Vitamin D Dosing Safety in a Randomized, Controlled Trial

No increase in adverse events was reported compared to placebo.



New data has been released from the Vitamin D Type 2 Diabetes (D2d) study [1]. This study is a randomized, controlled trial that includes overweight and obese people studied at 22 academic medical centers in the United States.

This data was collected between October 2013 and February 2017. After screening procedures and inclusion criteria, 2423 people with a mean age of 60 were assigned to either a vitamin D3 group or placebo. No significant differences were detected in baseline characteristics.

Few adverse events were reported

Upon initial testing, there were 36 cases of elevated blood calcium levels (hypercalcemia). Upon repeated testing, only ten cases were confirmed: six in the vitamin D3 group and four in the placebo group. Initial testing also showed 21 participants with newly elevated levels of calcium in urine (hypercalciuria), and repeated testing confirmed it in only two participants: one in the vitamin D3 group and one in the placebo group.

One participant in the vitamin D3 group and two participants in the placebo group had kidneys that filtered inadequate amounts of blood. Kidney stones were reported in 28 of the participants in the vitamin D3 group and 24 participants in the placebo group. Nausea and vomiting were reported in 20 participants in the vitamin D3 group and 9 people in the placebo group.

During the follow-up period of the study, 8304 adverse events occurred. Interestingly, the incidence of reporting these was higher in the placebo group than the vitamin D3 group.


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Serious adverse events were more frequent in the placebo group

529 serious adverse events were reported during follow-up. The number of serious adverse events reported between the groups was not significantly different. The highest reported serious event was hospitalization, though the groups did not differ in hospitalization rates. However, when investigators examined musculoskeletal events and injuries, the vitamin D3 group reported fewer adverse events and fewer serious adverse events than the placebo group.


In this large, multi-center, randomized control trial, a vitamin D3 dose of 4000 IU per day was well tolerated and did not increase adverse events, serious or not, compared to placebo. This is the first safety study of the tolerable upper limit of vitamin D3 given to prediabetic American adults who are above the recommended BMI. Some of the authors report no conflicts of interest, but some of the authors reported multiple potential conflicts of interest.

The authors mention that further trials are warranted to study the efficiency of higher vitamin D doses. The benefits and risks may be different in different populations due to factors such as disease state, skin pigmentation, weight status, and geographical location. A prior study supplemented healthy participants with vitamin D3 at 10000 IU, 4000 IU, or 400 IU for three years. Participants taking the higher doses, 4000 and 10000 IU, had significantly lower radial bone mineral density [2]. This study did not measure this; instead, it reported data on musculoskeletal adverse events.

According to the USDA 2020-2025 Dietary Guidelines for Americans, “Vitamin D recommendations are harder to achieve through natural sources from diet alone and would require consuming foods and beverages fortified with vitamin D. In many cases, taking a vitamin D supplement may be appropriate especially when sunlight exposure is limited due to climate or the use of sunscreen.” This can also be taken to apply to people whose daily lives seldom expose them to unfiltered sunlight.

Dosing of vitamin D3 has been a controversy in the research field for quite some time. These debates are common after studies on essential nutrients for human health. As more research is published, it may result in physicians creating personalized recommendations based on individual risk for vitamin D deficiency.


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This article is only a very brief summary. It is not intended as an exhaustive guide and is based on the interpretation of research data, which is speculative by nature. This article is not a substitute for consulting your physician about which supplements may or may not be right for you. We do not endorse supplement use or any product or supplement vendor, and all discussion here is for scientific interest.

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[1] Johnson, K. C., Pittas, A. G., Margolis, K. L., Peters, A. L., Phillips, L. S., Vickery, E. M., Nelson, J., Sheehan, P. R., Reboussin, D., Malozowski, S., Chatterjee, R., & D2d research group (2022). Safety and tolerability of high-dose daily vitamin D3 supplementation in the vitamin D and type 2 diabetes (D2d) study-a randomized trial in persons with prediabetes. European journal of clinical nutrition, 10.1038/s41430-022-01068-8. Advance online publication. https://doi.org/10.1038/s41430-022-01068-8

[2] Burt, L. A., Billington, E. O., Rose, M. S., Raymond, D. A., Hanley, D. A., & Boyd, S. K. (2019). Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial. JAMA, 322(8), 736–745. https://doi.org/10.1001/jama.2019.11889

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About the author


Tovah has been a Registered Dietitian Nutritionist (RDN) for the past 11 years in clinical, research, teaching, community, and industry roles. Her dissertation work was focused on nutritional and behavioral neuroscience approaches for chronic disease prevention. She was a writer for Lifespan.io from 2021-22 and is still an active volunteer with the org.