And a brief review of the growing body of knowledge of vitamin D

by Michael Passwater

Key Points

  • The Harvard led Vitamin D and Omega 3 trial (VITAL), involving 12,786 men 50 years or older and 13,085 women 55 years or older, recently published findings showing a meaningful (22%) and statistically significant reduction in the incidence of autoimmune disease in older adults taking 2000 IU (50 mcg) per day for 5 years
  • Maintaining vitamin D levels in the 40-60 ng/mL (100-150 nmol/L) range is associated with lower risk of autoimmunity, respiratory disease, and other illnesses; this can be achieved by adjusting sunlight exposure, vitamin D3 intake, and co-factors, and testing vitamin D levels regularly
  • Dose amounts for vitamin D are dependent on the individual dose-response and level achieved. While the recommended intake of vitamin D from 220 vitamin D experts is 2000 to 4000 IU/day, the personal supplementation amount of 193 of these experts ranged from 0-50,000 IU/day and averaged 5,175 IU/day. The bottom line is to dose according to how much vitamin D reaches the blood and tissues, as measured by a vitamin D test, and to maintain sufficient or therapeutic levels rather than waiting until illness occurs.
  • Vitamin D is important for a wide range of functions in human biology from conception onward. We now have more evidence pointing towards the importance of maintaining a vitamin D level in the 40-60 ng/mL range, as reviewed in this article, along with maintaining adequate levels of synergistic nutrients to fight infections, sustain helpful immunity, and also to prevent harmful autoimmune reactions.

OMNS (Feb. 17, 2022) The Harvard led Vitamin D and Omega 3 trial (VITAL), recently published findings showing a meaningful (22%) and statistically significant (p = 0.05, Hazard ratio = 0.78 95% CI = 0.61 – 0.99) reduction in the incidence of autoimmune disease in older adults taking 2000 IU (50 mcg) per day for 5 years. [1] This was a large nationwide study involving 12,786 men 50 years or older and 13,085 women 55 years or older. It was a randomized double blind, placebo-controlled trial. The British Medical Journal notes, “The clinical importance of this trial is high because these are well tolerated, non-toxic supplements, and other effective treatments to reduce the incidence of autoimmune diseases are lacking“. In 2017, the National Institutes of Health (NIH) estimated that 23.5 million Americans, >7% of the population, suffered from an autoimmune disease. The NIH noted that the prevalence appeared to be rising. [2]

Illustrating the high prevalence of vitamin D deficiency and insufficiency in the USA, 13% of participants in the VITAL trial had vitamin D levels < 20 ng/mL (50 nmol/L) at the start of the trial, and 45% had levels < 30 ng/mL (75 nmol/L). A subgroup of participants (1,644 people) had vitamin D levels tested one year into the study. In aggregate, participants taking 2000 IU vitamin D had an increase of 40% in vitamin D levels to 41.8 ng/mL (104.5 nmol/L), while participants in the soybean oil placebo group remained similar to baseline (30.7 ng/mL, 77.1 nmol/L). Strengths of this study include its size and diversity; its design as a prospective, placebo controlled, randomized trial — the “gold standard” for medical drug studies; its baseline measurement of blood levels of vitamin D and follow-up testing of a sample of participants, rather than relying on intake estimates; the use of a meaningful, safe dose more than double the US RDA for vitamin D, and its duration with a median follow-up time of 5.3 years.

“P values” are an expression of the degree of probability that the results of an experiment testing a hypothesis are due to chance. Generally speaking, the lower the P value, the higher the reliability of the data.

But nutrient studies require different approaches than drug studies. [3,4,5] A weakness of the VITAL trial was the absence of evaluation of synergistic nutrients. Additionally, with appreciation for Roger Williams’ principle of biochemical individuality, [6] it would have been interesting and helpful to compare the outcomes for each range of vitamin D levels achieved after the fixed dose intervention (e.g. stratifying participants by vitamin D levels achieved < 20, 20 – 29, 30-39, 40-49, 50-59). However, this would have required more measurements, thus increasing the expense of the trial.

