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Biological Domain Classification System

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Critical Analysis of v1.0 (12 Domains)

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Structural Problems

IssueDescriptionExamples
Inconsistent granularityMixing very specific systems with very broad categoriesCholinergic (specific neurotransmitter) vs. Neuroprotection (broad outcome)
Missing major neurotransmitterGlutamate is the brain’s PRIMARY excitatory neurotransmitterGlycine is an NMDA co-agonist; Mg is NMDA modulator — where do they map?
Noradrenergic omissionNorepinephrine is distinct from dopamine with different functionsTyrosine → L-DOPA → Dopamine → Norepinephrine — this pathway is incomplete
Redundant energy domainsMitochondrial, ATP Systems, NAD+ Metabolism overlap significantlyAll are “cellular energy” — unclear boundaries
Missing vascular domainNo place for L-Citrulline, NO, blood flowA core Neuraldrink™ mechanism has no domain
Missing immune/inflammatoryOmega-3s, adaptogens affect inflammationNo domain for this major pathway
Outcome vs. mechanism confusion”Neuroprotection” is an outcome, not a biological systemBDNF, NGF, antioxidants are mechanisms; “protection” is the result

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Missing Domains (Critical)

Omitted DomainWhy It MattersNTRPX Ingredients That Target It
Glutamatergic/NMDAPrimary excitatory neurotransmitter; glycine’s sleep mechanism works via NMDAGlycine, Magnesium, Theanine
NoradrenergicAlertness, attention, stress response; distinct from dopamineTyrosine, Caffeine, Paraxanthine
Vascular/Nitric OxideBlood flow to brain and body; endothelial functionL-Citrulline, DHA/EPA
Immune/InflammatoryCytokine modulation, inflammation controlOmega-3s, Ashwagandha, Cordyceps
Glucose MetabolismBrain’s primary fuel; insulin sensitivityChromium, B-vitamins, Glucose itself

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Boundary Ambiguities

IngredientCurrent Assignment Problem
GlycineAssigned to “Circadian” but mechanism is NMDA → hypothalamic thermoregulation
L-TheanineAssigned to “GABAergic” but also modulates glutamate
MagnesiumAffects GABA, NMDA, ATP, HPA — where does it primarily belong?
Omega-3sAssigned to “Structural” but also anti-inflammatory and neuroprotective
CreatineIs it “ATP Systems” or “Mitochondrial”?

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Proposed Domain Classification v2.0

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Design Principles

  1. Mechanistic, not outcome-based — Domains describe biological pathways, not desired results
  2. Consistent granularity — All domains at similar level of specificity
  3. Mutually exclusive, collectively exhaustive (MECE) — Minimal overlap, complete coverage
  4. Supplement-relevant — Domains map to ingredients we can actually modulate
  5. Hierarchically organized — Related domains grouped into super-categories

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The 16-Domain Classification System

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Domain Definitions & Key Markers

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Domain 1: Cholinergic System

Definition: Acetylcholine synthesis, release, receptor activation, and degradation pathways.
AspectDetails
Primary neurotransmitterAcetylcholine (ACh)
Key enzymesCholine acetyltransferase (ChAT), Acetylcholinesterase (AChE)
ReceptorsNicotinic (nAChR), Muscarinic (mAChR)
FunctionsMemory encoding, sustained attention, learning, neuromuscular junction
NTRPX ingredientsCDP-Choline, Alpha-GPC, Huperzine A, Phosphatidylserine
BiomarkersRBC AChE activity, choline levels

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Domain 2: Catecholaminergic System

Definition: Dopamine AND norepinephrine/epinephrine synthesis, release, reuptake, and degradation. Combined because they share a biosynthetic pathway.
AspectDopaminergicNoradrenergic
FunctionsMotivation, reward, executive functionAlertness, attention, stress response
ReceptorsD1-D5α1, α2, β1, β2, β3
DegradationMAO-A/B, COMTMAO-A, COMT
NTRPX ingredientsTyrosine, Mucuna (L-DOPA), Salidroside (MAO-B)Tyrosine, Caffeine, Paraxanthine
Why combined: Tyrosine supplementation feeds BOTH pathways. MAO inhibition affects both. They cannot be cleanly separated at the intervention level.

