what to make of that. You can fall back to the idea that ancestral levels are safer, but ancestral levels aren't always best. It's even conceivable that we could discover some pathway through which vitamin D might be harmful.
right! And even then, since the acute vit D toxicity level seems to be crazy high, it would probably need to be some kind of additional interaction with something else. Which is what I thought of when I read the part where you note that vitamin D is supplemented frequently in margarine. What if, as some do, you believe that margarine isn't good for you? If lots of people's vit D consumption was inextricably linked to margarine consumption across the course of those studies, what would we expect to see?
Ha, yes, good point! Once you start fortifying foods, vitamin D levels become a weak signal for diet patterns that would otherwise be irrelevant.
The fortification of foods seems to be incredibly random. For example, New Zealand doesn't currently make any effort to fortify, but it just so happens that almost all the margarine consumed in New Zealand comes from Australia, where margarine is fortified.
And why fortify margarine in the first place? I guess you could argue that it's replacing natural vitamin D that would be lost if someone substitutes vitamin D for butter. But margarine is fortified WAY beyond the level that's in non-fortified butter...
Yeah seems like the question is why is margarine commonly fortified with vitamins D and only margarine.
I wish I had the time to read more about it, but yeah, the whole "fortified foods" (how much, what vitamin, in what cases, alongside what things?) thing seems like a underrated gold mine for bad science and misunderstanding causes and effects.
I am always incredibly happy to see a new Dynomight post. Really phenomenal work here.
I had just sufficient levels of Vitamin D. I tried to get the levels higher with a daily tablet followed by a weekly high dose Calciferol tablet. Nothing moved the needle, until a doctor recommended taking daily drops (at about 4000 IU). That worked incredibly well.
I wonder how much of an outlier I am, in that the form of the supplement made a huge difference.
It seems that (all?) the RCTs have done a very poor job in assessing the claim that increasing from the 25th percentile to the 75th percentile decreases overall mortality.
It's hard to say how unusual that is. On average, all the trials seemed successful in raising vitamin D levels regardless of the particular intervention they gave. (https://dynomight.net/vitamin-d/#fn:19) But that might conceal lots of person-to-person variation.
But... yes, I think the trials on the whole didn't do a great job of assessing that claim. Arguably the best single trial on that count is probably RECORD, simply because it happened to be done in a time and place with low baseline levels and it had a pretty big sample. And the results of RECORD are pretty good. But they didn't seem to measure levels at the end, and there were only 5000 people, which isn't enough to detect plausible effects.
"people also noticed that..."
I find this thing I already knew newly terrifying. As if medical science just waits around for people to notice things.
This is where we came in with Jenner, and Fleming.
Isn't there a way to notice EVERYTHING‽ Could there be?
Maybe AI can help, if it doesn't kill us all first one way or another.
You're talking about parathyroid hormone levels rising as vitamin D levels drop from 70 nmol/L to 25 nmol/L? I see no particular reason to be terrified about that. To the best of my knowledge, having a little extra parathyroid hormone floating around isn't obviously bad. It's just a weird thing, suggesting that maybe we don't fully understand even the traditional endocrine view of vitamin D.
No, I'm talking about health science not moving unless "someone notices something" THAT scares me.
I'd like it to move something like a filesystem scans a directory: no questions unasked.
But I realize that's not efficiently possible. Even if one could, we'd drown in unchewable data.
I wish there were a more affirmative process for ASKING, not as big a reliance on serendipity (which has given us some amazing stuff (vaccination, antibiotics), but wow, why weren't we on the hunt for them?)
what about animal trials?
To the best of my knowledge, there are few if any animal studies studying things like the outcome of vitamin D on mortality over a lifetime. (There are studies, but they are usually short term and/or focused on toxicity.)
I assume the reason is the same we have few animal studies for other nutrition or longevity interventions, namely that that the expense is ungodly. With a modest hazard ratio like 0.95, you'd need many thousands of animals and you'd need to maintain them for years and years. A single day of maintaining a monkey in a research facility is something like $75. Multiply that by a monkey lifetime and then again for thousands of monkeys, and the problem appears.
Oddly, if it's ethical to do an intervention in people, using people is far cheaper than animals, because people keep themselves alive at their own expense!
The other issue is that results of interventions in animals are only weakly correlated with those in humans. This is one reason so many prospective drugs fail in human clinical trials even after "successful" animal trials.
For vitamin D in particular, the effect sizes you show in this article are so small to begin with that I would never trust an animal vitamin D trial's results to transfer to humans.
I think also, if I remember correctly, that the human vitamin-D generation and use process is sufficiently different than most commonly studied animals. Particularly ones totally covered in fur/hair.
Just when I think you can't raise the bar any higher, you go in depth on D3, and compliment other high quality observers, and raise the bar. I'm glad you're here.
If Professor Steve Jones of UCL says anyone living on the same meridian as London or higher should take it....and now dynomight. It must be at least considered.
Thank you! Though from a quick search I fear that Steve Jones and I might arrive at that conclusion from quite a different point of view, in that he seems far less suspicious of correlational evidence than me.
Interestingly, in this letter he seems to suggest it would be better to take storage vitamin D (calcifediol) rather than regular vitamin D:
https://www.bmj.com/content/372/bmj.n484/rr-0
Nothing crazy about that, since it would presumably be easier to absorb since it doesn't need to be processed by the liver, and people eat storage vitamin D naturally if you eat animal products. But I wonder what the logic is. Apparently, there are some supplements with this form, although not common.
Thank you.
By "regular vitamin D" you're referring to D3? At least, in the UK that's the regular D I see most often in stores.
https://www.hollandandbarrett.com/shop/product/solgar-vitamin-d3-1000iu-tablets-60001430
This podcast regarding sunshine is really interesting; I've put the book on reserve at the library: https://www.econtalk.org/the-case-for-sunshine-with-rowan-jacobsen/
I moved to Arizona for Seasonal Affective Disorder, but am glad to see this argument for sunshine, too. :-)