The 3 Ds for vitamin D (and any nutrient) assessments:

Dose – how much of the nutrient reached the blood/tissue; whether the individual achieved and maintained sufficient or therapeutic levels.

Duration – how long sufficient or therapeutic levels were maintained.

Vitamin D has extensive epigenetic effects, impacting over 3,000 genes. It has been estimated that as much as 3-4% of the genome may be influenced by vitamin D. These genetic influences may be especially important during fetal development. [8] The half-life of the active form of vitamin D is about 4 hours, and the half-life of the pre-hormone form of vitamin D is 2-3 weeks. However, it may take even longer for the effects of proteins from genes upregulated and downregulated by vitamin D to make their biological impact. Bruce Ames’ concept of “longevity proteins” applies. [9] With saturation of a full set of nutrients, cell metabolism is able to expand from production of only survival proteins to producing additional proteins he called “longevity proteins”. For these reasons, it is important to maintain vitamin D in the healthy range on an ongoing basis rather than waiting until illness occurs. When rescue therapy is needed, calcifediol (25OHD) increases active vitamin D levels more rapidly than cholecalciferol (D3). [10-12] (see http://www.orthomolecular.org/resources/omns/v17n17.shtml and http://www.orthomolecular.org/resources/omns/v16n55.shtml for discussions of nutritional support in critical illness).

Dynamic interactions – were sufficient levels of synergistic cofactors maintained?

Magnesium is necessary in eight steps of vitamin D metabolism. [13,14] Intracellular selenocysteine can also be a rate limiting factor in vitamin D production and function. Increasing glutathione and cysteine can increase production of vitamin D even without vitamin D intake or sunlight exposure. In turn, vitamin D increases production of several selenoproteins. [15-17] Vitamin C and zinc also assist actions of vitamin D, and it is important to balance vitamin D with vitamin K2 to ensure mobilized calcium gets where it is needed rather than being deposited in arteries. 100 mcg K2 for every 5000 IU D3 is a good ratio for wellness. [18,19]

In research, controls matter too. This same VITAL study also looked at the effects of supplementing 1000 mg/day of omega-3 vs. placebo. A 15% reduction in the incidence of autoimmune disease was seen compared to the control group. However, this did not reach statistical significance. Interestingly, olive oil, which is known to be anti-inflammatory and a source of vitamin K, was used as the placebo for comparison. It is possible that the choice of a non-inert placebo blunted the signal of true benefit from the omega-3 intervention.

Vitamin D: influence on the immune system

The VITAL study adds important support on the benefits of vitamin D for the immune system. Vitamin D regulates calcium and phosphate homeostasis in the body. Calcium is important for much more than strong bones. [20-23] Mobilized ionized calcium is essential for muscle contractions, nerve impulses, cell signalling, blood clotting, immune function, and catalyzing hundreds of enzymatic reactions throughout the body. Nearly all cells in the body have vitamin D receptors (VDRs). Intestine, bone, kidney, parathyroid glands, and immune cells (T cells, B cells, Dendritic Cells, Macrophages) have high levels of VDRs. The CYP27B1 enzyme which produces the active form of vitamin D and the ligand for VDR is also widely expressed in many cells throughout the body. The liver and kidney produce much of the active vitamin D in the body, however activated immune cells will also produce 1,25(OD)2D when the 25OHD substrate is present for conversion into the active hormone. Parathyroid Hormone (PTH) regulates the production of the active form of vitamin D in non-immune cells. Active vitamin D production in immune cells is not influenced by PTH, but is instead regulated by cytokines and the availability of the prehormone 25OHD in the local cellular environment.

