Vitamin D supplementation in humans: formulas, doses, benefits, and risks

Forms & Formulations

• Main forms: vitamin D3 (cholecalciferol) and D2 (ergocalciferol). D3 is standard in supplements and generally more effective at raising 25(OH)D than D2 at similar doses (Solnier et al., 2024; Flores-Aldana et al., 2023).
• Novel forms: micellar D3 softgels and sprays can increase bioavailability vs standard oil capsules at 1,000 IU/day, but differences diminish at higher doses (Solnier et al., 2024; Žmitek et al., 2020).
• Calcifediol (25(OH)D): a more potent prescription form; weekly 100–125 µg (≈4,000–5,000 IU) rapidly corrects severe deficiency with good tolerability (Pérez-Castrillón et al., 2025).
• Combined products: D3 with B12 (e.g., 2,000–2,500 IU D3 + 1,000 µg B12) effectively corrects both deficiencies and may improve adherence (Angelopoulos et al., 2025).

Typical Doses and 25(OH)D Response

Figure 1: Representative vitamin D regimens, responses, and outcomes.

Benefits by Context (RCT Evidence)

• General/chronic disease prevention: Large trials in adults at mostly sufficient baseline levels show little or no benefit on fractures, CVD, diabetes progression, respiratory infections, or COVID‑19 when adding high‑dose vitamin D vs placebo or standard doses (Sluyter et al., 2017; Joseph et al., 2022; Johnson et al., 2022; Jolliffe et al., 2022; Courbebaisse et al., 2023; Jorde et al., 2016).
• Respiratory/immune: High‑dose vs no/standard vitamin D did not reduce acute respiratory infections or COVID‑19 in community adults (Annweiler et al., 2022; Jolliffe et al., 2022). In extremely preterm infants, 800 IU/day improved 25(OH)D and may reduce metabolic bone disease but did not change bronchopulmonary dysplasia severity (Salas et al., 2025).
• Metabolic: In prediabetic women, intermittent 50,000 IU improved insulin secretory indices without improving glucose, lipids, or weight (Molani-Gol et al., 2025). Multiple large prediabetes trials show no prevention of diabetes (Johnson et al., 2022; Jorde et al., 2016).
• Cardiovascular parameters: Monthly high‑dose vitamin D improved central blood pressure and arterial stiffness only in those deficient at baseline (<50 nmol/L), not overall (Sluyter et al., 2017).
• Neuropsychiatric/post‑COVID: 60,000 IU/week for 8 weeks reduced fatigue and anxiety and modestly improved cognition in post‑COVID syndrome, without serious AEs (Charoenporn et al., 2024).
• Asthma: 125 µg/day (~5,000 IU) for 12 weeks slightly improved FEV1/FVC in mild–moderate adult asthma; no effect on symptoms or inflammation markers; no AEs in this short trial (Watkins et al., 2024).
• Transplant recipients: High vs low monthly D3 (100,000 vs 12,000 IU) after kidney transplant was safe and reduced fractures but did not affect composite CV/diabetes/cancer outcomes (Courbebaisse et al., 2023).
• Sports/bone turnover: A single 150,000 IU dose before ultramarathon favored bone formation and reduced resorption markers after extreme exertion (Stankiewicz et al., 2025).

Safety & Side Effects (High‑Quality RCTs)

Biochemical safety:

• Daily 400–4,000 IU for 3 years: no increase in adverse events, serious adverse events, nephrolithiasis, hypercalcemia, or hypercalciuria at 4,000 IU/day vs placebo when carefully monitored (Johnson et al., 2022).
• Up to 10,000 IU/day: more hypercalciuria and rare mild hypercalcemia, but similar overall AE profile; events resolved on repeat testing (Billington et al., 2019).

Kidney stones and calcium:

• Monthly 100,000 IU for ~3.3 years: no increase in kidney stone events or hypercalcemia vs placebo in >5,000 adults (Malihi et al., 2019).

Falls, hospitalizations:

• Some meta‑analyses (cited in asthma trial) suggest long‑term 80–100 µg/day (3,200–4,000 IU) may increase falls/hospitalizations in certain people, but individual RCTs here did not clearly confirm this over 12 weeks (Watkins et al., 2024).

Short‑term high doses in illness:

• In very old adults hospitalized with COVID‑19, a single 400,000 IU dose vs 50,000 IU improved 14‑day mortality without more adverse events, but benefit disappeared by 28 days and the trial was open‑label and underpowered (Annweiler et al., 2022).

Dose–Response & Individual Factors

• Deficiency vs sufficiency: Many trials showing no benefit enrolled participants with baseline 25(OH)D ~60–80 nmol/L (sufficient) (Sluyter et al., 2017; Joseph et al., 2022; Johnson et al., 2022; Jorde et al., 2016). Where benefits appeared (arterial stiffness, fractures, bone markers), they were often in deficient subgroups or specific high‑risk settings (Salas et al., 2025; Sluyter et al., 2017; Courbebaisse et al., 2023; Stankiewicz et al., 2025; Pérez-Castrillón et al., 2025).
• BMI: Supplementation efficiency is lower in people with higher BMI; normal‑weight subjects had larger 25(OH)D increases to 1,000 IU/day than overweight/obese (Žmitek et al., 2020).
• Form & schedule: Daily dosing of 800–2,000 IU is consistently effective and safe for raising levels; very high intermittent boluses (e.g., ≥60,000 IU monthly) have mixed or adverse long‑term outcome data (Sluyter et al., 2017; Joseph et al., 2022; Malihi et al., 2019).

