Vitamin D data - Why observation is preferred to clinical trial - Grant Oct 2025

Youtube - 62 minutes

The central message of this video is that current official vitamin D recommendations are far too low and are heavily shaped by structural problems in the U.S. medical and research system, including industry influence, misuse of randomized controlled trials (RCTs) for nutrients, and selective publication/communication of evidence. Dr. William Grant argues that well‑conducted observational studies, interpreted via Hill’s criteria for causality, provide far better guidance for vitamin D policy than the majority of existing RCTs.

Below is an organized summary of the key points.

1. Big Picture: Why There Is a “Disconnect”

The U.S. medical system is structurally oriented around treating disease, not preventing it.
Patented drugs are favored over non‑patentable, inexpensive interventions like vitamin D and sunlight, because drugs generate far higher profit.
U.S. health spending is extremely high (around 17% of GDP) yet life expectancy is lower than many European countries that spend far less.
In this environment, vitamin D is systematically under‑recognized and under‑recommended, despite extensive evidence from non‑drug style research.

2. Institutions and the “Disinformation Playbook”

Dr. Grant applies the “disinformation playbook” (originally formulated to describe how industries undermine unwanted science) to vitamin D:

Counterfeit science
- NIH‑funded vitamin D RCTs are often designed in ways that virtually guarantee null results (high baseline levels, low dosing, contamination of control group, wrong analysis).
Harass and discredit independent scientists
- Example: Michael Holick was publicly attacked for financial ties, framing him as biased, which chills others from speaking strongly on vitamin D.
Manufacture uncertainty
- Claiming that because large RCTs are “negative,” the many positive observational studies must be unreliable, thereby creating doubt where strong evidence already exists.
Use alliances and media to shape perception
- Universities, professional societies, and major journals receive substantial pharma funding and advertising.
- Mass media, dependent on pharma advertising, rarely highlight vitamin D benefits and heavily amplify “no benefit” narratives.
Influence policy (“the fix”)
- Leadership at NIH, FDA, CDC often moves through a revolving door with industry.
- These agencies set or shape vitamin D fact sheets, RCT design funding, and labeling rules, consistently keeping vitamin D framed as “bone only” with insufficient recognition of broader benefits.

3. Key U.S. Agencies and Guidelines on Vitamin D

NIH (Office of Dietary Supplements):
- Funds RCTs that cap doses and recruit participants with relatively high baseline levels.
- Fact sheets often state “no proven benefit” for outcomes like prediabetes progression, despite strong newer evidence.
FDA:
- Officially recognizes vitamin D for calcium absorption and bone health (rickets, osteoporosis).
- Restricts supplement manufacturers from making broader disease‑prevention claims because they are “not supported by RCTs.”
CDC:
- Emphasizes vaccination and pharmaceutical prevention strategies.
- Sees vitamin D as a kind of competitor to vaccine/drug‑centric strategies and does little to promote it.
Institute of Medicine (now National Academy of Medicine) 2011:
- Set 600 IU/day for ages 1–70 and 800 IU/day for 71+.
- Dr. Grant argues this committee was crafted and influenced to keep recommendations low, thereby limiting widespread optimization of vitamin D status.
Endocrine Society Guidelines (2011 vs 2024):
- 2011 Holick et al. guideline:
  - Defined deficiency as (<20) ng/mL, insufficiency 20–30 ng/mL, sufficiency (>30) ng/mL.
  - Recognized that many adults need 1500–2000 IU/day or more to reach ≥30 ng/mL.
- 2024 DeMay et al. guideline:
  - Relies almost exclusively on pharmaceutical‑style RCTs.
  - Essentially re‑endorses 600–800 IU/day empirically.
  - Avoids strong 25(OH)D targets and recommends against general screening, except where “cost‑effective.”
  - Prompted strong pushback from vitamin D researchers, including Dr. Grant’s widely cited rebuttal.

4. Why Most Vitamin D RCTs Are “Designed to Fail”

RCT design assumes: - Drug vs no drug, - Zero baseline exposure in placebo group, - A single, fixed dose with clear pharmacologic effect.

For vitamin D, most RCTs: - Enroll people with relatively high baseline 25(OH)D (often ~30 ng/mL), where further benefit is smaller. - Use low daily doses (e.g., 2000 IU/day in VITAL), even allowing participants to take extra vitamin D outside the trial. - Permit sun exposure and off‑protocol supplements in both arms (contaminating control). - Analyze outcomes by intention‑to‑treat (treatment vs placebo), without focusing on achieved 25(OH)D levels.

As a result, true biological effects are diluted, and most such trials report “no benefit.”

How vitamin D RCTs should be designed (per Haney & Grant)

Use observational studies first to understand the dose–response relationship between 25(OH)D and disease risk.
Enroll participants with low 25(OH)D for the specific disease risk of interest.
Dose vitamin D to reach a target 25(OH)D shown to be beneficial (and adjust during trial).
Withhold vitamin D from the control group, but give both arms adequate co‑nutrients so the effect reflects vitamin D itself.
Analyze by achieved 25(OH)D, not just “assigned group.”