Vitamin D has important influences on many phases in the innate branch of the immune system (cellular, complement, antimicrobial peptides, lectins, non-antibody producing aspects of immunity), and also in the adaptive branch of the immune system (antibody-producing aspects of immunity). The adaptive branch of the immune system has two major phases. The effector phase involves antibody production while the regulatory phase involves removal of B cells producing antibodies that cross-react with self-cells. The antibody-antigen lock and key fit isn’t always exact. Even healthy people have self-reactive B cell clones. [24] Similarity between a “foreign” antigen and a host cell membrane element may exist or an antibody may overlap the membrane portion of a neoantigen-membrane complex. When B cells with these self-reacting or self-cross-reacting antibodies are stimulated to mass divide and produce their antibodies, they must be destroyed by the regulatory immune cells (Tregs) to minimize self-injury. Imbalance or dysfunction in the regulatory phase of the adaptive immune response is the major mechanism of autoimmune diseases in humans. [25] Interestingly, several sensitive areas of the body, the brain, anterior chamber of the eyes, and testes, are devoid of adaptive immune responses. The risk of collateral damage from antibody production in these areas is too great.

The active form of vitamin D: [26,27]

  • Increases production of cathelicidin and defensins
  • Decreases the maturation of dendritic cells, the expression of HLA DR antigen presenting molecules, and expression of co-stimulation molecules such as CD40, CD80, and CD86
  • Decreases Th1, Th9, Th17 lymphocytes, decreasing IL-2, IL-6, IFN-gamma, IL-12, IL-17, IL-23
  • Increases Treg production and production of the cytokine IL-10
  • Increases production and maintenance of immune memory cells
  • The overall effect is a stronger innate immune response, and a safer adaptive immune response.

A short history of clinical observations about vitamin D

  • In 1903, Niels Ryberg Finsen received the Nobel Prize in Physiology and Medicine “in recognition of his contribution to the treatment of diseases…with concentrated light radiation, whereby he has opened a new avenue for medical science.” [28]
  • Sanatoriums and cod liver oil were common treatments for tuberculosis and other infections for many decades. [29]
  • Two studies in South Carolina in the past decade showed significant reductions in preterm births (57% fewer 95% CI RR = 0.22 – 0.83, and 62% fewer p = 0.002) in women with vitamin D levels ≥ 40 ng/mL compared to women with vitamin D levels < 20 ng/mL. [30,31]
  • A pooled analysis of over 2300 women ≥ 55 years of age from a randomized controlled trial and a prospective cohort study showed participants with a vitamin D level ≥ 40 ng/mL had a 67% lower risk of invasive cancer compared to participants with a vitamin D level < 20 ng/mL. [32] Similar results were seen with breast cancer when people with vitamin D levels >60 ng/mL were compared to people with vitamin D levels < 20 ng/mL. [33]
  • In 2018, the VITAL trial research group published a conclusion that 2000 IU of supplemental vitamin D per day had no impact on cancer risk. [34] However, their data show a 25% reduction in cancer risk after the first 2 years of the study. [35]
  • A meta-analysis of 32 studies was published in 2014 showing a greater risk of all-cause mortality in people with a vitamin D level = 30 ng/mL compared to those with a vitamin D level > 30 ng/mL (Hazard Ratio = 1.9, 95% CI = 1.6 – 2.2, p=0.001). [36]

