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.
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:
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 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.
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:
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:
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).
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.