Comprehensive B-Vitamin Forms Evaluation

Evidence-Based Analysis for NTRPX Systems Integration

Document Version: 1.0
Date: January 24, 2026
Classification: Internal R&D Evaluation
Scope: All 8 essential B vitamins, all available supplemental forms

Executive Summary

RECOMMENDATION: FORM-SPECIFIC APPROVAL FOR NTRPX SYSTEMS This document provides the definitive evidence-based evaluation of all B-vitamin forms for NTRPX Systems integration. After comprehensive analysis of bioavailability data, clinical trials, mechanisms, and safety profiles, the following optimal forms are recommended:

Vitamin	Optimal Form(s)	Confidence	Primary System
B1	Benfotiamine + TTFD	HIGH	Sustain + Sprint
B2	Riboflavin-5’-Phosphate	MODERATE	All Systems
B3	Nicotinamide Riboside	HIGH	Recover
B5	D-Calcium Pantothenate	HIGH	All Systems
B6	Pyridoxal-5’-Phosphate	HIGH	All Systems
B7	D-Biotin	HIGH	All Systems
B9	L-5-MTHF (Quatrefolic)	HIGH	All Systems
B12	Methylcobalamin + Adenosylcobalamin	HIGH	All Systems

KEY PRINCIPLES APPLIED:

Evidence over theory
Proven over promising
Independent replication required
No compromises on safety
Bioavailable forms preferred over precursors
Active coenzyme forms preferred where evidence supports

Evaluation Standards
B1: Thiamine
B2: Riboflavin
B3: Niacin
B5: Pantothenic Acid
B6: Pyridoxine
B7: Biotin
B9: Folate
B12: Cobalamin
Cross-Cutting Analysis
NTRPX Systems Integration
Final Specifications
References

1. Evaluation Standards

NTRPX Evidence Hierarchy

┌─────────────────────────────────────────────────────────────────┐
│                    EVIDENCE QUALITY TIERS                       │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  TIER 1: PROVEN                                                 │
│  ├── Meta-analyses of RCTs                                      │
│  ├── Multiple independent RCTs (n≥30 each)                      │
│  └── Replicated findings across research groups                 │
│                                                                 │
│  TIER 2: PROBABLE                                               │
│  ├── Single large RCT (n≥100)                                   │
│  ├── Multiple smaller RCTs with consistent direction            │
│  └── Strong mechanistic + observational alignment               │
│                                                                 │
│  TIER 3: POSSIBLE                                               │
│  ├── Pilot RCTs (n<30)                                          │
│  ├── Observational studies only                                 │
│  └── Strong preclinical, limited human data                     │
│                                                                 │
│  TIER 4: THEORETICAL                                            │
│  ├── Preclinical only                                           │
│  ├── Mechanistic extrapolation                                  │
│  └── Traditional use without clinical validation                │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

Form Selection Criteria

Criterion	Weight	Description
Bioavailability	30%	Absorption, tissue distribution, cellular uptake
Clinical Evidence	25%	Human RCTs demonstrating superiority
Safety Profile	20%	Adverse effects, toxicity thresholds, interactions
Mechanism Validation	15%	Understanding of how form confers advantage
Practical Factors	10%	Stability, cost, availability, formulation compatibility

2. B1: Thiamine

2.1 Compound Overview

Property	Value
Active Coenzyme	Thiamine diphosphate (ThDP/TPP)
Key Enzymes	Pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, transketolase
Primary Functions	Glucose metabolism, ATP production, pentose phosphate pathway
Deficiency Syndromes	Beriberi (peripheral), Wernicke-Korsakoff (CNS)
RDA	1.1-1.2 mg/day

2.2 Available Forms

┌─────────────────────────────────────────────────────────────────┐
│                    THIAMINE FORM HIERARCHY                      │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  1. TTFD (Thiamine Tetrahydrofurfuryl Disulfide)               │
│     ├── Confirmed BBB penetration (PET imaging)                 │
│     ├── Superior CNS tissue distribution                        │
│     ├── Non-enzymatic membrane crossing                         │
│     ├── Unique non-coenzyme effects                             │
│     └── ★ RECOMMENDED FOR CNS/COGNITIVE                         │
│                                                                 │
│  2. BENFOTIAMINE (S-benzoylthiamine-O-monophosphate)           │
│     ├── 1,147% plasma bioavailability vs HCl                    │
│     ├── 196% erythrocyte ThDP vs HCl                            │
│     ├── Excellent peripheral tissue distribution                │
│     ├── BBB penetration uncertain/delayed                       │
│     └── ★ RECOMMENDED FOR PERIPHERAL/METABOLIC                  │
│                                                                 │
│  3. SULBUTIAMINE (O-isobutyryl Thiamine Disulfide)             │
│     ├── Crosses BBB                                             │
│     ├── Antiasthenic properties                                 │
│     ├── May cause mood issues without other B vitamins          │
│     └── ⚠️ CONDITIONAL - Specific applications only             │
│                                                                 │
│  4. THIAMINE HCl / MONONITRATE                                  │
│     ├── Poor bioavailability (saturable transport)              │
│     ├── Limited tissue penetration                              │
│     ├── Adequate for preventing deficiency                      │
│     └── ✗ NOT OPTIMAL - Use as baseline only                    │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

2.3 Form Comparison Table

Form	Plasma Bioavailability	BBB Penetration	Tissue Distribution	Mechanism
Thiamine HCl	Baseline (1x)	Poor	Limited	Active transport (THTR1/2)
Benfotiamine	11.5x higher	Uncertain	Peripheral excellent	Enzymatic cleavage → thiamine
TTFD	~5x higher	✅ Confirmed	CNS + peripheral	Non-enzymatic reduction
Sulbutiamine	High	✅ Confirmed	CNS emphasis	Non-enzymatic reduction

2.4 Critical Distinction: Thioesters vs Disulfides

Property	Thioesters (Benfotiamine)	Disulfides (TTFD, Sulbutiamine)
Chemical class	S-acyl derivative	Open-ring disulfide
Membrane crossing	Requires alkaline phosphatase	Non-enzymatic reduction
BBB penetration	Controversial/delayed	Confirmed
Peak effect	1-2 hours	Rapid
Primary target	Peripheral tissues	CNS + peripheral
Non-coenzyme effects	AGE inhibition	Anti-inflammatory, antioxidant

2.5 Clinical Evidence

Benfotiamine

Study	Design	Population	Intervention	Outcome
Stracke et al. 1996	RCT	Diabetic neuropathy	320mg/day, 3 weeks	✅ Significant symptom improvement
Haupt et al. 2005	RCT	Diabetic neuropathy	300mg/day, 6 weeks	✅ Neuropathy score improved
Gibson et al. 2020	Open-label	Mild AD (n=5)	300mg/day, 18 months	✅ Cognitive improvement (no placebo)
Bioavailability studies	Crossover	Healthy adults	Single dose	✅ 1,147% vs thiamine HCl