From Tuberculosis to COVID

  • Two recent Spanish studies on treatment of acute Covid-19 showed the efficacy of calcifediol for reducing ICU admission and mortality. [11-12]
  • In February 2022, a retrospective study in Israel of 253 consecutive adults admitted to the hospital for treatment of SARS-CoV-2 infection with a vitamin D measurement available 14 – 730 days prior to admission showed a greater risk of severe illness (48.1% vs. 10%) and death (25.6% vs. 5%) in those with vitamin D levels < 20 ng / mL vs. ≥ 20 ng / mL. [33] This was a follow up study to a large retrospective case-controlled population study associating vitamin D deficiency with a higher risk of Covid-19 infection. [37,38]
  • Studies in three different countries showed an association between selenium deficiency and severe SARS-CoV-2 disease [39-41]. Even though relationships between vitamin D and selenoproteins are now established, no studies measuring both selenium and vitamin D in SARS-CoV-2 patients have been published.
  • A study published in February 2022 from Mexico showed improved survival of high risk SARS-CoV-2 patients admitted to the hospital when given extra nutritional support. [42] 7 (17.5%) of 40 patients given standard of care died, while 1 (2.5%) of 40 patients given special nutritional support died. The extra nutritional support consisted of:
    • B-complex: 10 mg of cyanocobalamin, 100 mg of thiamin, and 100 mg of pyridoxine administered intramuscularly every 24 h for the first 5 days.
    • One envelope package taken orally after morning meals and another after evening meals, diluted in 400 mL of water each, during the whole intervention for a maximum of 21 days. Each envelope contained: Spirulina Maxima 2.5 g, folic acid 5 mg, glutamine 5 g, vegetable protein 10 g, brewer’s yeast, amaranth, ascorbic acid 1 g, zinc 20 mg, selenium 100 mcg, cholecalciferol (D3) 2000 IU, resveratrol 200 mg, Omega-3 fatty acids 1 g, L-Arginine 750 mg, inulin 20 g, and magnesium 400 mg.
    • Probiotics: Saccharomyces boulardii 500 mg daily for 6 days orally
  • A robust series of publications from 2021 showed the benefits of vitamin D for Covid-19 and other major diseases. See “Top Vitamin D Papers in 2021: Benefits ignored at a time they are most needed” by William B. Grant, PhD http://orthomolecular.org/resources/omns/v18n02.shtml


Vitamin D is important for a wide range of functions in human biology from conception onward. We now have more evidence pointing towards the importance of maintaining a vitamin D level in the 40-60 ng/mL range, along with maintaining adequate levels of synergistic nutrients to fight infections, sustain helpful immunity, and also to prevent harmful autoimmune reactions.

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1. Hahn J, Cook NR, Alexander EK, et al. (2022) Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ 376:e066452. https://pubmed.ncbi.nlm.nih.gov/35082139

2. NIH Autoimmune Diseases Coordinating Committee: Autoimmune Diseases Research Plan, March 2005. https://www.niaid.nih.gov/sites/default/files/adccfinal.pdf

3. Heaney RP. (2014) Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev 72:48-54. https://pubmed.ncbi.nlm.nih.gov/24330136

4. Smith RG. (2022) Vitamins and Minerals for Lowering Risk of Disease: Adding to the Evidence. Orthomolecular Medicine News Service. http://orthomolecular.org/resources/omns/v17n10.shtml

5. Cheng RZ. (2020) Covid-19 Highlights the Shortcomings of Evidence-based Medicine. J Orthomol Med. 35:1-7. https://isom.ca/article/covid-19-highlights-the-shortcomings-of-evidence-based-medicine

6. Williams RJ (1998) Biochemical Individuality. McGraw Hill; 1st edition (September 11, 1998) ISBN-13: 978-0879838935

7. Over 200 Scientists, Doctors, & Leading Authorities Call For Increased Vitamin D Use To Combat COVID-19 Scientific evidence indicates vitamin D reduces infections & deaths. Open Letter #VitaminDforAll, October 2020. https://vitamind4all.org/letter.html

8. Wagner CL and Hollis BW (2018) The Implications of Vitamin D Status During Pregnancy on Mother and her Developing Child. Front Endocrinol. 9:500. https://pubmed.ncbi.nlm.nih.gov/30233496

9. Ames BN (2018) Prolonging healthy aging: Longevity vitamins and proteins. Proc Nat Acad Sci USA 115:10835-10844. https://pubmed.ncbi.nlm.nih.gov/30322941

10. Bouillon R, Quesada-Gomez JM (2021) Vitamin D Endocrine System and COVID-19. JBMR Plus. 5:e10576. https://pubmed.ncbi.nlm.nih.gov/34950831

11. Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, et al. (2020) Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study. J Steroid Biochem Mol Biol. 203:105751. https://pubmed.ncbi.nlm.nih.gov/32871238

12. Nogues X, Ovejero D, Pineda-Moncusí M, et al. (2021) Calcifediol Treatment and COVID-19-Related Outcomes. J Clin Endocrinol Metab. 106:e4017-e4027. https://pubmed.ncbi.nlm.nih.gov/34097036

