I am sick of people rejecting good evidence about vitamin D because they are confused about the bad evidence and can't be bothered to investigate, so I am going to explain it.

Let's look at this like a 19th century physician who woke up from a coma this morning to trawl the public internet for info (I helped), knowing about evolution and bodies and counting and skepticism but not about "metastudies" or "scientific consensus" or "USDA guidelines." How much vitamin D do we need?

Hunter-gatherers in the environment where most of our evolution happened might have been outside all day shirtless. On average the sun's halfway from peak, so that might be equivalent to 8 hours of peak sunlight at the equator. If you're Fitzpatrick Type III like me, your skin adapted to absorb sunlight somewhat more efficiently since your ancestors were exposed to less over an evolutionarily relevant period, so let's cut that in half and say your body evolved for the equivalent of 4 hours of peak sunlight a day. An experimental study says:

Peak ultraviolet B irradiation for vitamin D synthesis occurs around 12 pm Eastern Standard Time (EST). In Boston, MA, from April to October at 12 pm EST an individual with type III skin, with 25.5% of the body surface area exposed, would need to spend 3 to 8 minutes in the sun to synthesize 400 IU of vitamin D. It is difficult to synthesize vitamin D during the winter in Boston, MA. For all study months in Miami, FL, an individual with type III skin would need to spend 3 to 6 minutes at 12 pm EST to synthesize 400 IU. Vitamin D synthesis occurs faster in individuals with lighter Fitzpatrick skin types.

There's another one that's paywalled if someone wants to pay or steal and check.

400 IU per 5 minutes is 8000 IU per hour is 32,000 IU (800 micrograms) per day by this estimate.

When deciding how much is actually appropriate to supplement, we need to take into account diminishing returns; eventually the sunlight starts producing other secondary metabolites which are also good for us, so a 16,000 IU supplement is lower-quality than sunlight but similar in the effective dosage of the most important chemical our evolutionary ancestors' bodies would have made from sunlight; in practice I wouldn't take more than that.

If someone wants to pay some people to have their blood drawn and analyzed before and after a full sunny day at the beach, great, but I can't be bothered. It would also be nice to see a study done on black people.

We know we get MUCH LESS vitamin D than this, and we already know what kinds of effects to look for. If you get no sunlight or supplemental vitamin D, your bones break down. If you live in an area with very little sun you're much more likely to be depressed and get sick. We know mechanistically that vitamin D plays a role in immune function. We observe that if you take a huge amount of supplemental vitamin D (>100,000 IU/day) you end up with too much calcium in your blood.

Let's use something where we have better intuitions about effective doses: exercise. Vitamin D supplementation equivalent to 4 hours of peak sunlight is like 4 hours of brisk treadmill walking - plausibly similar in dosage but lower in quality to the kind of movement our ancestors would actually get in a day.

Now let's look at the object-level studies that Scott Alexander says show that vitamin D doesn't work. I'm just going to look at the randomized controlled trials because observational studies for or against vitamin D are trash for anything except hypothesis generation unless they have a very carefully selected instrumental variable.

The largest randomized trial ever done on the subject, a 36,282-person behemoth, found zero effect of vitamin D on its two measured endpoints of colon cancer or breast cancer and in fact the vitamin D group had nonsignificantly more cancer than controls.

The colon cancer link is broken but the breast cancer study reports a dosage of 400 IU/day. On the exercise scale that's FIVE MINUTES of brisk walking. FIVE MINUTES is not very long at all compared with FOUR HOURS. If you went to see Lord of the Rings and only saw the first five minutes you would not be satisfied with a partial refund. If you showed up fasted to Thanksgiving dinner in the expectation of a full day's calories (the official US ration is 2000), this is like getting a single banana.

And a randomized controlled trial of 2700 people investigating all-cause mortality found zilch.

The intervention is 100,000 IU every four months. On the exercise scale this is like saying that because we live totally sedentary lives, instead of four hours of brisk walking every day, we should RUN A DOUBLE MARATHON ONCE EVERY FOUR MONTHS IN OUR OTHERWISE SEDENTARY LIVES. The marathon is named after the time when a messenger ran 26 miles home from the battle of Marathon, delivered the news, ran all the way back on the same day, delivered instructions to the general, and then died of exhaustion on the spot.

If on the other hand we amortize the dosage uniformly over the four months, that amounts to about 800 IU/day, or ten minutes of brisk walking on the exercise scale. Not nothing, but not at all the same sort of thing as four hours.

Now for the meta-analyses:

A meta-analysis by the Systematic Evidence Reviews people (who know their stuff) concluded that "Vitamin D and/or calcium supplementation also showed no overall effect on CVD, cancer, and mortality."

