Why 50 ng/mL May Be the Sweet Spot for Vitamin D

Revisiting the physiological and clinical case for optimal vitamin D levels

For years, most public-health agencies have treated 20 ng/mL of serum 25-hydroxyvitamin D [25(OH)D] as “sufficient.” Yet a growing body of work—synthesized most comprehensively by endocrinologist Sunil J. Wimalawansa in Biomedicines (2023, 11:1542)—argues that true physiological sufficiency begins closer to 50 ng/mL.

His review, together with his prior analyses (Nutrients 2022; 14:2997 and J Steroid Biochem Mol Biol 2022; 219:106930), lays out why this higher threshold is not only safe but necessary for optimal immune, metabolic, and hormonal health.

The Evolutionary Baseline: How Much Vitamin D Did Nature Intend?

Sun-exposed hunter-gatherers, lifeguards, and outdoor workers naturally maintain serum 25(OH)D levels between 40 and 65 ng/mL, averaging around 46 ng/mL. These values—documented in studies cited as [3], [8], and [9] in the Biomedicines review—represent humanity’s evolutionary set-point.Wimalawansa argues that this range defines physiological normalcy; anything below 40 ng/mL is a modern artifact of indoor life and sunscreen-heavy behavior.

The Cellular Logic: Why Immune and Endocrine Cells Need More

Vitamin D’s active hormone, calcitriol [1,25(OH)₂D], is made inside many cell types, including immune cells, pancreatic islets, and vascular tissue. These cells rely on circulating 25(OH)D as substrate for the enzyme CYP27B1 to synthesize calcitriol locally.

At concentrations below ~50 ng/mL, there simply isn’t enough substrate to fuel these intracrine and paracrine reactions.

Citations [10], [20], [35–38] describe how adequate 25(OH)D enables immune cells to:

• Shift from pro-inflammatory Th1/Th17 responses to anti-inflammatory Th2/Treg states,

• Produce antimicrobial peptides,

• Stabilize epithelial barriers,

• Suppress cytokine storms and oxidative stress.

Thus, 50 ng/mL is not arbitrary—it’s the functional threshold that allows immune and endocrine tissues to generate their own hormone when needed.

The Clinical Evidence: Where Outcomes Improve

a. Infection and COVID-19

Across > 120 clinical trials and observational studies ([43–44], [64–65], [99–103], [123–125]), patients with 25(OH)D above 50 ng/mL experienced:

• Dramatic reductions in respiratory infection severity,

• Lower ICU admissions, and

• Reduced mortality from COVID-19 and sepsis.

In contrast, large randomized trials that failed to reach those levels (e.g., VITAL and ViDA) often found no effect—because participants started sufficient or were under-dosed.

b. Chronic and Autoimmune Disease

Evidence summarized in citations [52–59], [110–111], and [128] links higher vitamin D to lower risks of metabolic syndrome, type 2 diabetes, cardiovascular events, autoimmune disorders such as multiple sclerosis and inflammatory bowel disease, and even improved cancer prognosis.

The pooled data (Figure 3 of the Biomedicines paper) show that the greatest clinical gains cluster between 45 and 55 ng/mL.

The Safety Margin: Far from Toxic, Well within Normal Biology

Wimalawansa cites [4–6] to emphasize that vitamin D toxicity—with hypercalcemia and suppressed parathyroid hormone—occurs only when 25(OH)D exceeds 150 ng/mL.

Maintaining 40–80 ng/mL is therefore threefold below any risk threshold. Real-world data from lifeguards and outdoor populations confirm long-term safety at these levels.

Population and Policy Implications

The review contends that outdated RDAs—400–800 IU/day—are inadequate to lift population levels even above 20 ng/mL.

Achieving 50 ng/mL typically requires 2,000–5,000 IU of vitamin D₃ daily, or weekly equivalents, and consistent magnesium sufficiency to support activation enzymes (CYP450 system).

Because vitamin D₃ is inexpensive, non-patented, and safe, maintaining population sufficiency above 40–50 ng/mL is presented as the most cost-effective public-health intervention for reducing chronic disease, infection-related deaths, and healthcare costs ([14], [48–49], [73], [124], [142–147], [161]).

Wimalawansa’s Broader Perspective

Across his trilogy of analyses, the author reframes vitamin D as:

“A pleiotropic regulatory nutrient whose sufficiency underpins metabolic, immune, and endocrine stability.”

• 2022 Nutrients paper (14:2997) provided the pharmacokinetic and dose-response modeling, showing how 5,000 IU/day safely sustains ≈ 50 ng/mL.

• 2022 J Steroid Biochem Mol Biol review detailed the molecular pathways—gene regulation, VDR polymorphisms, and redox signaling—that require this level.

• 2023 Biomedicines review integrated decades of evidence, correcting misconceptions about RCT failures and codifying ≥ 50 ng/mL as the physiologic optimum.

The Take-Home Message

50 ng/mL is not “high”—it’s healthy. It mirrors ancestral sunlight exposure, fuels intracellular hormone synthesis, strengthens immunity, and sits comfortably within nature’s safety window.

Maintaining this level—through sensible sun exposure or daily D₃ supplementation—is a simple, evidence-based way to reinforce resilience against both chronic and infectious diseases.

Wimalawansa SJ. Physiological Basis for Using Vitamin D to Improve Health. Biomedicines 2023; 11:1542. https://doi.org/10.3390/biomedicines11061542

Wimalawansa SJ. Rationale for the Use of High-Dose Vitamin D in Prevention and Treatment of COVID-19. Nutrients 2022; 14(14):2997.

Wimalawansa SJ. Vitamin D Deficiency: Molecular and Clinical Perspectives. J Steroid Biochem Mol Biol 2022; 219:106930.