Vitamin D is a group of vitamins which regulate several biological mechanisms in the human body. Vitamin D deficiency is considered a global health problem, with a worldwide prevalence of 30%, which increases up to 60% depending on age, melanin pigmentation/skin color and lifestyle. Vitamin D₂ (ergocalciferol) and D₃ (cholecalciferol) are the most common forms of vitamin D. Vitamin D₃ is produced in our skin under exposure to sunlight and is also commonly found in eggs, oily fish and cod liver oil. Vitamin D₂ can be found in some mushrooms exposed to sunlight and both vitamin D₂ and D₃ can be produced under laboratory conditions to be used as supplements (Holick, 2017).

Biological function

Vitamin D targets the vitamin D receptor (VDR), which is expressed in cells from almost any organ of the human body, where it regulates multiple mechanisms related to energy homeostasis, nutrient absorption, the immune system, the endocrine system and bone formation. Vitamin D is considered sufficient when blood levels reach 20 to 30 ng/mL (Holick, 2017).

Clinical relevance

Vitamin D deficiency has been associated to clinical conditions related to bone strength, lung infections, dental caries, periodontitis, autoimmune disorders, cardiovascular diseases, diabetes, neurological disorders and some types of cancer. Its deficiency during pregnancy can also lead to gestational diabetes, low birthweight, and preeclampsia. (Amrein et al., 2020; Holick, 2017).

A daily dose of 20–50 μg is safe and sufficient to avoid vitamin D deficiency. Also, vitamin D intoxication is considered rare and associated to high supplementation over long periods of time (Amrein et al., 2020)

Bone health

Among the clinical conditions related to vitamin D deficiency most evidence exists for a role of vitamin D in maintaining healthy bones. Vitamin D is responsible for calcium absorption, which is directly related to bone strength and formation.  People with high risk of bone fracture could benefit from vitamin D monitoring and supplementation when needed (Lawley et al., 2020).

Lung infection and COVID-19

Vitamin D has immunomodulatory, anti-inflammatory and anti-infective properties and it may help in prevention and treatment of lung infections (Amrein et al., 2020).

Vitamin D deficiency has been proposed as a risk factor for COVID-19. Despite a lack of solid scientific evidence public institutions are now encouraging vitamin D supplementation for the general population in an effort to fight the pandemic (Endocrinology, 2021). 

Immune system disorders

Vitamin D deficiency has been shown to be more prevalent in patients with Inflammatory Bowel Disease (IBD) when compared to general population and it has been also related with worse disease prognosis (Olmedo-Martín et al., 2019).

Patients suffering of septic shocks show vitamin D deficiency and its supplementation may help due to the immunomodulatory properties of vitamin D, which can reduce pro-inflammatory IL-1β and IL-6 (Amrein et al., 2020)

Also, patients undergoing organ transplantation show Vitamin D deficiency, and its supplementation may reduce the occurrence of organ rejection (Amrein et al., 2020)

Metabolic syndrome

Vitamin D deficiency has been related to obesity, insulin resistance, diabetes, dyslipidemia, hepatosteatosis and hypertension (Amrein et al., 2020; Di Marzo & Silvestri, 2019)

Vitamin D deficiency has been related to increased risk of hypertension and cardiovascular disease (Wang, 2016).

Cancer

Vitamin D deficiency is also linked to increased risk of certain types of cancer such as melanoma, breast cancer and colorectal cancer as well as a poor prognosis for these diseases. Supplementation of vitamin D has been associated to lower mortality due to cancer. In fact, vitamin D analogues have been shown to inhibit tumor cell growth both in vitro and in animal models and are being currently tested in clinical trials (Amrein et al., 2020; Duffy et al., 2017; Niedermaier et al., 2021).

Other clinical conditions

Vitamin D deficiency is also more prevalent in patients with chronic kidney disease (CKD), which is also related to a dysfunction in mineral metabolism (Chau & Kumar, 2012).

Pregnant woman are also at risk of vitamin D deficiency, which is associated to low birthweight, preeclampsia and gestational diabetes (Amrein et al., 2020).

Endocannabinoid System

It has been shown that exposure to sunlight, which increases vitamin D levels, modify CB₁ mRNA expression (Di Marzo & Silvestri, 2019). This modulation on CB₁ mRNA expression might be linked to vitamin D levels.

In fact, Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein, has been linked to the modulation of the gene expression of the endocannabinoid system in autistic children, including a downregulation of CB₂ (Siniscalco et al., 2014). Furthermore, vitamin D deficiency has been linked to altered levels of AEA and 2-AG in the gastrointestinal tract, as well as other changes in the endocannabinoid system at the spinal cord, like CB₁ downregulation and CB₂ and PPARα upregulation (Guida et al., 2020). Hence, vitamin D might modulate endocannabinoid receptors CB_1, CB₂ and PPARα. This modulation might have an impact on the therapeutic effects of cannabinoids.