When this is done (rarely), vitamin D shows substantial benefits.

5. Hill’s Criteria and Observational Evidence

Dr. Grant argues that Hill’s criteria for causality in biological systems are well suited to vitamin D:

Relevant criteria applied to vitamin D: - Strength of association: Large relative risk reductions at low 25(OH)D levels. - Consistency: Similar patterns across different populations/studies. - Temporality: Prospective studies measuring baseline 25(OH)D before disease onset. - Biological gradient: Clear dose–response between 25(OH)D and disease risk (often particularly strong below ~20 ng/mL). - Plausibility & mechanisms: Extensive mechanistic data (immune modulation, cell cycle control, anti‑inflammatory effects, etc.). - Coherence/analogy: Coherence with broader biology and with effects observed in related diseases.

Conclusion from his synthesis: - Observational studies + Hill’s criteria provide strong causal support for vitamin D benefits across many diseases, whereas most RCTs are underpowered or mis‑designed to show them.

6. Disease‑Specific Highlights

6.1 Cancer

Evidence lines: - Ecological/geographical UVB–cancer maps (his original work using NASA UVB data and U.S. cancer mortality atlases). - Case‑control and cohort studies relating 25(OH)D to cancer incidence and mortality. - Mechanistic work (e.g., with Alberto Muñoz) on vitamin D’s anti‑cancer pathways.

Key points: - Historical U.S. maps (1950–1994) show higher breast and other cancer mortality in low‑UVB regions (e.g., Northeast, coastal California) and lower rates in sunnier southern regions. - At that time: - Obesity was lower. - People spent more time outdoors. - Sunscreens and sun avoidance were far less common. - Modern data are “noisier” (more confounders, better treatments) but the earlier period gives a clear signal of UVB/vitamin D benefit.

Dose–response: - For colon/colorectal cancer, risk rises sharply below ~20 ng/mL, flattening above ~30–40 ng/mL. - GrassrootsHealth and Lappe‑type data show substantial reductions in cancer incidence as 25(OH)D rises from roughly 15 to 60–70 ng/mL.

VITAL trial (Harvard, ~25,000 participants, 2000 IU/day): - Baseline 25(OH)D ≈ 31 ng/mL. - Treatment group reached ~41–43 ng/mL; control levels were unknown but clearly not “deficient.” - Abstract claims no effect on total cancer incidence or major CVD. - However, inside the paper (not in abstract/headlines), they observed: - 25% reduction in all‑cancer incidence in participants with BMI < 25. - Borderline 25% reduction in cancer incidence for African Americans. - Significant 25% reduction in cancer mortality overall. - The main message broadcast publicly was “vitamin D doesn’t prevent cancer,” ignoring these beneficial secondary findings.

Practical implication: - The difference between ~30 and ~40 ng/mL is too small to show the full power of vitamin D seen when rising from deficient (<20) to optimal (~40–60+ ng/mL).

6.2 Cardiovascular Disease (CVD)

Mainstream claim: “Vitamin D doesn’t reduce cardiovascular risk.”

Grant’s critique: - No major RCT was properly designed to test observational findings: - They did not restrict enrollment to participants with low 25(OH)D (<20 ng/mL). - Doses and analysis frameworks were again suboptimal.

Observational data: - Multiple cohorts show steeply rising CVD risk at 25(OH)D below ~15–20 ng/mL, with relatively smaller changes above ~30 ng/mL. - More recent analyses show: - All‑cause mortality improvements mainly up to ~20 ng/mL, but - CVD mortality continues to decline up to roughly 50–60 ng/mL, with reductions up to about 50% vs. 20 ng/mL.

Time‑decay of observational signals: - Using Framingham‑style data, Grant highlights that baseline biomarkers diverge by quintile early, but converge over decades as people change behavior, diet, meds, etc. - Long follow‑up (e.g., 10+ years) using a single baseline 25(OH)D measurement underestimates the real effect of vitamin D; shorter follow‑up (1–5 years) shows much stronger associations.

Positive supplementation evidence: - A Canadian community program (~8000 participants) aimed to push 25(OH)D above 40 ng/mL (100 nmol/L) with about 5000 IU/day: - Many had adequate 25(OH)D by standard criteria but still had hypertension. - Over about a year: - ~71% of those initially hypertensive were no longer hypertensive. - Systolic BP dropped ~14–18 mmHg; diastolic ~12 mmHg, with similar benefit whether or not they were on blood pressure meds. - This suggests clinically meaningful blood pressure improvement when raising 25(OH)D to higher ranges.