Let's forget about the fact that "vitamin D and/or calcium" is a stupid metric, except let's not, because it is a stupid metric we should not care about for anything except bone health. If vitamin D has specific effects on immune function or general wellness, there's no reason to expect that Calcium is a valid substitute. I also looked up the Study Characteristics of Included Studies, to see which ones had a treatment arm with vitamin D and found:

  • Dean 2011 gave 5,000 IU/day to 63 people and measured "cognitive and emotional functioning", treatment period unspecified. Reasonable dosage - on the exercise scale that's an hour of brisk walking - but terribly underpowered.
  • Graat 2002 used 200 IU/day of vitamin D. On the exercise scale that's TWO AND A HALF MINUTES. Also it was in a multivitamin with lots of confounding stuff, and group size was slightly more than 150.
  • Lappe 2007 used 1000 IU/day. Twelve and a half minutes of walking.
  • RECORD used 800 IU/day (ten minutes).
  • Trivedi 2003 used 100,000 IU (DOUBLE MARATHON) every four months.
  • WHI used 200 IU/day (two and a half minutes).

Wang et al found much the same (although their conclusions section does a terrible job elucidating this).

Broken link but I found the study on Internet Archive, and the abstract describes "moderately high doses" as averaging to about 1000 IU/day (twelve and a half minutes).

Autier looks at 172 randomized trials (!) and finds "Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence". [sic]

The highest dosage mentioned in the abstract is 2000 IU (25 minutes), which is at least getting somewhere. Maybe that's why "supplementation in elderly people (mainly women) with 20 μg vitamin D per day seemed to slightly reduce all-cause mortality." Also, a SIGNIFICANT REDUCTION IN ALL-CAUSE MORTALITY is a huge deal. That is the gold-standard outcome metric that everyone wishes their study was adequately powered to hit. Last time I checked statins don't reach all-cause mortality significance and they're widely prescribed. I don't independently find this meta-analysis very persuasive because the effect is barely significant, but summarizing this as a negative result is totally bonkers.

This is starting to get out of scope, and I'm not really interested in a conversation about whether Scott's characterizations are honest, so I'm going to stop here. Let's look for comparison at a study I liked.

The Spanish RCT studying vitamin D for COVID used a dosage regimen that - according to Chris Masterjohn's summary - was "equivalent to 106,400 IU vitamin D on day 1, 53,200 IU on days 3 and 7, and 53,200 IU weekly thereafter." Some of these are heroic doses, and the dosage regimen hardly seems optimal, but this is for people who had already been hospitalized with COVID, a situation of acute illness where the body might be churning through a tremendous amount of vitamin D. (For similar reasons I've started taking vitamin C megadoses when I get sick, because several grams per day could easily make a big difference even though the much smaller doses in RCTs don't.) On the exercise scale, this is equivalent to walking a double marathon on the first day, a single marathon on days 3 and 7, and weekly thereafter.

Intense, and not spaced out as much as I'd like, which is some evidence against the validity of the study - but neither obviously too small to make a difference nor spaced too far apart to be meaningful. I would expect better results from an equivalent daily dosage schedule. Masterjohn's calculation: "If this were given as daily doses, it would be the equivalent of 30,400 per day for the first week, followed by a maintenance dose of 7,600 IU per day."

ETA: In the comments on LessWrong Scott Alexander found a study estimating Hadza hunter-gatherer sunlight exposure equivalent to daily oral supplementation of 2000 IU. This seems like a better target for long-run supplementation than the maintenance dose in the Spanish RCT, and it's at a more comfortable distance from the estimated tolerable upper limit of 10,000 IU per day.

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I don't think hunter-gatherers get 16000 to 32000 IU of Vitamin D daily. This study suggests Hadza hunter-gatherers get more like 2000. I think the difference between their calculation and yours is that they find that hunter-gatherers avoid the sun during the hottest part of the day. It might also have to do with them being black, I'm not sure.

Hadza hunter gatherers have serum D levels of about 44 ng/ml. Based on this paper, I think you would need total vitamin D (diet + sunlight + supplements) of about 4400 IU/day to get that amount. If you start off as a mildly deficient American (15 ng/ml), you'd need an extra 2900 IU/day; if you start out as an average white American (30 ng/ml), you'd need an extra 1400 IU/day. The Hadza are probably an overestimate of what you need since they're right on the equator - hunter-gatherers in eg Europe probably did fine too. I think this justifies the doses of 400 - 2000 IU/day in studies as reasonably evolutionarily-informed.

Please don't actually take 16000 IU/day of vitamin D daily, if taken long-term this would put you at risk for vitamin D toxicity.

I also agree with the issues about the individual studies which other people have brought up.

Thanks, the Hadza study looks interesting. I'd have to read carefully at length to have a strong opinion on it but it seems like a good way to estimate the long-run target. I agree 16,000 is probably too much to take chronically, I've been staying below the TUL of 10,000, and expect to reduce the dosage significantly now that it's been a few years and COVID case rates are waning.

400 IU per 5 minutes is 8000 IU per hour is 32,000 IU (800 micrograms) per day by this estimate.

That's not how it works. When Vitamin D3 gets produced it's first on the skin. If you just stay longer outside then a lot of the Vitamin D3 that gets produced gets destroyed by radiation before it enters the bloodstream if you stay longer in the sun.

If someone wants to pay some people to have their blood drawn and analyzed before and after a full sunny day at the beach, great, but I can't be bothered. It would also be nice to see a study done on black people.

