Vitamin D and Other Surprisingly Complex Questions

It is widely known that Vitamin D is important for strong bones. That’s because Vitamin D helps calcium absorption and plays a crucial role in calcium and bone metabolism, along with parathyroid hormone.

But Vitamin D also has other effects on health as it influences a variety of cell lines. Vitamin D deficiency has been potentially implicated in pathologies such as cancer,[1][2] inflammation,[3] auto-immune disorders,[4] and diabetes.[5] Whether Vitamin D deficiency is causative or a consequence, or possibly both, is unclear. [6][7]

How much Vitamin D should we take? You can find a long list at the Mayo Clinic’s website as possible guidelines for different health conditions. [8]

NIH, Office of Dietary Supplements, recommends an upper limit on daily intake of 4000 IU/day.[9] The reasoning behind that is set out in a detailed research review by a committee formed for the purpose of analyzing safe upper limits of long-term, possibly life-long, Vitamin D supplementation.[10]

The reason why there has to be an upper limit is that Vitamin D in large doses can be toxic. The acute toxicity of Vitamin D is well known. But the research findings on chronic ingestion of Vitamin D are quite variable. How high a dose is preventive and how high a dose is toxic is not that easy to determine.

10,000 IU/day of Vitamin D appears to be the upper limit where no adverse effects are observed, if the marker for adverse effects is taken to be hypercalcemia (Ca+ > 10.5 mg/dL in the blood).[11] Prolonged hypercalcemia is an important factor in organ damage and other adverse effects.

The circulating variant measured in the blood as a marker of Vitamin D status is 25-hydroxyvitamin D (converted in the liver), 25(OH)D in short. 25(OH)D levels are presumably a more sensitive marker for adverse effects than hypercalcemia.

25(OH)D concentrations seem to have a reverse-J-shaped benefit curve on several health parameters such as all-cause mortality, cardiovascular disease, as well as falls and fractures. That is, a low level of 25(OH)D is associated with an increased risk of several health conditions, but beyond point, high levels of 25(OH)D also seem to be risky.

For example, levels of 25(OH)D <30 nmol/L seem to be associated with increased all-cause mortality, and rising levels are associated with decreased risk, but only up to a point. Once levels rise beyond 75-120 nmol/L they appear to be associated with increased all-cause mortality again. [12]

There are numerous conflicting studies on the dose of Vitamin D beyond which adverse effects are seen, some of which suggest that much higher 25(OH)D concentrations can be tolerated with no adverse effects reported. To quote the paper from the NIH committee, “The vagaries of serum 25(OH)D measures in general, the sparse data available, and the uncertainty as to the nature of the adverse effects preclude strong conclusions.”

What would natural levels of Vitamin D be? Our lifestyle after the industrial era has changed to keep most people indoors much longer than they would have been earlier in human history.

Significant sun exposure in outdoor occupations and recreations seems to result in concentrations between 125-150 nmol/L, [13] and a study of traditionally living men in East Africa with a pastoral and hunter-gatherer lifestyle measured a mean 25(OH)D concentration of 115 nmol/L.[14] This is possibly a reasonable guideline to go by, though all these are measurements in healthy men, not in an elderly age group or people with specific health problems.

One of the few longer duration studies suggested that doses of 5000 IU/day result in 25(OH)D serum concentrations from 100-150 nmol/L but do not exceed 150 nmol/L after around 20 weeks of administration.[15] (Again, this was in healthy men.) With some leeway for uncertainty, given the rather diverse research findings, the recommendation comes down from 5000 IU/day to 4000 IU/day.

Also, steady smaller doses seem to result in reduction in fractures and falls, while there was one Australian study that tried 500,000 IU annually and found an increase in falls and fractures.[16]

But all this said, the therapeutic doses of Vitamin D would likely have to be much higher. For example, a pilot study that used does of 35,000 IU/day for six months found significant benefit in vitiligo and psoriasis, and the 25(OH)D concentrations rose to as high as ~265 ± 79 nmol/L and ~ 330 ± 37 nmol/L in patients with psoriasis and vitiligo respectively.

