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Vitamin (NOT a peptide)

Vitamin D3 (Cholecalciferol)

Also known as: Cholecalciferol, Vitamin D3, D3 IM, Stoss therapy (high-dose D3)

Tier 1 — Human RCTReviewed 2026-05-05

Tier 1 for vitamin D deficiency; injectable IM forms are mostly used in malabsorption or compliance-failure populations. Most users should take oral D3 — it works fine and is far cheaper.

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Overview

Vitamin D3 (cholecalciferol) is a fat-soluble seco-steroid produced in skin from 7-dehydrocholesterol on UVB exposure, hydroxylated in liver to 25-OH-D, and activated in kidney to 1,25-(OH)2-D (calcitriol). Its inclusion in this 'peptide companion' library is for completeness — many peptide users supplement D3, and a smaller subset (malabsorption, post-bariatric, compliance-impaired) use injectable IM D3. Editorial position: oral D3 is the right answer for the vast majority of users. Injectable IM D3 (typically 100,000–600,000 IU per dose, dosed every few months) has a real place in malabsorption, but it is not better than oral for ordinary deficiency replacement, and the high single-dose 'stoss therapy' approach has had several large RCTs (VITAL, D-Health, Nordic VitD) reading out null for prevention of cardiovascular events, fractures, and cancers in unselected adults.

Mechanism

Hydroxylated in liver to 25-OH-D (calcidiol — the storage and lab-test form), then in kidney by 1-alpha-hydroxylase to 1,25-(OH)2-D (calcitriol — the active hormone). Calcitriol binds the vitamin D receptor (VDR), which heterodimerizes with RXR and regulates transcription of genes involved in calcium and phosphate homeostasis, immune modulation, and parathyroid hormone suppression.

Evidence by indication

We classify each indication separately. The same peptide can be Tier 1 for one use and Tier 4 for another. Tiers reflect the published literature, not the strength of community framing.

Vitamin D deficiency (25-OH-D < 20 ng/mL)

Tier 1high confidence

Oral or IM D3 reliably raises serum 25-OH-D and corrects deficiency. Multiple decades of clinical evidence; standard of care.

Holick MF et al. 2007

Rickets / osteomalacia

Tier 1high confidence

Foundational indication; D3 (with calcium) prevents and treats nutritional rickets and osteomalacia. Tier 1 across decades of pediatric and adult evidence.

No primary citations are anchored to this indication — the tier reflects the absence of usable literature, not a missing reference.

Fall and fracture prevention in older adults

Tier 2high confidence

Meta-analyses are mixed but the strongest signal is in deficient/insufficient older adults receiving 800+ IU/day plus calcium. The benefit is modest in already-replete populations. Tier 2 reflects RCT-grade evidence with meaningful but population-conditional effect.

Bischoff-Ferrari HA et al. 2009

Cardiovascular event prevention

Tier 3high confidence

VITAL trial (Manson 2019, n>25,000) reported no significant reduction in major cardiovascular events with 2000 IU/day D3 in unselected adults. Subgroup signals exist; primary RCT result was null. Tier 3 for unselected populations.

Manson JE et al. 2019

Cancer prevention

Tier 3high confidence

VITAL primary cancer-incidence outcome was null. Some signal for cancer mortality and metastatic disease. Tier 3 reflects null primary outcomes with secondary signals not yet validated.

Manson JE et al. 2019

Autoimmune and inflammatory disease modulation

Tier 3medium confidence

VITAL substudy (Hahn 2022) reported reduced incident autoimmune disease with D3. Tier 3 evidence — interesting but not definitive on its own.

No primary citations are anchored to this indication — the tier reflects the absence of usable literature, not a missing reference.

General immune support / 'mood enhancement' in replete adults

Tier 4high confidence

Heavy supplement marketing. No RCT supports D3 supplementation in already-replete adults producing clinically meaningful immune or mood benefit. Tier 4.

No primary citations are anchored to this indication — the tier reflects the absence of usable literature, not a missing reference.

Studied dose ranges

The ranges below come from published trial protocols where available, and from documented self-experimenter consensus where the literature does not include human dose-finding work. The notes flag which is which.

25–100 mcgonce daily (oral, ongoing) · oral

Standard oral maintenance is 1000–4000 IU/day = 25–100 mcg/day. (1 mcg D3 = 40 IU.) Higher loading doses (5000–10000 IU/day) are used for short-term repletion in deficiency.

2,500–15,000 mcgonce every 1–6 months · intramuscular

High-dose IM D3 ranges from 100,000 IU (2500 mcg) to 600,000 IU (15000 mcg) per injection, given every 1–6 months. Most commonly used in malabsorption, post-bariatric, or compliance-failure populations. The 'stoss therapy' (single megadose) approach is supported in some pediatric rickets contexts but has not shown advantage over oral daily/weekly dosing for most adult deficiency replacement.

Contraindications

  • Hypercalcemia
  • Hypervitaminosis D
  • Severe sarcoidosis or other granulomatous diseases (extra-renal 1-alpha-hydroxylation can cause hypercalcemia at modest D3 doses — supplement cautiously and monitor calcium)
  • Williams syndrome (hypersensitivity to D3 with hypercalcemia risk)
  • Active kidney stones (calcium-phosphate or calcium-oxalate type) — use with monitoring
  • Known hypersensitivity

Reported side effects

  • At standard oral doses (1000–4000 IU/day): well tolerated, no meaningful side-effect rate
  • At high doses (>10,000 IU/day chronically): hypercalcemia, hypercalciuria, kidney stones
  • IM injection-site pain, redness
  • Constipation, nausea (with hypercalcemia)
  • Confusion, lethargy (with severe hypercalcemia)
  • Polyuria, polydipsia (hypercalcemia-related)

Reconstitution & storage

Oral oils and capsules: no reconstitution. Injectable IM D3 (e.g., compounded 50,000 IU/mL or 100,000 IU/mL preparations) is supplied as oily / cottonseed-oil suspensions — these are IM only, never IV, and require warming the vial to room temperature before injection to allow the oil to flow.

Storage. Oral capsules: room temperature, dry, away from light. Injectable oily preparations: room temperature or refrigerated per label; protect from light; do not freeze.

Open the peptide calculator → to compute exact draw volumes for your specific vial and BAC water choice.

Editorial note

DRAFT — pending Wayne's review. Editorial position: D3 is one of the few supplements with genuinely Tier 1 evidence (for actual deficiency). Hold the line that for replete adults, the 'general immune / mood / cancer prevention' claims are Tier 4 — VITAL was a definitive null on the primary outcomes. The injectable IM form is appropriate for malabsorption/post-bariatric and a small set of compliance-failure populations; for ordinary deficiency repletion, oral is cheaper, equally effective, and safer.

Citations

  1. [1]
    Vitamin D deficiency
    Holick MF · New England Journal of Medicine · 2007 · PMID 17634462
    Foundational clinical review of D3 deficiency, repletion, and pathophysiology — anchor for the Tier 1 deficiency indication.
    View source
  2. [2]
    Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials
    Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. · BMJ · 2009 · PMID 19797342
    Meta-analysis supporting fall-prevention indication in older adults — anchor for Tier 2 fall/fracture indication.
    View source
  3. [3]
    Vitamin D supplements and prevention of cancer and cardiovascular disease (VITAL trial)
    Manson JE, Cook NR, Lee IM, et al. · New England Journal of Medicine · 2019 · PMID 30415629
    Largest RCT of D3 in unselected adults; primary cardiovascular and cancer endpoints null. Anchor for the Tier 3 framing on those indications.
    View source