Evidence Tier: TIER 2 (Probable) for peripheral neuropathy; TIER 3 (Possible) for cognitive

TTFD

Study	Design	Population	Intervention	Outcome
Mimori et al. 1996	RCT	Mild cognitive impairment	100mg/day, 12 weeks	✅ Improved cognition vs control
Lonsdale (1973-2013)	Case series	Various neurological	Variable doses	✅ Hundreds of patients, no toxicity
PET imaging studies	Mechanistic	Healthy	Single dose	✅ Confirmed brain/spinal cord entry

Evidence Tier: TIER 3 (Possible) - Strong mechanistic, limited RCT replication

2.6 Safety Profile

Form	Adverse Effects	Toxicity Threshold	Drug Interactions
Benfotiamine	Minimal; GI upset rare	None established; 2g/day tolerated	None significant
TTFD	Garlic odor possible; paradoxical reaction initially	None established	None significant
Sulbutiamine	Brain fog, mood changes reported	Caution at high doses	Unknown
Thiamine HCl	Extremely safe	None (water-soluble)	None significant

Paradoxical Reaction (TTFD): Some individuals experience temporary worsening of symptoms when initiating TTFD. Mechanism: rapid mobilization of thiamine-dependent enzymes. Management: Start low (33mg), titrate up over 1-2 weeks.

2.7 NTRPX Recommendation: B1

┌─────────────────────────────────────────────────────────────────┐
│                 B1 THIAMINE - NTRPX VERDICT                     │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  RECOMMENDATION: DUAL-FORM APPROACH                             │
│                                                                 │
│  SUSTAIN/BOOST/RECOVER:                                         │
│  └── Benfotiamine 150-300mg                                     │
│      • Peripheral metabolic support                             │
│      • AGE inhibition                                           │
│      • Excellent safety profile                                 │
│                                                                 │
│  SPRINT (Cognitive Focus):                                      │
│  └── TTFD 50-100mg                                              │
│      • CNS penetration confirmed                                │
│      • Cognitive support                                        │
│      • Start at 50mg, may titrate                               │
│                                                                 │
│  BASELINE (All Formulas):                                       │
│  └── Thiamine HCl 10-25mg                                       │
│      • Insurance against deficiency                             │
│      • Negligible cost                                          │
│                                                                 │
│  AVOID: Sulbutiamine (mood concerns without full B-complex)     │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

3. B2: Riboflavin

3.1 Compound Overview

Property	Value
Active Coenzymes	FMN (flavin mononucleotide), FAD (flavin adenine dinucleotide)
Key Functions	Electron transport, drug/steroid metabolism, B6/folate/niacin metabolism
Enzymes Dependent	~70-80 flavoenzymes
Deficiency Signs	Angular cheilitis, glossitis, seborrheic dermatitis
RDA	1.1-1.3 mg/day

3.2 Available Forms

Form	Structure	Notes
Riboflavin	Free vitamin	Standard form; must be phosphorylated
Riboflavin-5’-Phosphate (R5P/FMN)	Phosphorylated	Active coenzyme form
FAD	Adenylated FMN	Full coenzyme; hydrolyzed before absorption

3.3 Bioavailability Analysis

Critical Finding: All forms have similar bioavailability (~95%) because:

FAD and FMN are hydrolyzed to free riboflavin by intestinal phosphatases before absorption
Free riboflavin is then re-phosphorylated intracellularly by flavokinase
Absorption is saturable at ~27mg per dose regardless of form

Form	Absorption	Conversion Required	Practical Difference
Riboflavin	~95% up to 27mg	Yes (flavokinase)	Standard
R5P	~95% up to 27mg	Dephosphorylated, then rephosphorylated	Minimal for most people
FAD	~95% up to 27mg	Fully hydrolyzed first	No advantage

3.4 When R5P May Matter

R5P (riboflavin-5’-phosphate) may provide advantage in specific populations:

Population	Rationale	Evidence Level
Impaired flavokinase activity	Bypasses phosphorylation step	Theoretical
MTHFR polymorphisms	FMN required for MTHFR function	Indirect support
Liver dysfunction	Primary site of phosphorylation	Theoretical
High-dose B6 users	Flavokinase uses same enzyme family	Theoretical

Evidence Tier: TIER 4 (Theoretical) for R5P superiority - No direct clinical trials comparing forms

3.5 Critical Metabolic Role

┌─────────────────────────────────────────────────────────────────┐
│              RIBOFLAVIN METABOLIC DEPENDENCIES                  │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  RIBOFLAVIN → FMN → FAD                                         │
│       │                                                         │
│       ├──→ Required for B6 activation                           │
│       │    (Pyridoxine → PLP requires FMN-dependent oxidase)    │
│       │                                                         │
│       ├──→ Required for folate metabolism                       │
│       │    (MTHFR requires FAD as cofactor)                     │
│       │                                                         │
│       ├──→ Required for niacin synthesis                        │
│       │    (Tryptophan → NAD+ requires FAD)                     │
│       │                                                         │
│       └──→ Required for glutathione recycling                   │
│            (Glutathione reductase requires FAD)                 │
│                                                                 │
│  IMPLICATION: Riboflavin deficiency impairs B6, B9, B3 status   │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

3.6 Safety Profile

Parameter	Value
UL	None established
Toxicity	No known toxicity even at high doses
Adverse effects	Yellow-orange urine discoloration (harmless)
Half-life	~1 hour (rapid turnover)
Drug interactions	Minimal; may reduce efficacy of some antibiotics

3.7 NTRPX Recommendation: B2

┌─────────────────────────────────────────────────────────────────┐
│                 B2 RIBOFLAVIN - NTRPX VERDICT                   │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  RECOMMENDATION: RIBOFLAVIN-5'-PHOSPHATE (R5P)                  │
│                                                                 │
│  Rationale:                                                     │
│  • Provides active coenzyme form                                │
│  • Supports impaired phosphorylation (theoretical benefit)      │
│  • Better solubility for formulation                            │
│  • Marginal cost increase justified by precautionary principle  │
│  • No disadvantage vs free riboflavin                           │
│                                                                 │
│  ALL SYSTEMS: 10-25mg R5P                                       │
│                                                                 │
│  Migraine prevention: 400mg/day (either form acceptable)        │
│                                                                 │
│  Confidence: MODERATE                                           │
│  (No direct evidence of superiority, but no downside)           │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

4. B3: Niacin

4.1 Compound Overview

Property	Value
Active Coenzymes	NAD+ (nicotinamide adenine dinucleotide), NADP+
Enzymatic Reactions	>400 enzymes
Key Functions	Energy metabolism, DNA repair, sirtuin activation, PARP activity
Age-Related Decline	~50% NAD+ reduction by age 60
Deficiency Syndrome	Pellagra (dermatitis, diarrhea, dementia, death)
RDA	14-16 mg NE/day