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Domain 3: Serotonergic System

Definition: Serotonin (5-HT) synthesis, release, reuptake, and receptor modulation.
AspectDetails
Primary neurotransmitterSerotonin (5-hydroxytryptamine, 5-HT)
BiosynthesisTryptophan → 5-HTP → Serotonin
Receptors5-HT1A through 5-HT7 (14+ subtypes)
FunctionsMood regulation, emotional well-being, gut motility, sleep onset
NTRPX ingredientsSaffron (reuptake), Bacopa (5-HT modulation)
Note95% of serotonin is in gut; CNS serotonin is synthesized locally

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Domain 4: GABAergic System

Definition: Gamma-aminobutyric acid synthesis, receptor modulation, and inhibitory tone.
AspectDetails
Primary neurotransmitterGABA (gamma-aminobutyric acid)
BiosynthesisGlutamate → GABA (via GAD; requires P5P)
ReceptorsGABA-A (ionotropic, fast), GABA-B (metabotropic, slow)
Binding sitesGABA site, Benzodiazepine site, Barbiturate site, Neurosteroid site
FunctionsInhibitory tone, anxiety reduction, sleep, muscle relaxation
NTRPX ingredientsL-Theanine, Taurine, Apigenin, Magnesium, Ashwagandha

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Domain 5: Glutamatergic System (NEW)

Definition: Glutamate signaling, NMDA/AMPA receptor modulation, and excitatory-inhibitory balance.
AspectDetails
Primary neurotransmitterGlutamate (THE primary excitatory NT)
Key receptorsNMDA, AMPA, Kainate (ionotropic); mGluR (metabotropic)
NMDA requirementsGlutamate + Glycine (co-agonist) + Depolarization + Mg²⁺ unblock
FunctionsLearning, memory consolidation, synaptic plasticity, LTP
NTRPX ingredientsGlycine (NMDA co-agonist), Magnesium (voltage-dependent block), L-Theanine (glutamate modulation)
Critical insight: Glycine’s sleep-onset mechanism works via NMDA receptors in the hypothalamus, triggering thermoregulatory changes. This is a GLUTAMATERGIC mechanism, not purely “circadian.”

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Domain 6: Mitochondrial System

Definition: Mitochondrial biogenesis, dynamics (fusion/fission), and oxidative phosphorylation efficiency.
AspectDetails
Biogenesis pathwayPGC-1α → NRF1/2 → TFAM → mtDNA transcription
Key activatorsAMPK, SIRT1, CREB
Electron transport chainComplex I-IV + ATP synthase
NTRPX ingredientsPQQ (biogenesis), CoQ10 (ETC), Cordyceps (O₂ utilization)
BiomarkersMitochondrial DNA copy number, citrate synthase activity

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Domain 7: Bioenergetics (ATP/Phosphocreatine)

Definition: Immediate and short-term energy buffering systems; ATP regeneration.
SystemTimeframeNTRPX Ingredients
Phosphocreatine (PCr)0-10 secondsCreatine
Glycolytic10 sec - 2 minGlucose, B-vitamins (cofactors)
Oxidative>2 minMitochondrial support
Key enzyme: Creatine kinase (PCr + ADP ⇌ Cr + ATP)

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Domain 8: NAD+ Metabolism

Definition: Nicotinamide adenine dinucleotide synthesis, consumption, and salvage pathways.
NTRPX IngredientsMechanism
NR (Niagen®)NAD+ precursor (salvage pathway)
ApigeninCD38 inhibitor (preserves NAD+)
NiacinamideDirect NAD+ precursor

