L-Citrulline Evaluation for NTRPX
Executive Summary: L-Citrulline is a strong candidate for Neuraldrink™ inclusion. It provides cerebrovascular support that complements the existing cognitive ingredients (creatine), synergizes with taurine, and delivers meaningful cardiovascular benefits at a dose achievable in a drink format. Not recommended for All Systems Go capsules due to bulk requirements.
1. Ingredient Overview
What Is L-Citrulline?
L-Citrulline is a non-essential amino acid first isolated from watermelon (Citrullus lanatus). It serves as the most efficient oral precursor for L-Arginine and, subsequently, nitric oxide (NO) production.
Why Citrulline Over Arginine?
| Parameter | L-Citrulline | L-Arginine |
|---|
| Oral bioavailability | ~83% | ~20% |
| First-pass metabolism | Minimal (bypasses gut/liver arginase) | Extensive (degraded by intestinal/hepatic arginase) |
| Plasma arginine increase | 227% (at 3.8g) | 90% (at equivalent dose) |
| GI tolerance | Excellent | Dose-dependent GI distress |
| Duration of effect | Sustained (slow conversion) | Acute spike (rapid clearance) |
| Tmax for arginine | 1-2 hours | 30-60 minutes |
Link: PMC2291275
2. Mechanism of Action
Primary Pathway: NO Synthesis
L-Citrulline’s benefits derive from its role in the Nitric Oxide cycle:
- Absorption: L-Citrulline is absorbed intact in the intestine (no degradation by arginase)
- Renal Conversion: Kidneys convert L-Citrulline → L-Arginine via argininosuccinate synthase/lyase
- NO Production: Endothelial NOS (eNOS) converts L-Arginine → Nitric Oxide + L-Citrulline
- Recycling: The L-Citrulline byproduct is recycled back to L-Arginine (citrulline-NO cycle)
Cerebrovascular Mechanism
L-Citrulline crosses the blood-brain barrier (BBB) via the LAT1 (Large Amino Acid Transporter 1) system:
- LAT1 expression is 187-fold higher than alternative transporters in brain capillaries
- Brain conversion to L-Arginine supports neuronal NOS (nNOS) activity
- Enhanced NO in brain → improved neurovascular coupling → better oxygen/nutrient delivery
Citation: Lee KE, Kang YS. Characteristics of L-citrulline transport through blood-brain barrier in the brain capillary endothelial cell line (TR-BBB cells). J Biomed Sci. 2017;24(1):28.
Link: PMC5424428
3. Clinical Evidence
Cerebral Blood Flow & Cognitive Function
| Study | Model | Dose | Duration | Key Findings |
|---|
| Yabuki 2013 | Mouse (ischemia) | 50-100 mg/kg | 10 days | Prevented neuronal death, restored eNOS, improved memory |
| Lee & Kang 2017 | In vitro BBB | — | — | LAT1-mediated transport confirmed |
| Taekwondo athletes 2024 | Human RCT | 8.8g | 5 days | Improved cerebrovascular recovery (ΔBHI) post-exercise |
| Shafqat 2016 | Human (n=16) | 1.5g | 4 weeks | ↑ NO levels, ↓ pulse wave velocity, trend for ↓ mood disturbance |
Link: PubMed 23685189
| Meta-Analysis | Studies | N | SBP Change | DBP Change |
|---|
| Barkhidarian 2019 | 8 RCTs | ~200 | -4.1 mmHg (p=0.037) | -2.1 mmHg (≥6g/day: -2.75, p=0.04) |
| 2025 Meta (elderly) | 15 RCTs | 415 | -4.0 mmHg (p=0.002) | -2.5 mmHg (p=0.004) |
- Effects more pronounced at ≥6 weeks duration
- Lower doses (≤4g/day) still showed significant SBP reduction
- Pre-hypertensive/hypertensive populations show greater benefit
Citation: Barkhidarian B, et al. Effects of L-citrulline supplementation on blood pressure: A systematic review and meta-analysis. Avicenna J Phytomed. 2019;9(1):10-20.