4.2 Available Forms

┌─────────────────────────────────────────────────────────────────┐
│                      NIACIN FORM HIERARCHY                      │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  NAD+ PRECURSOR EFFICIENCY (Clinical 2023 Study, 1g doses):     │
│                                                                 │
│  1. NICOTINAMIDE             ████████████████████  MOST         │
│                                                                 │
│  2. NICOTINIC ACID (Niacin)  ████████████████                   │
│                                                                 │
│  3. NICOTINAMIDE RIBOSIDE    ██████████████                     │
│                                                                 │
│  4. NMN                      ████████████                       │
│                                                                 │
│  5. INOSITOL HEXANICOTINATE  ████              INEFFECTIVE      │
│     (Flush-free niacin)                                         │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

4.3 Form Comparison Table

Form	NAD+ Boosting	Flush	Lipid Effects	Sirtuin Concern	Regulatory Status
Nicotinic Acid	High	YES (vasodilation)	✅ ↑HDL, ↓LDL/TG	None	GRAS
Nicotinamide	Highest	No	None	High doses may inhibit	GRAS
NR (Niagen)	Moderate-High	No	Minimal	None	GRAS
NMN	Moderate	No	Minimal	None	⚠️ Not legal as supplement (FDA 2022)
Inositol Hexanicotinate	None/Minimal	No	None proven	N/A	GRAS

4.4 Pathway Analysis

┌─────────────────────────────────────────────────────────────────┐
│                    NAD+ BIOSYNTHESIS PATHWAYS                   │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  NICOTINIC ACID (Preiss-Handler Pathway):                       │
│  Nicotinic acid → NaMN → NaAD → NAD+                            │
│  • 3 enzymatic steps                                            │
│  • Causes prostaglandin-mediated flush                          │
│                                                                 │
│  NICOTINAMIDE (Salvage Pathway):                                │
│  Nicotinamide → NMN → NAD+                                      │
│  • 2 enzymatic steps (most efficient)                           │
│  • Rate-limited by NAMPT enzyme                                 │
│  • High doses may inhibit sirtuins (product inhibition)         │
│                                                                 │
│  NICOTINAMIDE RIBOSIDE (NRK Pathway):                           │
│  NR → NMN → NAD+                                                │
│  • 2 enzymatic steps                                            │
│  • Bypasses NAMPT rate-limitation                               │
│  • Crosses cell membranes directly                              │
│  • No sirtuin inhibition concern                                │
│                                                                 │
│  NMN (Direct):                                                  │
│  NMN → NAD+                                                     │
│  • 1 step but requires dephosphorylation for cell entry         │
│  • Variable oral bioavailability                                │
│  • FDA ruled not legal as supplement (Nov 2022)                 │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

4.5 Clinical Evidence

Nicotinamide Riboside (NR)

Study	Design	Population	Intervention	Outcome
Martens et al. 2018	RCT	Healthy older adults (n=24)	1g NR/day, 6 weeks	✅ ↑NAD+ 60%, ↓BP trend
Dollerup et al. 2018	RCT	Obese men (n=40)	1g NR/day, 12 weeks	✅ ↑NAD+, no metabolic changes
Elhassan et al. 2019	RCT	Older adults (n=12)	1g NR/day, 3 weeks	✅ ↑NAD+ in muscle
Conze et al. 2019	Safety	Healthy adults (n=140)	Up to 2g/day, 8 weeks	✅ Well-tolerated

Evidence Tier: TIER 2 (Probable) for NAD+ elevation; TIER 3 for functional outcomes

Nicotinamide

Study	Design	Population	Intervention	Outcome
Multiple NAD+ studies	Comparative	Healthy adults	1g single dose	✅ Highest NAD+ boost
Diabetes prevention	Large RCTs	At-risk children	Various doses	❌ Did not prevent T1D

Evidence Tier: TIER 1 (Proven) for NAD+ elevation; functional benefits less clear

4.6 Safety Profile

Form	Key Safety Concern	UL	Notes
Nicotinic Acid	Hepatotoxicity at high doses; flush	35mg (as niacin)	Sustained-release more hepatotoxic
Nicotinamide	Possible sirtuin inhibition; hepatotoxicity at very high doses	35mg (as niacin)	Generally safer than nicotinic acid
NR	Well-tolerated	None established	Up to 2g/day in trials
NMN	Limited long-term data	N/A	Regulatory concerns

4.7 NTRPX Recommendation: B3

┌─────────────────────────────────────────────────────────────────┐
│                   B3 NIACIN - NTRPX VERDICT                     │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  PRIMARY RECOMMENDATION: NICOTINAMIDE RIBOSIDE (NR)             │
│                                                                 │
│  Rationale:                                                     │
│  • Efficient NAD+ elevation without flush                       │
│  • No sirtuin inhibition concern                                │
│  • GRAS status, well-tolerated to 2g/day                        │
│  • Bypasses NAMPT rate-limitation                               │
│  • Clean regulatory status                                      │
│                                                                 │
│  RECOVER: 250-500mg NR (NAD+ support, cellular repair)          │
│  SUSTAIN: 100-250mg NR (maintenance)                            │
│                                                                 │
│  ALTERNATIVE: Nicotinamide 100-500mg                            │
│  • More cost-effective                                          │
│  • Higher NAD+ boost per mg                                     │
│  • Sirtuin concern only at very high doses (>1g)                │
│                                                                 │
│  AVOID:                                                         │
│  • Inositol hexanicotinate (ineffective for NAD+)               │
│  • NMN (regulatory issues)                                      │
│  • High-dose nicotinic acid (flush, hepatotoxicity)             │
│                                                                 │
│  Confidence: HIGH                                               │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

5. B5: Pantothenic Acid

5.1 Compound Overview

Property	Value
Active Coenzyme	Coenzyme A (CoA)
Key Functions	Fatty acid synthesis/oxidation, acetylcholine synthesis, steroid hormones
Ubiquity	Name derives from Greek “pantos” (everywhere) - found in all foods
Deficiency	Extremely rare
AI	5 mg/day

5.2 Available Forms

Form	Structure	Use Case
D-Calcium Pantothenate	Calcium salt of D-pantothenic acid	Standard supplement form
D-Pantothenic Acid	Free acid	Less stable than calcium salt
Pantethine	Disulfide of pantetheine (CoA precursor)	Lipid modification
Dexpanthenol	Alcohol form (provitamin)	Topical/injectable

5.3 Critical Distinction: Pantothenate vs Pantethine

PANTETHINE ≠ PANTOTHENIC ACID clinically

Property	D-Calcium Pantothenate	Pantethine
Relationship to CoA	5 enzymatic steps away	2 steps away (direct precursor)
Lipid effects	None demonstrated	✅ Significant
Dose for effect	5-10mg (RDA support)	600-1200mg (therapeutic)
Cost	Low	High
Primary use	Nutritional	Therapeutic (dyslipidemia)