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Domain 9: Glucose Metabolism (NEW)

Definition: Glucose uptake, glycolysis, gluconeogenesis, and insulin signaling.
AspectDetails
Brain requirement~120g glucose/day; 20-25% of body’s total
Key transportersGLUT1 (BBB), GLUT3 (neurons), GLUT4 (insulin-responsive)
Glycolysis cofactorsThiamine (B1), Riboflavin (B2), Niacin (B3), Pantothenic acid (B5), Magnesium
Insulin sensitivityChromium, Magnesium
NTRPX ingredientsD-Glucose, Chromium, B-vitamins, Magnesium
Critical for Neuraldrink™: The brain REQUIRES glucose. This domain captures the carbohydrate fuel system.

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Domain 10: Methylation / Epigenetic

Definition: One-carbon metabolism, methylation reactions, and epigenetic regulation.
AspectDetails
Universal methyl donorS-adenosylmethionine (SAMe)
200+ reactionsDNA methylation, neurotransmitter synthesis, creatine synthesis, phospholipid synthesis
Key variantsMTHFR C677T (30%+ population)
NTRPX ingredientsL-5-MTHF, Methylcobalamin, Adenosylcobalamin, P5P, R5P

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Domain 11: Membrane & Structural Integrity

Definition: Phospholipid composition, membrane fluidity, and structural support.
ComponentFunctionNTRPX Ingredients
PhosphatidylcholinePrimary membrane phospholipidCDP-Choline (provides choline + uridine)
PhosphatidylserineInner leaflet; signalingPhosphatidylserine
DHANeuronal membrane fluidity; 50%+ of brain PUFADHA (algal)
EPAAnti-inflammatory; membrane precursorEPA (algal)
CholesterolMembrane structure; myelin(Endogenous)

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Domain 12: Cellular Homeostasis (Autophagy & Repair)

Definition: Protein quality control, autophagy, DNA repair, and cellular maintenance.
ProcessDescriptionModulators
Autophagy”Self-eating” — degradation of damaged componentsAMPK activation, mTOR inhibition
MitophagySelective autophagy of damaged mitochondriaPINK1/Parkin pathway
DNA repairBase excision, nucleotide excision, double-strand break repairNAD+ (PARP substrate), Zinc
ProteostasisProtein folding, chaperones, proteasomeHeat shock proteins
NTRPX ingredientsNR (NAD+ for PARP), Zinc, Apigenin (autophagy modulation)

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Domain 13: HPA Axis & Stress Response

Definition: Hypothalamic-pituitary-adrenal axis function, cortisol regulation, and stress adaptation.
AspectDetails
Key hormonesCRH, ACTH, Cortisol
Diurnal rhythmCortisol peaks AM, lowest at midnight
Adaptogen mechanismsHSP70 induction, cortisol modulation, neurotransmitter balance
NTRPX ingredientsAshwagandha, Rhodiola/Salidroside, Phosphatidylserine, Cordyceps

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Domain 14: Circadian & Sleep Architecture

Definition: Sleep-wake cycle regulation, melatonin signaling, and core body temperature rhythm.
ProcessMechanismNTRPX Ingredients
Sleep onsetCore temp ↓, melatonin ↑Glycine (thermoregulation), Melatonin (0.3mg)
Sleep architectureNREM/REM cycling, slow-wave sleepMagnesium, Taurine, Apigenin
Clock genesCLOCK, BMAL1, PER, CRYLight exposure, feeding timing
Adenosine clearanceA2A receptor antagonism (wake-promoting)Paraxanthine, Caffeine
Note: Glycine’s mechanism involves NMDA receptors (Domain 5) but the outcome is circadian (sleep onset). Classification by PRIMARY functional impact.