Practical Takeaways (from RCTs only)

• For most adults without proven deficiency:
  • Doses up to 2,000 IU/day effectively raise 25(OH)D; 4,000 IU/day appears safe over several years but has not shown broad prevention benefits for diabetes, CVD, or common infections (Angelopoulos et al., 2025; Joseph et al., 2022; Johnson et al., 2022; Jolliffe et al., 2022; Jorde et al., 2016).
• For documented deficiency or high‑risk states:
  • 1,000–2,000 IU/day or structured loading (e.g., calcifediol 100 µg/week, short‑term 50,000 IU intermittently) corrects deficiency and is well tolerated under monitoring (Angelopoulos et al., 2025; Molani-Gol et al., 2025; Flores-Aldana et al., 2023; Pérez-Castrillón et al., 2025).
  • Very high bolus doses (≥60,000 IU monthly long‑term) should be used cautiously given the mortality signal in TIPS‑3 (Joseph et al., 2022).
• Children/infants: 400–1,000 IU/day improves status and appears safe over 2 weeks to 3 months (Salas et al., 2025; Flores-Aldana et al., 2023).
• Monitoring: For doses above typical guidelines (>2,000 IU/day) or in people with kidney disease, transplant, or on high‑dose/bolus regimens, RCTs used regular monitoring of serum calcium, creatinine, 25(OH)D, and sometimes urine calcium (Sluyter et al., 2017; Annweiler et al., 2022; Billington et al., 2019; Johnson et al., 2022; Malihi et al., 2019; Courbebaisse et al., 2023; Pérez-Castrillón et al., 2025).

Conclusion

Across high‑quality human randomized trials, vitamin D3 (and calcifediol) reliably raises 25(OH)D, with daily doses up to about 4,000 IU/day generally safe under monitoring. Clear clinical benefits are strongest in people who are truly deficient or in specific conditions (certain bone, vascular, or post‑COVID outcomes), whereas large, long‑term trials in mostly sufficient adults show little prevention benefit and, in at least one case, higher mortality with chronic high‑dose boluses. Decisions about dose and formulation are best tailored to baseline levels, BMI, comorbidities, and treatment goals, with periodic lab monitoring for higher or prolonged doses.

References

• Salas, A., Argent, T., Jeffcoat, S., Tucker, M., Ashraf, A., & Travers, C. (2025). Early Vitamin D Supplementation in Infants Born Extremely Preterm and Fed Human Milk: A Randomized Controlled Trial. The Journal of pediatrics, 114754. https://doi.org/10.1016/j.jpeds.2025.114754
• Charoenporn, V., Tungsukruthai, P., Teacharushatakit, P., Hanvivattanakul, S., Sriyakul, K., Sukprasert, S., Kamalashiran, C., Tungsukruthai, S., & Charernboon, T. (2024). Effects of an 8‐week high‐dose vitamin D supplementation on fatigue and neuropsychiatric manifestations in post‐COVID syndrome: A randomized controlled trial. Psychiatry and Clinical Neurosciences, 78. https://doi.org/10.1111/pcn.13716
• Sluyter, J., Camargo, C., Stewart, A., Waayer, D., Lawes, C., Toop, L., Khaw, K., Thom, S., Hametner, B., Wassertheurer, S., Parker, K., Hughes, A., & Scragg, R. (2017). Effect of Monthly, High‐Dose, Long‐Term Vitamin D Supplementation on Central Blood Pressure Parameters: A Randomized Controlled Trial Substudy. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 6. https://doi.org/10.1161/jaha.117.006802
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• Courbebaisse, M., Bourmaud, A., Souberbielle, J., Sberro-Soussan, R., Moal, V., Meur, L., Kamar, N., Albano, L., Thierry, A., Dantal, J., Danthu, C., Moreau, K., Morelon, E., Heng, A., Bertrand, D., Arzouk, N., Perrin, P., Morin, M., Rieu, P., Presne, C., Grimbert, P., Ducloux, D., Büchler, M., Quintrec, L., Ouali, N., Pernin, V., Bouvier, N., Durrbach, A., Alamartine, E., Randoux, C., Besson, V., Hazzan, M., Pages, J., Colas, S., Piketty, M., Friedlander, G., Prié, D., Alberti, C., & Thervet, E. (2023). Nonskeletal and skeletal effects of high doses versus low doses of vitamin D3 in renal transplant recipients: Results of the VITALE (VITamin D supplementation in renAL transplant recipients) study, a randomized clinical trial. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. https://doi.org/10.1016/j.ajt.2022.12.007
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