5.4 Pantethine Clinical Evidence

Study Type	Findings
Meta-analysis (2005)	28 trials, n=646: ↓TG 32.9%, ↓TC 15.1%, ↓LDL 20.1%, ↑HDL 8.4% at 4 months
US RCT (2011)	n=32, 600mg/day: ↓TC 8.4%, ↓LDL 11.8%, maintained at 16 weeks
Mechanism studies	Inhibits HMG-CoA reductase, fatty acid synthesis; increases fatty acid oxidation

Evidence Tier: TIER 2 (Probable) for pantethine lipid effects; TIER 4 (Theoretical) for pantothenate superiority over other forms

5.5 Safety Profile

Parameter	Value
UL	None established
Toxicity	No known toxicity
Adverse effects	Mild GI upset at very high doses (10g+)
Drug interactions	None significant

5.6 NTRPX Recommendation: B5

┌─────────────────────────────────────────────────────────────────┐
│              B5 PANTOTHENIC ACID - NTRPX VERDICT                │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  RECOMMENDATION: D-CALCIUM PANTOTHENATE                         │
│                                                                 │
│  Rationale:                                                     │
│  • Standard form is sufficient for CoA synthesis                │
│  • No evidence other forms provide advantage for general use    │
│  • Cost-effective, stable, well-tolerated                       │
│  • Deficiency virtually impossible with any intake              │
│                                                                 │
│  ALL SYSTEMS: 10-50mg D-Calcium Pantothenate                    │
│                                                                 │
│  OPTIONAL ADD-ON (Lipid-focused formulas):                      │
│  └── Pantethine 300-600mg                                       │
│      • Only if targeting lipid modification                     │
│      • Significant cost increase                                │
│      • Not necessary for general B-vitamin support              │
│                                                                 │
│  Confidence: HIGH (for calcium pantothenate selection)          │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

6. B6: Pyridoxine

6.1 Compound Overview

Property	Value
Active Coenzyme	Pyridoxal-5’-phosphate (PLP/P5P)
Enzymatic Reactions	>140 PLP-dependent enzymes (~4% of all classified activities)
Key Functions	Amino acid metabolism, neurotransmitter synthesis, hemoglobin, gene expression
Half-life	25-33 days
RDA	1.3-2.0 mg/day

6.2 Available Forms

┌─────────────────────────────────────────────────────────────────┐
│                   B6 FORM HIERARCHY                             │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  1. PYRIDOXAL-5'-PHOSPHATE (P5P/PLP)                           │
│     ├── Active coenzyme form                                    │
│     ├── No conversion required                                  │
│     ├── MINIMAL NEUROTOXICITY                                   │
│     ├── Better retention                                        │
│     └── ★ NTRPX RECOMMENDED                                     │
│                                                                 │
│  2. PYRIDOXINE HCl                                              │
│     ├── Most common supplement form                             │
│     ├── Requires conversion to PLP                              │
│     ├── ⚠️ NEUROTOXICITY RISK AT HIGH DOSES                     │
│     ├── May competitively inhibit PLP                           │
│     └── ✗ NOT RECOMMENDED - Safety concern                      │
│                                                                 │
│  3. PYRIDOXAMINE                                                │
│     ├── Found in animal foods                                   │
│     ├── Intermediate form                                       │
│     └── Limited supplement availability                         │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

6.3 The Pyridoxine Paradox

CRITICAL SAFETY FINDING: High-dose pyridoxine supplementation can cause the very symptoms it should prevent.

Mechanism	Explanation
Competitive inhibition	Inactive pyridoxine competes with active PLP for enzyme binding sites
Neuronal toxicity	Pyridoxine induces concentration-dependent cell death in neurons
Sensory neuropathy	>50 cases reported since 2014 of pyridoxine-induced peripheral neuropathy
P5P safety	Cell viability studies show minimal neurotoxicity with P5P

┌─────────────────────────────────────────────────────────────────┐
│                  PYRIDOXINE PARADOX MECHANISM                   │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  HIGH-DOSE PYRIDOXINE                                           │
│        │                                                        │
│        ├──→ Overwhelms conversion enzymes                       │
│        │                                                        │
│        ├──→ Unphosphorylated pyridoxine accumulates             │
│        │                                                        │
│        ├──→ Competes with PLP for enzyme binding                │
│        │                                                        │
│        └──→ NET RESULT: Functional B6 deficiency                │
│                  └──→ Sensory neuropathy                        │
│                                                                 │
│  This does NOT occur with P5P supplementation                   │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

6.4 Conversion Pathway

Step	Enzyme	Cofactor Required
Pyridoxine → Pyridoxine-5’-phosphate	Pyridoxal kinase	ATP
Pyridoxine-5’-phosphate → PLP	Pyridoxine-5’-phosphate oxidase	FMN (B2)

Implication: B2 status affects B6 activation. Riboflavin deficiency impairs PLP production.

6.5 Clinical Evidence

Study Type	Findings
Cell viability (2017)	Pyridoxine causes concentration-dependent neuronal death; P5P does not
Case series (2014-2024)	>50 cases pyridoxine-induced neuropathy at doses >50mg/day chronic
Bioavailability	P5P: Higher retention, more stable plasma levels
MTHFR populations	P5P may be preferred (no conversion bottleneck)

Evidence Tier: TIER 2 (Probable) for P5P safety advantage; TIER 3 for efficacy superiority

6.6 Safety Profile

Form	Neurotoxicity Risk	UL	Recommendation
Pyridoxine HCl	Significant at >50mg/day chronic	100mg/day	Avoid high doses
P5P	Minimal	Not established separately	Preferred

6.7 Drug Interactions

Drug	Interaction	Clinical Action
Levodopa	B6 increases peripheral conversion (reduces efficacy)	Use only with carbidopa
Phenytoin, phenobarbital	Increased B6 catabolism	May need supplementation
Cycloserine	Increased urinary B6 excretion	Supplement recommended
Isoniazid	B6 antagonist	Supplement required

6.8 NTRPX Recommendation: B6

┌─────────────────────────────────────────────────────────────────┐
│                   B6 PYRIDOXINE - NTRPX VERDICT                 │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  RECOMMENDATION: PYRIDOXAL-5'-PHOSPHATE (P5P) EXCLUSIVELY       │
│                                                                 │
│  Rationale:                                                     │
│  • Active coenzyme form - no conversion required                │
│  • CRITICAL: Avoids pyridoxine neurotoxicity risk               │
│  • Better retention and utilization                             │
│  • Supports those with impaired conversion                      │
│  • Aligns with "no compromises on safety" principle             │
│                                                                 │
│  ALL SYSTEMS: 10-25mg P5P                                       │
│                                                                 │
│  DO NOT USE: Pyridoxine HCl in any NTRPX formula                │
│                                                                 │
│  Confidence: HIGH                                               │
│                                                                 │
│  Note: Higher cost of P5P is justified by safety advantage      │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