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Domain 15: Vascular Function & Nitric Oxide (NEW)

Definition: Endothelial function, nitric oxide production, and blood flow regulation.
AspectDetails
Key enzymeEndothelial nitric oxide synthase (eNOS)
CofactorsBH4, NADPH, FAD, FMN
FunctionsVasodilation, blood pressure regulation, exercise performance, cognitive blood flow
NTRPX ingredientsL-Citrulline, L-5-MTHF (BH4 recycling), Cordyceps
Critical for Neuraldrink™ Sol: This domain captures the L-Citrulline mechanism that had no home in v1.0.

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Domain 16: Inflammatory Balance & Immune (NEW)

Definition: Pro-inflammatory vs. anti-inflammatory balance, cytokine modulation, and immune function.
ProcessPro-InflammatoryAnti-Inflammatory
CytokinesIL-1β, IL-6, TNF-αIL-10, TGF-β
Lipid mediatorsAA → Prostaglandins, LeukotrienesEPA/DHA → Resolvins, Protectins
PathwaysNF-κB activationNrf2 activation
NTRPX ingredients—DHA, EPA, Ashwagandha, Cordyceps
AspectDetails
ZincImmune cell function, wound healing
Omega-3sResolution of inflammation; specialized pro-resolving mediators
AdaptogensImmunomodulatory; cytokine balance

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v2.0 Domain Coverage Matrix

Rating Scale:
  • ★★★★★ = Primary target with maximum support (multiple ingredients, primary mechanism)
  • ★★★★ = Strong support (1-2 dedicated ingredients)
  • ★★★ = Moderate support (indirect or secondary mechanism)
  • ★★ = Mild support (tertiary effect)
  • ★ = Minimal support
  • — = Intentionally excluded (circadian appropriateness or not relevant)

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Complete Coverage Matrix (16 Domains × 7 Products)

DomainBoost™Sustain™Recover™Sol™Luna™ParaCaffeine +™Sprint™
I. NEUROTRANSMISSION
1. Cholinergic★★★★★★★★★——★★★★★★★
2. Catecholaminergic★★★★★★★—★★★—★★★★★★★★★
3. Serotonergic★★★★★★★★————
4. GABAergic—★★★★★★★—★★★★★——
5. Glutamatergic★★★★★★★—★★★★——
II. ENERGY METABOLISM
6. Mitochondrial★★★★★★★★★★★★★★★★★★★★★★
7. Bioenergetics (ATP)★★★★★★★★★★★★★★★★★★★★★★★★★★
8. NAD+ Metabolism★★★★★★★★★★—★★★—★★
9. Glucose Metabolism★★★★★★★★★★★★★★★★★★★★★★★
III. CELLULAR PROCESSES
10. Methylation★★★★★★★★★★★★★★★★★★★★★★
11. Membrane Integrity★★★★★★★★★★★★★★★★★★★
12. Cellular Homeostasis★★★★★★★★★★★★★★★★——
IV. REGULATORY SYSTEMS
13. HPA Axis★★★★★★★★★★★★★★★★★★★★
14. Circadian★★★★★★★★★★★★★★★★★★★★★★★
V. CARDIOVASCULAR
15. Vascular/NO★★★★★★★★★★★★★★★★★★
16. Inflammatory Balance★★★★★★★★★★★★★★——

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Domain-to-Ingredient Mapping

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Which Ingredients Target Which Domains?