Link: PMC6369322
| Study | Design | Dose | Duration | Key Findings |
|---|
| Suzuki 2016 | RCT, crossover | 2.4g/day | 7 days | Improved 4-km cycling time trial; ↑ plasma NOx |
| Bailey 2015 | RCT, crossover | 6g/day | 7 days | 12% ↑ severe exercise tolerance; faster VO2 kinetics |
| Rhim 2020 (Meta) | Meta-analysis | Various | Various | Significantly ↓ RPE and muscle soreness |
Link: Springer
NO Biomarkers (Pharmacodynamic Effects)
The Schwedhelm 2008 study demonstrated dose-dependent effects of L-Citrulline on NO signaling:
| Dose | L-Arginine/ADMA Ratio | Urinary Nitrate | Urinary cGMP |
|---|
| Placebo | 186 ± 8 (baseline) | 92 ± 10 | 38 ± 3.3 |
| L-Citrulline 3g BID | 278 ± 14 (p<0.01) | 125 ± 15 (p=0.01) | 50 ± 6.7 (p=0.04) |
4. Dose-Response Analysis
Minimum Effective Doses by Application
| Application | Minimum Dose | Optimal Dose | Evidence Level |
|---|
| Arginine elevation | 0.18g | 3g | Strong (doubles plasma Arg) |
| Vascular support (FMD) | 0.8g/day | 3g/day | Moderate (angina study) |
| Blood pressure (SBP) | 3g/day | 6g/day | Strong (meta-analyses) |
| Blood pressure (DBP) | 6g/day | 6g/day | Strong |
| Exercise performance | 2.4g/day | 6-8g/day | Moderate-Strong |
| Daily maintenance | 2-3g/day | 3g/day | Supported |
Key Pharmacokinetic Data
- Tmax (plasma citrulline): 0.5-1 hour
- Tmax (plasma arginine): 1-2 hours (delayed conversion)
- Plasma arginine elevation duration: 4-6 hours
- Steady-state benefits: Achieved within 7 days of daily dosing
5. Safety Profile
Adverse Events
L-Citrulline has an excellent safety profile:
| Parameter | Finding |
|---|
| LD50 | Not determinable (extremely low toxicity) |
| Maximum tested dose | 15g/day (no adverse effects) |
| GI tolerance | Superior to L-Arginine (no osmotic diarrhea) |
| Drug interactions | Caution with PDE5 inhibitors (additive hypotension) |
| Sleep effects | Minimal; morning dosing recommended for sensitive individuals |
Contraindications
- Active herpes infection: Theoretical concern (arginine may promote viral replication)
- Hypotension: May further lower blood pressure
- PDE5 inhibitor use: Additive vasodilation
- Pre-surgery: Discontinue 2 weeks prior (BP effects)
6. Synergy Analysis with NTRPX Ingredients
Neuraldrink™ Synergies
| Existing Ingredient | Synergy with L-Citrulline | Mechanism |
|---|
| Creatine | Strong | Both support cellular energy; citrulline improves nutrient delivery via ↑ blood flow |
| Taurine | Strong | Both support cardiovascular function; taurine is antioxidant for NO |
| Magnesium | Moderate | Mg is cofactor for NOS; citrulline provides substrate |
| Electrolytes (Na/K) | Supportive | Hydration + vasodilation improves fluid dynamics |
L-Citrulline + L-Arginine Synergy
Research shows combining citrulline with arginine produces greater effects than either alone:
| Treatment | Plasma Arginine at 1h |
|---|
| Placebo | +5.4 μM |
| L-Citrulline 2g | +66.3 μM |
| L-Arginine 2g | +72.3 μM |
| L-Citrulline 1g + L-Arginine 1g | +121.9 μM |
Link: Oxford Academic
Consideration: Could include small amount of L-Arginine (500mg-1g) in Neuraldrink to potentiate citrulline’s effects.