7. B7: Biotin

7.1 Compound Overview

Property	Value
Active Form	D-Biotin (only biologically active form)
Key Enzymes	5 carboxylases (pyruvate, acetyl-CoA, propionyl-CoA, methylcrotonyl-CoA, acetyl-CoA carboxylase 1&2)
Key Functions	Fatty acid synthesis, gluconeogenesis, amino acid catabolism
Deficiency	Very rare; screened at birth (biotinidase deficiency)
AI	30 mcg/day

7.2 Available Forms

ONLY ONE BIOLOGICALLY ACTIVE FORM EXISTS

Form	Activity	Notes
D-Biotin	✅ Active	The only form to use
L-Biotin	❌ Inactive	Enantiomer, no biological activity
Biocytin	Precursor	Protein-bound form in food; cleaved to D-biotin
DL-Biotin (racemic)	50% active	Avoid; half is inactive L-form

7.3 Bioavailability

Factor	Value
Food bioavailability	5% to ~100% depending on source
Supplement absorption	~100% even at pharmacologic doses (20mg)
Transport	SMVT (sodium-dependent multivitamin transporter)
Storage	Primarily liver

7.4 Hair/Nail Claims: Evidence Assessment

STATUS: NOT SUPPORTED BY EVIDENCE

Study Type	Findings
Systematic reviews	Insufficient evidence for hair/nail benefits in non-deficient individuals
RCTs	Studies had design flaws: no baseline biotin measurement, varied diagnoses
Confounding	Conditions like alopecia can resolve spontaneously

NTRPX Position: Do not market biotin for hair/nail health. Deficiency is extremely rare, and supplementation in non-deficient individuals shows no benefit.

7.5 Lab Test Interference

CRITICAL CLINICAL CONSIDERATION High-dose biotin can interfere with immunoassays using streptavidin-biotin interaction:

Affected Tests	Direction	Clinical Impact
Thyroid (TSH, T3, T4)	False positives/negatives	Misdiagnosis
Troponin	False negative	Missed MI
PSA	False negative	Missed cancer
Vitamin D	Variable	Incorrect supplementation
Pregnancy tests	Variable	Incorrect result

Recommendation: Discontinue high-dose biotin 48-72 hours before lab work

7.6 Safety Profile

Parameter	Value
UL	None established
Toxicity	No known toxicity
Adverse effects	None at any dose studied
Drug interactions	Anticonvulsants may deplete; raw egg whites bind biotin

7.7 NTRPX Recommendation: B7

┌─────────────────────────────────────────────────────────────────┐
│                   B7 BIOTIN - NTRPX VERDICT                     │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  RECOMMENDATION: D-BIOTIN                                       │
│                                                                 │
│  Rationale:                                                     │
│  • Only one active form exists - no form selection needed       │
│  • Ensure product specifies D-biotin (not DL-racemic)           │
│  • Deficiency extremely rare; low doses sufficient              │
│                                                                 │
│  ALL SYSTEMS: 30-100 mcg D-Biotin                               │
│                                                                 │
│  AVOID:                                                         │
│  • High-dose biotin (>1000 mcg) - lab interference concern      │
│  • Hair/nail health claims - not evidence-supported             │
│  • DL-Biotin (racemic) - 50% inactive                           │
│                                                                 │
│  Confidence: HIGH                                               │
│                                                                 │
│  Note: Include lab test warning on any high-dose products       │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

8. B9: Folate

8.1 Compound Overview

Property	Value
Active Form	5-methyltetrahydrofolate (5-MTHF, L-methylfolate)
Key Functions	DNA synthesis/repair, methylation, homocysteine metabolism, RBC formation
Critical Period	Pre-conception through first trimester (neural tube development)
Deficiency	Megaloblastic anemia, neural tube defects, elevated homocysteine
RDA	400 mcg DFE/day; 600 mcg pregnancy

8.2 Available Forms

┌─────────────────────────────────────────────────────────────────┐
│                     FOLATE FORM HIERARCHY                       │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  1. L-5-METHYLTETRAHYDROFOLATE (L-5-MTHF)                      │
│     ├── Active circulating form                                 │
│     ├── Bypasses entire folate metabolism                       │
│     ├── Not affected by MTHFR polymorphisms                     │
│     ├── Forms: Metafolin®, Quatrefolic®                         │
│     └── ★ NTRPX RECOMMENDED                                     │
│                                                                 │
│  2. FOLINIC ACID (Leucovorin/5-formyl-THF)                     │
│     ├── Reduced form, bypasses MTHFR                            │
│     ├── Few additional steps to active form                     │
│     ├── Good for methylation-sensitive individuals              │
│     └── ✓ Acceptable alternative                                │
│                                                                 │
│  3. FOLIC ACID (Synthetic)                                      │
│     ├── Requires multi-step conversion via slow DHFR            │
│     ├── ~40% population has impaired MTHFR conversion           │
│     ├── UMFA accumulation concern                               │
│     ├── Still CDC/WHO recommended for pregnancy (RCT evidence)  │
│     └── ⚠️ NOT PREFERRED - Use 5-MTHF instead                   │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

8.3 MTHFR Polymorphism

CRITICAL POPULATION CONSIDERATION

Genotype	Prevalence	MTHFR Activity	Folic Acid Conversion
CC (wild-type)	~45%	100%	Normal
CT (heterozygous)	~45%	~65%	Reduced
TT (homozygous)	~10%	~30%	Severely impaired

~40% of global population has reduced ability to convert folic acid to active 5-MTHF

8.4 Folic Acid Concerns

Concern	Explanation
UMFA accumulation	Unmetabolized folic acid detectable in plasma at doses >200 mcg
Receptor competition	UMFA may compete with 5-MTHF for folate receptors
DHFR saturation	Enzyme is slow and easily overwhelmed
Cord blood UMFA	Detected in infants; long-term effects unknown

8.5 5-MTHF Forms Comparison

Branded Form	Salt	Bioavailability	Notes
Quatrefolic®	Glucosamine salt	Highest	Most soluble, stable
Metafolin®	Calcium salt	High	Well-established
Generic L-5-MTHF	Various	Variable	Ensure (6S) isomer specified

Important: Only L- and (6S)- forms are biologically active. D- and (6R)- forms are not.