That's again not how things work. Vitamin D blood tests measure calcifediol and not cholecalciferol (Vitamin D3). It takes time for the cholecalciferol to be transformed, so you won't get the answer you are seeking by measuring after a single day.

I did write more about Vitamin D: https://www.lesswrong.com/posts/c5aycbSsSc38XWPEc/taking-vitamin-d3-with-k2-in-the-morning

The Autier et al review in which you note a SIGNIFICANT REDUCTION IN ALL-CAUSE MORTALITY

  • actually reports that in none of the studies they looked at where all-cause mortality was an endpoint was the observed reduction statistically significant
    • (of course I am aware that "is it statistically significant" is usually far from the most important question, but I think you shouldn't say "significant" in this context unless someone actually found statistical significance)
  • observes that these observed apparent reductions in all-cause mortality seem to be larger in studies that used smaller doses of vitamin D (10-20µg/day versus higher doses)
    • which I think makes it difficult to maintain simultaneously (1) that these results are accurate measurements of a real improvement and (2) that a good daily dose would be something on the order of 800µg/day
  • observes concerning these studies that "most trials included elderly women and a sizeable proportion of individuals were living in institutions" and claims more concretely that "gains in survival are mainly in elderly women living independently or in institutional care, who are likely to initially have a very low concentration of 25(OH)D with a substantial risk of falls and fractures" (but: it is not clear to me how carefully they have verified that latter claim)

So maybe it supports your thesis, but the authors of the review itself seem unconvinced and have a specific claimed explanation for these findings which, if correct, wouldn't indicate any benefit to younger basically-healthy individuals at negligible risk of the fall-fracture-death sequence.

(I am not passing any judgement on the rest of what you say; it does seem curious to me that the medical establishment generally seems to prefer what seem like very small doses of vitamin D, and that apparently no one has thought it interesting to try giving 1000 people 2000 IU/day or so and seeing what happens to them.)

(I am not passing any judgement on the rest of what you say; it does seem curious to me that the medical establishment generally seems to prefer what seem like very small doses of vitamin D, and that apparently no one has thought it interesting to try giving 1000 people 2000 IU/day or so and seeing what happens to them.)

There's the VITAL study where they gave 2000 IU/day with 12,927 assigned to Vitamin D.

Good catch. They looked at cancer, cardiovascular events (heart attack, stroke, death from cardiovascular causes), and deaths-from-cancer among men aged 50+ and women aged 55+. They found some "small but nonsignificant" improvements for the ones taking vitamin D (6.13% of vitamin D takers got cancer, versus 6.36% of people taking placebo vitamin D; 3.06% of vitamin D takers had cardiovascular events, versus 3.16% on placebo). They list a number of other things for which supplemental vitamin D didn't help significantly but for those they don't give the actual numbers (a cynic might conjecture that those numbers show small increases rather than small reductions).

On the other hand, they found a not-so-small reduction in cancer deaths among vitamin D takers ("a suggestive 17% reduction"; I guess the language indicates that this too was statistically insignificant because the numbers of deaths in the two cases were rather small, but I don't know; if they exclude deaths in the first two years of follow-up, which apparently is a reasonable thing to do for slowly developing diseases like cancer, though that rationale feels to me like it makes more sense for measuring getting cancer rather than dying of it?, that becomes a 25% reduction.

They also found "a suggestive 23% reduction in cancer risk" for African Americans specifically.

Which is all interesting but there's a bit of a whiff of data-mining here that makes me reluctant to get too excited.

More details here. The cynic mentioned above would be at least partly correct. For instance, cardiovascular deaths were 11% higher among people getting real vitamin D, as were incidences of a couple of specific kinds of cancer they tracked; all-cause mortality was pretty much identical between the two groups.

Following up on gjm's comment (sorry I'm a little late commenting on this post - I came to it via Scott Alexander's "Contra Hoffman" post), there was an interesting followup analysis of the cancer mortality effect in VITAL that concluded that "supplementation with vitamin D reduced the incidence of advanced (metastatic or fatal) cancer in the overall cohort, with the strongest risk reduction seen in individuals with normal weight." https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2773074 

This study is interesting because, among other things, it bridges the cancer "incidence" and cancer "mortality" questions by looking closely at "incidence" of advanced / metastatic cancer as well as cancer mortality. To address the "data mining" concern, cancer incidence and cancer mortality were both preregistered outcomes of VITAL - those of us who follow Vitamin D research and lean toward (rather than contra) Hoffman with respect to Vitamin D had expected the VITAL researchers to preregister cancer mortality as a primary outcome and cancer incidence as a secondary outcome, not just because mortality seems more important than incidence - both are important, of course - but also because the leading theories of Vitamin D's physiological effects provide a mechanism for reducing cancer mortality whereas the mechanisms for reducing initial (not metastatic) cancer incidence are speculative if they exist at all. (Alas, in the VITAL preregistration cancer incidence was primary and mortality secondary. Still, they were both preregistered and not just something that popped out after looking for something of significance.) The discussion section in the JAMA article explains the issues in detail, and the studies cited in the "biological plausibility" section ("[a]n association between vitamin D supplementation and metastatic and fatal cancer is biologically plausible") are worth reviewing.