IngredientPrimary Domain(s)Secondary Domain(s)
CDP-Choline1. Cholinergic, 11. Membrane10. Methylation
Alpha-GPC1. Cholinergic—
Huperzine A1. Cholinergic—
L-Tyrosine2. Catecholaminergic13. HPA Axis
Salidroside2. Catecholaminergic, 13. HPA6. Mitochondrial
Mucuna (L-DOPA)2. Catecholaminergic—
Paraxanthine2. Catecholaminergic, 14. Circadian7. Bioenergetics
Caffeine2. Catecholaminergic, 14. Circadian7. Bioenergetics
Saffron3. Serotonergic—
Bacopa3. Serotonergic, 1. Cholinergic12. Cellular Homeostasis
L-Theanine4. GABAergic, 5. Glutamatergic14. Circadian
Taurine4. GABAergic7. Bioenergetics
Apigenin4. GABAergic, 8. NAD+12. Cellular Homeostasis
Ashwagandha4. GABAergic, 13. HPA Axis16. Inflammatory
Magnesium4. GABAergic, 5. Glutamatergic7. Bioenergetics, 9. Glucose
Glycine5. Glutamatergic (NMDA co-agonist)14. Circadian, 10. Methylation
PQQ6. Mitochondrial (biogenesis)—
CoQ106. Mitochondrial (ETC)—
Cordyceps6. Mitochondrial, 15. Vascular13. HPA Axis
Creatine7. Bioenergetics6. Mitochondrial
NR (Niagen)8. NAD+12. Cellular Homeostasis
B-vitamins (complex)9. Glucose, 10. Methylation6. Mitochondrial
Chromium9. Glucose—
D-Glucose9. Glucose7. Bioenergetics
Phosphatidylserine11. Membrane13. HPA Axis
DHA11. Membrane16. Inflammatory
EPA11. Membrane, 16. Inflammatory15. Vascular
Lion’s Mane12. Cellular Homeostasis1. Cholinergic (NGF)
Zinc12. Cellular Homeostasis16. Inflammatory
L-Citrulline15. Vascular—
Melatonin14. Circadian—

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v1.0 → v2.0 Comparison

Aspectv1.0 (12 Domains)v2.0 (16 Domains)
Neurotransmission4 domains (Cholinergic, Dopaminergic, Serotonergic, GABAergic)5 domains (+Glutamatergic, combined DA+NE as Catecholaminergic)
Energy3 domains (Mitochondrial, ATP, NAD+)4 domains (+Glucose Metabolism)
Cellular2 domains (Methylation, Cellular Repair)3 domains (+Membrane Integrity separated)
Regulatory2 domains (HPA, Circadian)2 domains (unchanged)
Cardiovascular0 domains2 domains (Vascular/NO, Inflammatory)
Neuroprotection1 domain (outcome-based)Distributed across Cellular Homeostasis, Membrane, Inflammatory
Total1216

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Key Improvements

ImprovementRationale
Added GlutamatergicThe brain’s PRIMARY excitatory neurotransmitter was missing; glycine’s mechanism now has a home
Combined DA + NEShare biosynthetic pathway; cannot be cleanly separated at intervention level
Added Vascular/NOL-Citrulline, a core Neuraldrink™ ingredient, had no domain
Added InflammatoryOmega-3s, adaptogens affect this critical pathway
Added Glucose MetabolismBrain fuel system; central to Neuraldrink™
Separated Membrane IntegrityDistinct from other cellular processes; phospholipids warrant own domain
Removed “Neuroprotection”Outcome-based; mechanisms distributed to appropriate domains

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Scientific Justification Summary

MECE Design

Mutually Exclusive, Collectively Exhaustive Each ingredient maps to specific domains without ambiguity

Mechanistic

Pathway-Based Domains describe biological mechanisms, not desired outcomes

Supplement-Relevant

Actionable Every domain can be modulated by nutritional intervention

Consistent Granularity

Balanced Specificity All domains at similar level of abstraction

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Document Control

VersionDateAuthorChanges
2.02026-01-26NTRPX R&DComplete redesign with 16 scientifically-rigorous domains
The NTRPX Biological Domain System v2.0 provides a comprehensive, scientifically-appropriate classification that:
  • Captures ALL major pathways relevant to cognitive and metabolic optimization
  • Provides clear homes for every NTRPX ingredient
  • Maintains consistent granularity across all domains
  • Separates mechanisms from outcomes
  • Adds critical missing domains (Glutamatergic, Vascular/NO, Inflammatory, Glucose Metabolism)