13. Dean C (2017) The Magnesium Miracle, 2nd Ed. Ballantine Books. ISBN-13 : 978-0399594441

14. Deng X, Song Y, Manson JE, et al. (2013) Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III. BMC Med 11:187. https://pubmed.ncbi.nlm.nih.gov/23981518

15. Jain SK, Parsanathan R, Achari AE, et al. (2018) Glutathione Stimulates Vitamin D Regulatory and Glucose Metabolism Genes, Lowers Oxidative Stress and Inflammation, and Increases 25-Hydroxy-Vitamin D Levels in Blood: A Novel Approach to Treat 25-Hydroxyvitamin D Deficiency. Antioxid Redox Signal. 29:1792-1897. https://pubmed.ncbi.nlm.nih.gov/30160165

16. Alvarez JA, Chowdhury R, Jones DP, et al. (2014) Vitamin D status is independently associated with plasma glutathione and cysteine thiol/disulphide redox status in adults. Clin Endocrinol (Oxf) 81:458-466. https://pubmed.ncbi.nlm.nih.gov/24628365

17. Parsanathan R, Jain SK. (2019) Glutathione deficiency induces epigenetic alterations of vitamin D metabolism genes in the livers of high-fat diet-fed obese mice. Sci Rep. 9:14784. https://pubmed.ncbi.nlm.nih.gov/31616013

18. Flore R, Ponziani FR, Di Rienzo TA, et al. (2013) Something more to say about calcium homeostasis: the role of vitamin K2 in vascular calcification and osteoporosis. Eur Rev Med Pharmacol Sci. 17:2433-2440. https://pubmed.ncbi.nlm.nih.gov/24089220

19. Schwalfenberg GK. (2017) Vitamins K1 and K2: The Emerging Group of Vitamins Required for Human Health. J Nutr Metab. 2017:6254836. https://pubmed.ncbi.nlm.nih.gov/28698808

20. Bikle DD. (2016) Extraskeletal actions of vitamin D. Ann N Y Acad Sci. 1376:29-52. https://pubmed.ncbi.nlm.nih.gov/27649525

21. Aranow C (2011) Vitamin D and the Immune System. J Investig Med. 59:881-886. https://pubmed.ncbi.nlm.nih.gov/21527855

22. Fan YG, Pang ZQ, Wu TY, et al. (2020) Vitamin D deficiency exacerbates Alzheimer-like pathologies by reducing antioxidant capacity. Free Radic Biol Med. 161:139-149. https://pubmed.ncbi.nlm.nih.gov/33068737

23. Gönen MS, Alaylioglu M, Durcan E, et al. (2021) Rapid and Effective Vitamin D Supplementation May Present Better Clinical Outcomes in COVID-19 (SARS-CoV-2) Patients by Altering Serum INOS1, IL1B, IFNg, Cathelicidin-LL37, and ICAM1. Nutrients 13:4047. https://pubmed.ncbi.nlm.nih.gov/34836309

24. Male D, Brostoff J, Roth DB, Roitt I. (2006) Immunology. 7th ed. Philadelphia, PA: Mosby Elsevier.

25. Rosenblum MD, Remedios KA, Abbas AK (2015) Mechanisms of human autoimmunity. J Clin Invest. 125:2228-2233. https://pubmed.ncbi.nlm.nih.gov/25893595

26. Cantorna MT, Snyder L, Lin Y0D, Yang L. (2015) Vitamin D and 1,25(OH)2D Regulation of T-cells. Nutrients 7:3011-3021. https://pubmed.ncbi.nlm.nih.gov/25912039

27. Looman KIM, Jansen MAE, Voortman T, et al. (2017) The role of vitamin D on circulating memory T cells in children: The generation R Study. Pediatr Allergy Immunol. 28:579-587. https://pubmed.ncbi.nlm.nih.gov/28686349

