Fat-Soluble Vitamin
Vitamin D3 (Cholecalciferol)
Moderate EvidenceStrong evidence that deficiency is harmful and worth correcting; observational links to cognition. But supplementation has not improved cognition in RCTs of replete/mildly-deficient adults.
Recommended Dose
2000–5000 IU daily (test blood levels first)
Timing
Morning with a fatty meal
Mechanism of Action
Binds to VDR receptors in the brain, modulating a broad range of genes involved in neuroplasticity, immune regulation, and calcium signaling. Supports serotonin synthesis via TPH2 activation.
Side Effects & Safety
Safe at recommended doses. Toxicity possible above 10,000 IU/day chronically. May raise calcium levels — pair with K2 for safety. Test 25(OH)D levels.
Do not use / talk to a doctor first
- Hypercalcaemia or hyperparathyroidism
- Sarcoidosis / granulomatous disease
- Kidney stones or significant kidney disease
Interactions
Thiazide diuretics
Raised hypercalcaemia risk — monitor serum calcium
Source: NIH ODS; PMC5623087
Digoxin / cardiac glycosides
Hypercalcaemia can increase arrhythmia risk
Source: NIH ODS
Vitamin K2
Commonly paired to direct calcium to bone — a precaution, not an antidote
Source: Common practice
Pregnancy & breastfeeding
Vitamin D is recommended in pregnancy at standard doses, but high-dose supplementation should be doctor-supervised; test 25(OH)D.
Who should avoid / see a doctor
Do not exceed 4,000 IU/day without medical monitoring. Test 25(OH)D. Special caution on thiazide diuretics or cardiac glycosides, or with hypercalcaemia, sarcoidosis, kidney stones or kidney disease.
Synergies
Used in These Stacks
See Vitamin D3 (Cholecalciferol) inside a full protocol — the stack pages cover when and why to combine it.
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References
- 1.Littlejohns 2014, Neurology — Severe vitamin D deficiency was associated with roughly double the risk of all-cause dementia and Alzheimer disease (n=1,658, Cardiovascular Health Study). (observational — association, not causation)
- 2.Patrick & Ames 2014, FASEB J — Vitamin D activates brain TPH2 transcription (serotonin synthesis). (molecular mechanism, not a clinical outcome)
- 3.VitaMIND RCT 2025, Alzheimer's & Dementia — Supplementation gave no significant benefit to cognition or executive function in adults with mild-to-moderate deficiency — the basis for the Moderate rating. (randomised controlled trial)
- 4.Institute of Medicine / NIH ODS — Vitamin D fact sheet — Adult tolerable Upper Intake Level of 4,000 IU/day; thiazide-diuretic interaction (hypercalcaemia); toxicity is a hypercalcaemia phenomenon. (authoritative body)
- 5.Aging Clin Exp Res 2021 — Hypercalcaemia occurred in 0% / 3% / 9% of participants at 400 / 4,000 / 10,000 IU/day over 3 years; toxicity generally above 25(OH)D ~150 ng/mL.
- 6.Drug–vitamin D interactions: a systematic review — Thiazide diuretics + vitamin D increase hypercalcaemia risk — monitor serum calcium.