8.6 Clinical Evidence

Study Type	Findings
MTHFR TT homocysteine	5-MTHF: Sustained reduction 6 months post-treatment; folic acid: effect waned
Depression adjunct	15mg L-methylfolate + SSRI: Significant improvement vs SSRI alone
Bioavailability	Quatrefolic: Higher Cmax and AUC than folic acid
Neural tube defects	Folic acid only has RCT evidence for NTD prevention (no 5-MTHF RCTs)

Evidence Tier: TIER 1 (Proven) for folate necessity; TIER 2 (Probable) for 5-MTHF superiority in MTHFR populations

8.7 Safety Profile

Form	Safety Concerns
5-MTHF	Generally well-tolerated; may cause overmethylation symptoms in sensitive individuals
Folic Acid	UMFA accumulation; may mask B12 deficiency
Folinic Acid	Well-tolerated; may be better for methylation-sensitive

8.8 NTRPX Recommendation: B9

┌─────────────────────────────────────────────────────────────────┐
│                   B9 FOLATE - NTRPX VERDICT                     │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  RECOMMENDATION: L-5-METHYLTETRAHYDROFOLATE (Quatrefolic®)      │
│                                                                 │
│  Rationale:                                                     │
│  • Active form - bypasses entire metabolic pathway              │
│  • Benefits ~40% of population with MTHFR variants              │
│  • No UMFA accumulation                                         │
│  • Superior bioavailability                                     │
│  • No B12 masking concern                                       │
│                                                                 │
│  ALL SYSTEMS: 400-800 mcg L-5-MTHF (as Quatrefolic®)            │
│                                                                 │
│  Specify: (6S)-5-methyltetrahydrofolate glucosamine salt        │
│                                                                 │
│  DO NOT USE: Folic acid in NTRPX formulas                       │
│                                                                 │
│  PREGNANCY NOTE:                                                │
│  CDC/WHO still recommend folic acid (only form with NTD RCT     │
│  evidence). For pregnancy-specific products, consider regulatory│
│  guidance, but 5-MTHF is mechanistically superior.              │
│                                                                 │
│  Confidence: HIGH                                               │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

9. B12: Cobalamin

9.1 Compound Overview

Property	Value
Active Coenzymes	Methylcobalamin, Adenosylcobalamin
Key Enzymes	Methionine synthase (methylB12), L-methylmalonyl-CoA mutase (adenosylB12)
Key Functions	DNA synthesis, methylation, nerve function, RBC formation
Deficiency	Megaloblastic anemia, neurological damage (potentially irreversible)
RDA	2.4 mcg/day

9.2 Available Forms

┌─────────────────────────────────────────────────────────────────┐
│                   B12 FORM HIERARCHY                            │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  ACTIVE COENZYME FORMS:                                         │
│                                                                 │
│  1. METHYLCOBALAMIN                                             │
│     ├── Coenzyme for methionine synthase                        │
│     ├── Primary form in blood, liver, brain                     │
│     ├── Methyl donor for homocysteine → methionine              │
│     ├── Higher retention than cyanocobalamin                    │
│     └── ★ NTRPX RECOMMENDED (with adenosyl)                     │
│                                                                 │
│  2. ADENOSYLCOBALAMIN                                           │
│     ├── Coenzyme for methylmalonyl-CoA mutase                   │
│     ├── Primary form in mitochondria                            │
│     ├── Required for energy production, odd-chain FA metabolism │
│     ├── Less common as standalone supplement                    │
│     └── ★ NTRPX RECOMMENDED (with methyl)                       │
│                                                                 │
│  PRECURSOR FORMS:                                               │
│                                                                 │
│  3. HYDROXOCOBALAMIN                                            │
│     ├── Natural bacterial form                                  │
│     ├── Longest retention (binds serum proteins well)           │
│     ├── Converts to methyl or adenosyl in body                  │
│     ├── Preferred for injection/severe deficiency               │
│     └── ✓ Acceptable alternative                                │
│                                                                 │
│  4. CYANOCOBALAMIN                                              │
│     ├── Synthetic, most stable, cheapest                        │
│     ├── Contains cyanide molecule (trace, safe)                 │
│     ├── Requires conversion to active forms                     │
│     ├── Lower retention, greater urinary losses                 │
│     └── ⚠️ NOT OPTIMAL - Active forms preferred                 │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

9.3 Form Comparison Table

Form	Coenzyme?	Retention	Conversion	Best Use
Methylcobalamin	✅ Yes	Higher	None needed	Methylation, neuro
Adenosylcobalamin	✅ Yes	Higher	None needed	Energy, mitochondria
Hydroxocobalamin	❌ No	Highest	1-2 steps	Injection, severe deficiency
Cyanocobalamin	❌ No	Lower	2+ steps	Budget formulas only

9.4 Why Both Active Forms?

Methylcobalamin and adenosylcobalamin serve different biochemical functions:

┌─────────────────────────────────────────────────────────────────┐
│              B12 COENZYME FUNCTIONS                             │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  METHYLCOBALAMIN                                                │
│  └── Methionine Synthase                                        │
│       └── Homocysteine + 5-MTHF → Methionine + THF              │
│            ├── Methylation reactions (SAMe production)          │
│            ├── Regenerates THF for DNA synthesis                │
│            └── Location: Cytoplasm                              │
│                                                                 │
│  ADENOSYLCOBALAMIN                                              │
│  └── Methylmalonyl-CoA Mutase                                   │
│       └── L-methylmalonyl-CoA → Succinyl-CoA                    │
│            ├── Odd-chain fatty acid metabolism                  │
│            ├── Propionate metabolism                            │
│            ├── Energy production (TCA cycle entry)              │
│            └── Location: Mitochondria                           │
│                                                                 │
│  USING ONLY ONE FORM = INCOMPLETE B12 SUPPORT                   │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

9.5 Clinical Evidence

Comparison	Findings
Methyl vs Cyano absorption	Similar initial absorption
Methyl vs Cyano retention	Methylcobalamin: Higher tissue retention, lower urinary losses
Liver storage	Cyanocobalamin: Lower hepatic accumulation
Neurological outcomes	Both effective; some preference for methylcobalamin in neuropathy

Evidence Tier: TIER 2 (Probable) for active form advantage; direct comparison RCTs limited

9.6 Absorption Considerations

B12 absorption is complex and can be impaired:

Factor	Impact
Intrinsic factor	Required for ileal absorption; absent in pernicious anemia
Gastric acid	Required to release B12 from food protein
Age	Absorption decreases with age (atrophic gastritis)
Metformin	Reduces B12 absorption
PPIs, H2 blockers	Reduce gastric acid, impair B12 release
Passive diffusion	~1% absorbed without IF (relevant for high-dose supplements)

9.7 Safety Profile

Parameter	Value
UL	None established
Toxicity	No known toxicity at any dose
Adverse effects	Rare: acne, rosacea flare (high-dose methylcobalamin)
Drug interactions	See absorption factors above

9.8 NTRPX Recommendation: B12

┌─────────────────────────────────────────────────────────────────┐
│                  B12 COBALAMIN - NTRPX VERDICT                  │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  RECOMMENDATION: METHYLCOBALAMIN + ADENOSYLCOBALAMIN            │
│                                                                 │
│  Rationale:                                                     │
│  • Both active coenzyme forms - no conversion required          │
│  • Each serves distinct biochemical functions                   │
│  • Higher retention than cyanocobalamin                         │
│  • Supports methylation AND energy production                   │
│  • No cyanide molecule (relevant for smokers, detox)            │
│                                                                 │
│  ALL SYSTEMS:                                                   │
│  • Methylcobalamin: 500-1000 mcg                                │
│  • Adenosylcobalamin: 250-500 mcg                               │
│                                                                 │
│  Alternative (budget): Hydroxocobalamin 1000 mcg                │
│  (Converts to both active forms; better retention than cyano)   │
│                                                                 │
│  DO NOT USE: Cyanocobalamin as primary B12 source               │
│                                                                 │
│  Confidence: HIGH                                               │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