There is also the possibility that individual variations in the response of 25(OH)D levels to Vitamin D supplementation are large, based on genetics, body mass, and baseline levels.[17]

The safest approach would be to get Vitamin D from sunlight. Anywhere between 10 minutes to 2 hours of sunlight may be required, however, depending on melanin in the skin, latitude, time of the year, time of the day and other factors. Regular and adequate sunlight exposure is unfortunately not easy in modern times for many people.

To err on the side of caution, if taking Vitamin D supplements in higher doses, measuring calcium, PTH, and 25(OH)D levels to observe how one responds is wise.

You can find useful summaries on several websites from specialists on this topic. Nonetheless, how definitive can a recommendation be when the underlying data is potentially variable from one individual to the next? My purpose in this post is partly to bring out a simple fact: it is truly complicated to research and understand the effect of even a single supplement on the body.

If research on Vitamin D delivers such complex results, is it surprising that research on herbs which may contain numerous bioactive compounds, or on holistic interventions such as breathing, movement, or lifestyle changes, can be enormously more variable and complex?

- Ganesh Mohan

[1] Hughes PJ, Marcinkowska E, Gocek E, Studzinski GP, Brown G. Vitamin D3-driven signals for myeloid cell differentiation - Implications for differentiation therapy. Leukemia research. 2010;34(5):553-565.

[2] Tanaka H, Abe E, Miyaura C, et al. 1 alpha,25-Dihydroxycholecalciferol and a human myeloid leukaemia cell line (HL-60). Biochem J 1982;204:713–719.

[3] Zhang Y, Leung DY, Richers BN, et al. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol. 2012;188(5):2127-35.

[4] Cantorna MT, Snyder L, Lin Y-D, Yang L. Vitamin D and 1,25(OH)2D Regulation of T cells. Nutrients. 2015;7(4):3011-3021. doi:10.3390/nu7043011.

[5] Pittas AG, Dawson-hughes B, Li T, et al. Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care. 2006;29(3):650-6.

[6] Mangin M, Sinha R, Fincher K. Inflammation and vitamin D: the infection connection. Inflammation Research. 2014;63(10):803-819.

[7] Albert PJ, Proal AD, Marshall TG. Vitamin D: the alternative hypothesis. Autoimmun Rev. 2009;8(8):639-44.



[10] Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, et al., editors. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011. 6, Tolerable Upper Intake Levels: Calcium and Vitamin D.

[11] Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. American Journal of Clinical Nutrition. 2007;85(1):6–18.

[12] Ginde AA, Scragg R, Schwartz RS, Camargo CA Jr. Prospective study of serum 25-hydroxyvitamin D level, cardiovascular disease mortality, and all-cause mortality in older U.S. adults. Journal of the American Geriatrics Society. 2009;57(9):1595–603.

[13] Barger-Lux MJ, Heaney RP. Effects of above average summer sun exposure on serum 25-hydroxyvitamin D and calcium absorption. Journal of Clinical Endocrinology and Metabolism. 2002;87(11):4952–6.

[14] Luxwolda MF, Kuipers RS, Kema IP, Dijck-brouwer DA, Muskiet FA. Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l. Br J Nutr. 2012;108(9):1557-61.

[15] Heaney RP, Davies KM, Chen TC, Holick MF, Barger-lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003;77(1):204-10.

[16] Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, Nicholson GC. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. Journal of the American Medical Association. 2010;303(18):1815–22.

[17] Sollid ST, Hutchinson MY, Fuskevåg OM, Joakimsen RM, Jorde R. Large Individual Differences in Serum 25-Hydroxyvitamin D Response to Vitamin D Supplementation: Effects of Genetic Factors, Body Mass Index, and Baseline Concentration. Results from a Randomized Controlled Trial. Horm Metab Res. 2016;48(1):27-34.