6.3 Prediabetes and Type 2 Diabetes

NIH/ODS fact sheets still claim no benefit for vitamin D in preventing progression from prediabetes to type 2 diabetes.
However, the Tufts University trial (D2d study):
- Used 4000 IU/day (stronger than the 2000 IU in VITAL).
- Enrolled prediabetics, a high‑risk group more likely to benefit.
- Traditional ITT analysis (treatment vs placebo) showed ~12% risk reduction for progression, not statistically significant, and was labeled “no effect.”
- But when re‑analyzed by achieved 25(OH)D levels:
  - Each 10 ng/mL (~25 nmol/L) increase in 25(OH)D was associated with about a 25% reduction in progression risk.
  - Achieving around 50 ng/mL (vs ~20–30 ng/mL) yielded about a 71% reduction in progression.
This more biologically appropriate analysis strongly contradicts the NIH fact sheet’s “no benefit” stance and illustrates how analysis choices decide the “story” of a trial.

6.4 COVID‑19

GrassrootsHealth/Grant and colleagues published one of the most highly cited vitamin D–COVID papers, arguing early that:
- Adequate vitamin D reduces infection risk, severity, and mortality.
Observational data (e.g., Holick’s work) show:
- Individuals with 25(OH)D ≥ 30–50 ng/mL had dramatically lower SARS‑CoV‑2 positivity rates than those <20 ng/mL.
- VA data showed lower hospitalization and mortality at higher 25(OH)D levels (e.g., up to ~60 ng/mL).
Despite this, mass media and many platforms suppressed or ignored vitamin D findings:
- Emphasis was put instead on vaccines and high‑priced pharmaceuticals, many of which themselves lacked classic RCT publication at the time of emergency deployment.
- Physicians using vitamin D (and other low‑cost agents like ivermectin) often faced professional risk, reinforcing drug‑only narratives.

6.5 Alzheimer’s Disease and Dementia

Multiple observational studies show lower risk of Alzheimer’s and dementia with higher 25(OH)D.
As with CVD:
- Many factors matter (diet, obesity, air pollution, genetics).
- Vitamin D is not the only factor, but appears to be a meaningful modifiable one.

7. Practical/Clinical Recommendations Mentioned

These are not formal guidelines, but points raised or endorsed in the discussion:

Target serum 25(OH)D:
- Many benefits, including for cancer, CVD, and metabolic outcomes, begin to plateau in the 40–60+ ng/mL (100–150 nmol/L) range.
- Dr. Grant personally would aim for at least ~60 ng/mL if faced with conditions like cancer.
Supplement doses:
- 600–800 IU/day is inadequate for most adults to reach optimal 25(OH)D.
- Typical requirements are often around 1500–2000 IU/day or more; many community programs safely use 4000–5000 IU/day to reach ≥40 ng/mL.
Safety and toxicity:
- Vitamin D toxicity is rare and usually due to gross manufacturing or dosing errors (e.g., mg vs µg errors leading to ~1,000,000 IU/day).
- Even in extreme toxicity, patients usually recover once dosing stops and levels fall; lethal outcomes are very unusual.
- The panelists emphasize: fear deficiency far more than toxicity at usual supplemental intakes like 4000–8000 IU/day in adults with monitoring.
Measurement and personalization:
- Because of genetic differences, absorption, body weight, and other factors, individual responses to a given dose vary widely.
- Therefore:
  - Measure 25(OH)D after starting or changing dose.
  - Adjust supplementation to achieve and maintain the desired range.
- This is central to the GrassrootsHealth “D*action” model.
Co‑nutrients:
- Vitamin D does not work in isolation.
- Magnesium, vitamin A (retinoic acid), zinc, and other co‑factors are crucial for:
  - Vitamin D receptor function (VDR/RXR dimer),
  - Enzymatic activation and signaling,
  - RNA polymerase activity (magnesium).
- Many RCTs ignored co‑nutrients, further undermining their ability to detect vitamin D’s full benefits.

8. Overall Conclusions from the Video

Most vitamin D RCTs to date are not true tests of vitamin D biology; they are constrained by a pharmaceutical RCT paradigm, poor design, and contaminated controls.
Observational evidence, mechanistic data, and properly analyzed trials together strongly support a causal role for vitamin D in reducing risk, progression, and mortality in many chronic diseases and infections.
Public health agencies, major journals, and the media, influenced by pharma interests, have downplayed or obscured these benefits, leading to overly conservative guidelines and public confusion.
For individuals and clinicians:
- Focus on 25(OH)D levels, not just “taking some vitamin D.”
- Aim for higher, but still physiologic, serum levels (often ~40–60+ ng/mL) with appropriate dosing and monitoring.
- Consider vitamin D as a foundational preventive measure and adjunctive therapy, not as a standalone cure, integrated with diet, lifestyle, and co‑nutrients.

If you want, a follow‑up can extract just the actionable numbers and ranges (target 25(OH)D, dosing brackets, disease‑specific thresholds) in a compact reference table you could reuse on your site.