10. Cross-Cutting Analysis

10.1 Methylation Pathway Integration

The methylation cycle requires coordinated function of B2, B6, B9, and B12:

┌─────────────────────────────────────────────────────────────────┐
│                  METHYLATION CYCLE INTEGRATION                  │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│                     DIETARY FOLATE                              │
│                          │                                      │
│                          ▼                                      │
│                    Dihydrofolate                                │
│                          │ (DHFR)                               │
│                          ▼                                      │
│                 Tetrahydrofolate (THF)                          │
│                          │                                      │
│                          ▼                                      │
│               5,10-Methylenetetrahydrofolate                    │
│                          │                                      │
│                          │ MTHFR (requires FAD from B2)         │
│                          ▼                                      │
│     ┌──────────► 5-MTHF ◄──────────┐                           │
│     │                │              │                           │
│     │                │ Methionine   │                           │
│     │                │ Synthase     │                           │
│     │                │ (requires    │                           │
│     │                │ MethylB12)   │                           │
│     │                ▼              │                           │
│     │         METHIONINE            │                           │
│     │                │              │                           │
│     │                ▼              │                           │
│     │              SAMe             │                           │
│     │     (universal methyl donor)  │                           │
│     │                │              │                           │
│     │                ▼              │                           │
│     │         HOMOCYSTEINE ─────────┘                           │
│     │                │                                          │
│     │                │ CBS (requires P5P from B6)               │
│     │                ▼                                          │
│     │           Cystathionine                                   │
│     │                │                                          │
│     │                ▼                                          │
│     │            Cysteine → Glutathione                         │
│     │                                                           │
│     └───────────── THF ◄────────────                            │
│                                                                 │
│  NTRPX IMPLICATION: All four vitamins must be in active forms   │
│  for optimal methylation support                                │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

10.2 Energy Metabolism Integration

B1, B2, B3, and B5 coordinate in energy production:

Vitamin	Coenzyme	Role in Energy Metabolism
B1	ThDP	Pyruvate dehydrogenase, α-ketoglutarate dehydrogenase
B2	FAD/FMN	Electron transport chain, fatty acid oxidation
B3	NAD+/NADP+	>400 redox reactions, TCA cycle, glycolysis
B5	CoA	Acetyl-CoA formation, fatty acid synthesis/oxidation

10.3 B Vitamin Synergies

Interaction	Mechanism	NTRPX Implication
B2 → B6	FMN required for pyridoxine oxidase	Ensure adequate B2 with P5P
B2 → B9	FAD required for MTHFR	Ensure adequate B2 with 5-MTHF
B2 → B3	FAD required for tryptophan→NAD+	B2 supports niacin status
B9 ↔ B12	Methylation cycle partners	Always supplement together
B6 → B9/B12	CBS enzyme requires P5P	B6 affects homocysteine clearance

10.4 Dosing Ratios

Based on RDA ratios and synergistic requirements:

Vitamin	RDA	NTRPX Suggested	Ratio to B2
B1	1.2 mg	25-100 mg (benfotiamine)	2-8x
B2	1.3 mg	10-25 mg (R5P)	1x (baseline)
B3	16 mg	100-500 mg (NR or NAM)	8-40x
B5	5 mg	25-100 mg	2-8x
B6	1.7 mg	10-25 mg (P5P)	1-2x
B7	30 mcg	100-300 mcg	-
B9	400 mcg	400-800 mcg (5-MTHF)	-
B12	2.4 mcg	500-1000 mcg (methyl+adenosyl)	-

11. NTRPX Systems Integration

11.1 All Systems Go - Sustain

Vitamin	Form	Dose	Rationale
B1	Benfotiamine	150-300 mg	Peripheral metabolic support, AGE inhibition
B2	R5P	15-25 mg	Coenzyme form, supports B6/B9 function
B3	NR or Nicotinamide	250-500 mg	NAD+ maintenance
B5	D-Calcium Pantothenate	50-100 mg	CoA synthesis
B6	P5P	15-25 mg	Active form, avoids neurotoxicity
B7	D-Biotin	100-300 mcg	Carboxylase support
B9	L-5-MTHF (Quatrefolic)	400-800 mcg	Methylation, no MTHFR concern
B12	Methyl + Adenosyl	500 + 250 mcg	Both coenzyme forms

11.2 All Systems Go - Boost

Vitamin	Form	Dose	Rationale
B1	Benfotiamine	150 mg	Energy metabolism
B2	R5P	10-15 mg	Electron transport
B3	Nicotinamide	100-250 mg	NAD+ for acute energy
B5	D-Calcium Pantothenate	25-50 mg	CoA availability
B6	P5P	10-15 mg	Neurotransmitter synthesis
B7	D-Biotin	100 mcg	Standard support
B9	L-5-MTHF	400 mcg	Methylation
B12	Methylcobalamin	500 mcg	Cognitive support

11.3 All Systems Go - Recover

Vitamin	Form	Dose	Rationale
B1	Benfotiamine	150-300 mg	Tissue repair, antioxidant
B2	R5P	15-25 mg	Glutathione recycling
B3	NR	250-500 mg	NAD+ for cellular repair
B5	D-Calcium Pantothenate	50-100 mg	Wound healing support
B6	P5P	15-25 mg	Protein metabolism
B7	D-Biotin	100-300 mcg	Standard support
B9	L-5-MTHF	600-800 mcg	Cell turnover, DNA repair
B12	Methyl + Adenosyl	750 + 500 mcg	Elevated for recovery

11.4 Sprint (Cognitive Focus)

Vitamin	Form	Dose	Rationale
B1	TTFD	50-100 mg	Confirmed BBB penetration
B2	R5P	10-15 mg	Neural metabolism
B3	Nicotinamide	100-250 mg	Brain NAD+
B5	D-Calcium Pantothenate	25-50 mg	Acetylcholine precursor
B6	P5P	10-25 mg	Neurotransmitter synthesis
B7	D-Biotin	100 mcg	Standard support
B9	L-5-MTHF	400 mcg	Neural methylation
B12	Methylcobalamin	1000 mcg	Cognitive, methylation