28. The Nobel Prize in Physiology or Medicine 1903. NobelPrize.org. Nobel Media AB 2020. https://www.nobelprize.org/prizes/medicine/1903/summary

29. Williams C. (1849) On the use and administration of cod-liver oil in pulmonary consumption. London Journal of Medicine 1849, 1:1-18.[Google Scholar]

30. Wagner CL, Baggerly C, McDonnell S, et al. (2016) Post-hoc Analysis of Vitamin D Status and Reduced Risk of Preterm Birth in Two Vitamin D Pregnancy Cohorts Compared with South Carolina March of Dimes 2009-2011 rates. J Steroid Biochem Mol Biol. 155:245-251. https://pubmed.ncbi.nlm.nih.gov/26554936

31. McDonnell SL, Baggerly KA, Baggerly CA, et al. (2017) Maternal 25(OH)D concentrations >40 ng/mL associated with 60% lower preterm birth risk among general obstetricalpatients at an urban medical center. PLoS One 12: e0180483. https://pubmed.ncbi.nlm.nih.gov/28738090

32. McDonnell SL, Baggerly C, French CB, et al. (2016) Serum 25-Hydroxyvitamin D Concentrations >40 ng/mL Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study. PLoS One 11:e0152441. https://pubmed.ncbi.nlm.nih.gov/27049526

33. McDonnell SL, Baggerly CA, French CB, et al. (2018) Breast cancer risk markedly lower with serum 25- hydroxyvitamin D concentrations > 60 vs < 20 ng/mL (150 vs. 50 nmol/L); Pooled analysis of two randomized trials and a prospective cohort. PLoS One 13:e0199265. https://pubmed.ncbi.nlm.nih.gov/29906273

34. Manson JE, Cook NR, Manson I-ML, et al. (2019) Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med. 380:33-44. https://pubmed.ncbi.nlm.nih.gov/30415629

35. GrassRoots Health Nutrient Research Institute. Risk Reduction with Vitamin D and Omega-3: VITAL Trial Results (2018). https://www.grassrootshealth.net/document/risk-reduction-vitamin-d-omega-3-vital-trial-results-2018

36. Garland CF, Kim JJ, Mohr SB, et al. (2014) Meta-analysis of All-cause Mortality According to Serum 25-Hydroxyvitamin D. Am J Public Health. 104:e43-e50. https://pubmed.ncbi.nlm.nih.gov/24922127

37. Dror AA, Morozov N, Daoud A, et al. (2022) Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness. PLoS One 17:e0263069. https://pubmed.ncbi.nlm.nih.gov/35113901

38. Israel A, Cicurel A, Feldhamer I, et al. (2022) Vitamin D deficiency is associated with higher risks for SARS-CoV-2 infection and COVID-19 severity: a retrospective case-control study. Intern Emerg Med. 2022 Jan 9; 1-11. https://pubmed.ncbi.nlm.nih.gov/35000118

39. Heller RA, Sun Q, Hackler J et al. (2021) Prediction of survival odds in COVID-19 by zinc, age, and selenoprotein P as composite biomarker. Redox Biology 38:101764. https://pubmed.ncbi.nlm.nih.gov/33126054

40. Moghaddam A, Heller RA, Sun Q, et al. (2020) Selenium deficiency is associated with mortality risk from COVID-19. Nutrients 12:2098. https://pubmed.ncbi.nlm.nih.gov/32708526

41. Zhang J, Taylor EW, Bennett K, et al. (2020) Association between regional selenium status and reported outcome of COVID-19 cases in China. Am J Clin Nutr. 111:1297-1299. https://pubmed.ncbi.nlm.nih.gov/32342979

42. Leal-Martínez F, Abarca-Bernal L, García-Pírez A, et al. (2022) Effect of a Nutritional Support System to Increase Survival and Reduce Mortality in Patients with COVID-19 in Stage III and Comorbidities: A Blinded Randomized Controlled Clinical Trial. Int J Environ Res Public Health 19:1172. https://doi.org/10.3390/ijerph19031172

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