Cannabinoid synergies

Cannabinoids are known to mediate bone metabolism through CB₁ and CB₂ receptors. Bones show a high density of CB₂ through which AEA and 2AG can modulate osteoblast formation, bone formation and osteoclast activity. CB₂ agonists can stimulate osteoblast proliferation and activity while CB₂ antagonists increase osteoclast activation. The anti-osteoporotic effects of the synthetic CB₂ agonist JWH-133 decreases when used in co-treatment with vitamin D (Apostu et al., 2019; Tortora et al., 2020). These results might be explained by the previous evidence of the potential CB₂ modulation properties of vitamin D (Guida et al., 2020; Siniscalco et al., 2014). We could speculate that vitamin D might downregulate CB₂ receptors, which could reduce the effect of CB₂ agonists. If this would be true, plant cannabinoid CB₂ agonists like THC would not be advisable to mix with vitamin D. However, there is no any evidence pointing to any interaction of vitamin D with other plant cannabinoids. Due to the lack of strong evidence, the potential interaction of cannabinoids and vitamin D is unknown and needs to be investigated.

Health Claims (EU/EFSA)

• Vitamin D contributes to normal absorption/utilization of calcium and phosphorus
• Vitamin D contributes to normal blood calcium levels
• Vitamin D contributes to the maintenance of normal bones
• Vitamin D contributes to the maintenance of normal muscle function
• Vitamin D contributes to the maintenance of normal teeth
• Vitamin D contributes to the normal function of the immune system
• Vitamin D has a role in the process of cell division
• Vitamin D helps to reduce the risk of falling associated with postural instability and muscle weakness. Falling is a risk factor for bone fractures among men and women 60 years of age and older.
• Vitamin D contributes to the normal function of the immune system in children.
• Vitamin D is needed for normal growth and development of bone in children.

References

Amrein, K., Scherkl, M., Hoffmann, M., Neuwersch-Sommeregger, S., Köstenberger, M., Tmava Berisha, A., Martucci, G., Pilz, S., & Malle, O. (2020). Vitamin D deficiency 2.0: An update on the current status worldwide. European Journal of Clinical Nutrition, 74(11), 1498–1513. https://doi.org/10.1038/s41430-020-0558-y

Apostu, D., Lucaciu, O., Mester, A., Benea, H., Oltean-Dan, D., Onisor, F., Baciut, M., & Bran, S. (2019). Cannabinoids and bone regeneration. Drug Metabolism Reviews, 51(1), 65–75. https://doi.org/10.1080/03602532.2019.1574303

Chau, Y.-Y., & Kumar, J. (2012). Vitamin D in chronic kidney disease. Indian Journal of Pediatrics, 79(8), 1062–1068. https://doi.org/10.1007/s12098-012-0765-1

Di Marzo, V., & Silvestri, C. (2019). Lifestyle and Metabolic Syndrome: Contribution of the Endocannabinoidome. Nutrients, 11(8). https://doi.org/10.3390/nu11081956

Duffy, M. J., Murray, A., Synnott, N. C., O’Donovan, N., & Crown, J. (2017). Vitamin D analogues: Potential use in cancer treatment. Critical Reviews in Oncology/Hematology, 112, 190–197. https://doi.org/10.1016/j.critrevonc.2017.02.015

Endocrinology, T. L. D. &. (2021). Vitamin D and COVID-19: Why the controversy? The Lancet Diabetes & Endocrinology, 9(2), 53. https://doi.org/10.1016/S2213-8587(21)00003-6

Guida, F., Boccella, S., Belardo, C., Iannotta, M., Piscitelli, F., De Filippis, F., Paino, S., Ricciardi, F., Siniscalco, D., Marabese, I., Luongo, L., Ercolini, D., Di Marzo, V., & Maione, S. (2020). Altered gut microbiota and endocannabinoid system tone in vitamin D deficiency-mediated chronic pain. Brain, Behavior, and Immunity, 85, 128–141. https://doi.org/10.1016/j.bbi.2019.04.006

Holick, M. F. (2017). The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention. Reviews in Endocrine & Metabolic Disorders, 18(2), 153–165. https://doi.org/10.1007/s11154-017-9424-1

Lawley, R., Syrop, I. P., & Fredericson, M. (2020). Vitamin D for Improved Bone Health and Prevention of Stress Fractures: A Review of the Literature. Current Sports Medicine Reports, 19(6), 202–208. https://doi.org/10.1249/JSR.0000000000000718

Niedermaier, T., Gredner, T., Kuznia, S., Schöttker, B., Mons, U., & Brenner, H. (2021). Vitamin D supplementation to the older adult population in Germany has the cost-saving potential of preventing almost 30,000 cancer deaths per year. Molecular Oncology. https://doi.org/10.1002/1878-0261.12924

Olmedo-Martín, R. V., González-Molero, I., Olveira, G., Amo-Trillo, V., & Jiménez-Pérez, M. (2019). Vitamin D in Inflammatory Bowel Disease: Biological, Clinical and Therapeutic Aspects. Current Drug Metabolism, 20(5), 390–398. https://doi.org/10.2174/1389200220666190520112003

Siniscalco, D., Bradstreet, J. J., Cirillo, A., & Antonucci, N. (2014). The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages. Journal of Neuroinflammation, 11(1), 78. https://doi.org/10.1186/1742-2094-11-78

Tortora, C., Punzo, F., Argenziano, M., Di Paola, A., Tolone, C., Strisciuglio, C., & Rossi, F. (2020). The Role of Cannabinoid Receptor Type 2 in the Bone Loss Associated With Pediatric Celiac Disease. Journal of Pediatric Gastroenterology and Nutrition, 71(5), 633–640. https://doi.org/10.1097/MPG.0000000000002863

Wang, T. J. (2016). Vitamin D and Cardiovascular Disease. Annual Review of Medicine, 67, 261–272. https://doi.org/10.1146/annurev-med-051214-025146