12. Final Specifications

12.1 NTRPX B-Vitamin Specification Summary

Vitamin	Approved Form(s)	NOT Approved
B1	Benfotiamine, TTFD, Thiamine HCl (baseline)	Sulbutiamine
B2	Riboflavin-5’-Phosphate (R5P)	-
B3	Nicotinamide Riboside, Nicotinamide	Inositol hexanicotinate, NMN
B5	D-Calcium Pantothenate, Pantethine (lipid only)	-
B6	Pyridoxal-5’-Phosphate (P5P)	Pyridoxine HCl
B7	D-Biotin	DL-Biotin (racemic)
B9	L-5-MTHF (Quatrefolic preferred)	Folic acid
B12	Methylcobalamin + Adenosylcobalamin	Cyanocobalamin

12.2 Quality Standards

Parameter	Specification
Identity	HPLC confirmation of stated forms
Purity	≥98% for all vitamins
Heavy metals	USP <232>/<233> limits
Microbial	USP <2021> standards
Stability	24-month shelf life at room temperature
Third-party testing	Required for all batches

12.3 Supplier Recommendations

Vitamin	Preferred Supplier/Brand
Benfotiamine	Multiple generic sources acceptable
TTFD	Ecological Formulas (Allithiamine), Thiamax
R5P	DSM, BASF
NR	ChromaDex (Niagen®)
P5P	DSM, BASF
L-5-MTHF	Gnosis (Quatrefolic®), Merck (Metafolin®)
Methylcobalamin	Multiple sources; ensure light-protected
Adenosylcobalamin	Specialty suppliers; verify stability

13. References

Primary Sources by Vitamin

Thiamine (B1)

Lonsdale D. A Review of the Biochemistry, Metabolism and Clinical Benefits of Thiamin(e) and Its Derivatives. Evidence-Based Complementary and Alternative Medicine. 2006;3(1):49-59.
Raj V, et al. Therapeutic potential of benfotiamine and its molecular targets. European Review for Medical and Pharmacological Sciences. 2018;22:3261-3273.
Pan X, et al. Powerful beneficial effects of benfotiamine on cognitive impairment and β-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice. Brain. 2010;133(5):1342-1351.
Gibson GE, et al. Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial. J Alzheimers Dis. 2020;78(3):989-1010.

Riboflavin (B2) 5. Powers HJ. Riboflavin (vitamin B-2) and health. Am J Clin Nutr. 2003;77(6):1352-1360. 6. Schoenen J, et al. Effectiveness of high-dose riboflavin in migraine prophylaxis. Neurology. 1998;50(2):466-470. Niacin (B3) 7. Martens CR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018;9:1286. 8. Elhassan YS, et al. Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Cell Rep. 2019;28(7):1717-1728. Pantothenic Acid (B5) 9. Rumberger JA, et al. Pantethine, a derivative of vitamin B5 used as a nutritional supplement, favorably alters low-density lipoprotein cholesterol metabolism in low- to moderate-cardiovascular risk North American subjects. Nutr Res. 2011;31(8):608-615. Pyridoxine (B6) 10. Vrolijk MF, et al. The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function. Toxicology in Vitro. 2017;44:206-212. 11. Hadtstein F, Vrolijk M. Vitamin B-6-Induced Neuropathy: Exploring the Mechanisms of Pyridoxine Toxicity. Advances in Nutrition. 2021;12(5):1911-1929. Biotin (B7) 12. Patel DP, et al. A Review of the Use of Biotin for Hair Loss. Skin Appendage Disorders. 2017;3(3):166-169. 13. Li D, et al. Biotin interference in clinical immunoassays. J Appl Lab Med. 2020;5(3):452-461. Folate (B9) 14. Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014;44(5):480-488. 15. Prinz-Langenohl R, et al. [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C→T polymorphism of methylenetetrahydrofolate reductase. Br J Pharmacol. 2009;158(8):2014-2021. Cobalamin (B12) 16. Paul C, Brady DM. Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms. Integr Med (Encinitas). 2017;16(1):42-49. 17. Obeid R, et al. Cobalamin coenzyme forms are not likely to be superior to cyano- and hydroxyl-cobalamin in prevention or treatment of cobalamin deficiency. Mol Nutr Food Res. 2015;59(7):1364-1372.

Document Control

Version	Date	Author	Changes
1.0	2026-01-24	NTRPX R&D	Initial comprehensive evaluation

This document represents NTRPX’s internal evaluation based on available clinical evidence as of the document date. Form selections are based on the principles of evidence over theory, proven over promising, and no compromises on safety. All recommendations are subject to revision as new evidence emerges.

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Method

Systems

Formulations

Ingredient Manual

Evaluations

Community

​Comprehensive B-Vitamin Forms Evaluation

​Evidence-Based Analysis for NTRPX Systems Integration

​Executive Summary

​Table of Contents

​1. Evaluation Standards

​NTRPX Evidence Hierarchy

​Form Selection Criteria

​2. B1: Thiamine

​2.1 Compound Overview

​2.2 Available Forms

​2.3 Form Comparison Table

​2.4 Critical Distinction: Thioesters vs Disulfides

​2.5 Clinical Evidence

​Benfotiamine

​TTFD

​2.6 Safety Profile

​2.7 NTRPX Recommendation: B1

​3. B2: Riboflavin

​3.1 Compound Overview

​3.2 Available Forms

​3.3 Bioavailability Analysis

​3.4 When R5P May Matter

​3.5 Critical Metabolic Role

​3.6 Safety Profile

​3.7 NTRPX Recommendation: B2

​4. B3: Niacin

​4.1 Compound Overview

​4.2 Available Forms

​4.3 Form Comparison Table

​4.4 Pathway Analysis

​4.5 Clinical Evidence

​Nicotinamide Riboside (NR)

​Nicotinamide

​4.6 Safety Profile

​4.7 NTRPX Recommendation: B3

​5. B5: Pantothenic Acid

​5.1 Compound Overview

​5.2 Available Forms

​5.3 Critical Distinction: Pantothenate vs Pantethine

​5.4 Pantethine Clinical Evidence

​5.5 Safety Profile

​5.6 NTRPX Recommendation: B5

​6. B6: Pyridoxine

​6.1 Compound Overview

​6.2 Available Forms

​6.3 The Pyridoxine Paradox

​6.4 Conversion Pathway

​6.5 Clinical Evidence

​6.6 Safety Profile

​6.7 Drug Interactions

​6.8 NTRPX Recommendation: B6

​7. B7: Biotin

​7.1 Compound Overview

​7.2 Available Forms

​7.3 Bioavailability

​7.4 Hair/Nail Claims: Evidence Assessment

​7.5 Lab Test Interference

​7.6 Safety Profile

​7.7 NTRPX Recommendation: B7

​8. B9: Folate

​8.1 Compound Overview

​8.2 Available Forms

​8.3 MTHFR Polymorphism

​8.4 Folic Acid Concerns

​8.5 5-MTHF Forms Comparison

​8.6 Clinical Evidence

​8.7 Safety Profile

​8.8 NTRPX Recommendation: B9

​9. B12: Cobalamin

​9.1 Compound Overview

​9.2 Available Forms

​9.3 Form Comparison Table

​9.4 Why Both Active Forms?