7. Product Placement Recommendation
Neuraldrink™ (RECOMMENDED)
Proposed Addition:
- Dose: 2,000 mg L-Citrulline per serving
- Form: L-Citrulline (not citrulline malate)
- Position: Add to “Metabolic Support” section
Rationale:
- ✓ Water-soluble: Dissolves well in drink format
- ✓ Bulky: 2g requires ~3-4 size 00 capsules (impractical for ASG)
- ✓ Timing-appropriate: Morning/afternoon aligns with Neuraldrink use
- ✓ Synergistic: Complements creatine, taurine, electrolytes
- ✓ Cognitive relevance: Supports cerebral blood flow (fits “neural” positioning)
- ✓ Cardiovascular benefit: Meaningful BP support at 2g/day
- ✓ Taste-neutral: No significant flavor impact
| Ingredient | Current | Proposed | Change |
|---|
| Creatine Monohydrate | 3,000 mg | 3,000 mg | — |
| Taurine | 1,000 mg | 1,000 mg | — |
| L-Citrulline | — | 2,000 mg | NEW |
| Vitamin C | 100 mg | 100 mg | — |
All Systems Go™ (NOT RECOMMENDED)
Why not include in ASG capsules:
- 2,000 mg = 3-4 additional capsules (excessive burden)
- Would require >15 total capsules daily
- Defeats purpose of streamlined capsule system
- Morning drink timing is appropriate for citrulline anyway
8. Comparison to Alternatives
L-Citrulline vs. Citrulline Malate
| Parameter | L-Citrulline | Citrulline Malate (2:1) |
|---|
| Citrulline content | 100% | ~56% (by weight) |
| Additional component | None | Malic acid (~44%) |
| Dose equivalence | 2g L-Citrulline | 3.5g Citrulline Malate |
| Additional benefits | None | Potential Krebs cycle support |
| Taste | Neutral | Slightly tart |
| Research base | Strong | Strong (often underdosed) |
- More precise dosing (100% active)
- Neutral taste (better for drink)
- Avoids need for larger powder volume
L-Citrulline vs. Beetroot/Nitrate
| Parameter | L-Citrulline | Beetroot Nitrate |
|---|
| Pathway | L-Arg → eNOS → NO | NO3⁻ → NO2⁻ → NO (bacteria) |
| Oxygen independence | No | Yes (works in hypoxia) |
| Consistency | High (standardized) | Variable (depends on oral bacteria) |
| Taste | Neutral | Earthy, strong |
| Color | None | Deep red (staining) |
9. Branded Ingredient Options
Kyowa Quality® L-Citrulline
- Manufacturer: Kyowa Hakko Bio (Japan)
- Form: L-Citrulline (not malate)
- Purity: ≥99%
- Production: Fermentation-derived
- Research: Multiple clinical trials using Kyowa material
- Status: GRAS affirmed, Non-GMO
Recommendation: Kyowa Quality® L-Citrulline is the gold standard with the most clinical validation.
Alternative: Citrulline HCl
Recent research (2025) suggests citrulline HCl may offer improved bioavailability:
- 2g citrulline HCl showed 226% relative arginine bioavailability vs. L-citrulline
- Faster Tmax (60 min vs. 120 min)
- Lower urinary excretion (better retention)
Consideration: Monitor citrulline HCl research; may become preferred form.
10. Summary Recommendation
✅ APPROVE for Neuraldrink™
| Criterion | Assessment |
|---|
| Efficacy evidence | Strong (meta-analyses, RCTs) |
| Mechanism relevance | High (cerebral + cardiovascular) |
| Safety profile | Excellent |
| Stack synergy | Strong (creatine, taurine) |
| Formulation fit | Ideal (water-soluble, bulky) |
| Cost-benefit | Favorable |
| Differentiation | Adds vascular support dimension |
Proposed Implementation
- Dose: 2,000 mg L-Citrulline per Neuraldrink serving
- Form: Kyowa Quality® L-Citrulline (fermentation-derived)
- Timing: Morning/afternoon with Neuraldrink (avoid evening)
- Label claim: “Supports healthy blood flow and cardiovascular function†”
- Marketing angle: “Cerebral circulation support” (ties to “Neural” branding)
Future Considerations
- Consider 2.5-3g dose if research supports greater benefits
- Monitor citrulline HCl bioavailability data
- Evaluate L-Citrulline + L-Arginine combination (1g + 1g) for enhanced acute effects
- Track emerging cognitive function RCTs for claim substantiation
References
-
Schwedhelm E, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine. Br J Clin Pharmacol. 2008;65(1):51-59. PMC2291275
-
Yabuki Y, et al. Oral L-citrulline administration improves memory deficits following transient brain ischemia. Brain Res. 2013;1520:157-167. PubMed 23685189
-
Lee KE, Kang YS. L-citrulline transport through blood-brain barrier. J Biomed Sci. 2017;24(1):28. PMC5424428
-
Barkhidarian B, et al. Effects of L-citrulline supplementation on blood pressure: Meta-analysis. Avicenna J Phytomed. 2019;9(1):10-20. PMC6369322
-
Bailey SJ, et al. L-Citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance. J Appl Physiol. 2015;119(4):385-395. PubMed 26023227
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Suzuki T, et al. Oral L-citrulline supplementation enhances cycling time trial performance. J Int Soc Sports Nutr. 2016;13:6. Springer
-
Morita M, et al. Combined oral L-citrulline and L-arginine supplementation effects on plasma L-arginine. Biosci Biotechnol Biochem. 2017;81(2):372-375. Oxford
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Rhim HC, et al. Effect of citrulline on post-exercise RPE, muscle soreness, and blood lactate: Meta-analysis. J Sport Health Sci. 2020;9(6):553-561. PMC7749242
Document Status: Under Review
Date: January 23, 2026
Recommendation: APPROVE for Neuraldrink™ at 2,000mg L-Citrulline
