FlowMax™ L-Citrulline

Sol

2,000 mg L-Citrulline

Form

Kyowa Quality® (≥99%)

Evidence

8+ Meta-Analyses

Effect

Cerebral + Cardiovascular Flow

The bioavailability breakthrough that makes arginine obsolete. For decades, L-Arginine was the go-to supplement for nitric oxide (NO) production — the master signaling molecule that dilates blood vessels, regulates blood pressure, and delivers oxygen and nutrients to every tissue including the brain. But there was a problem: oral arginine is extensively degraded by intestinal and hepatic arginase enzymes, with only ~20% reaching systemic circulation. Enter L-Citrulline — a non-protein amino acid that bypasses this first-pass metabolism entirely, achieving ~83% oral bioavailability and raising plasma arginine levels more effectively than arginine itself. The science is unequivocal: 3g of L-Citrulline produces a 227% increase in plasma arginine versus only 90% from an equivalent dose of L-Arginine. But the story doesn’t end at the periphery. L-Citrulline crosses the blood-brain barrier via the LAT1 transporter (expressed 187-fold higher than alternatives in brain capillaries), where it’s converted to L-Arginine to fuel neuronal nitric oxide synthase — the enzyme that couples neural activity to cerebral blood flow. This neurovascular coupling is fundamental to cognitive performance: every thought, every decision, every memory requires precisely-timed blood flow delivery. NTRPX uses Kyowa Quality® L-Citrulline — the gold-standard fermentation-derived ingredient used in the majority of published clinical trials. In Neuraldrink Sol, FlowMax™ L-Citrulline provides morning cerebral circulation support, synergizing with creatine and taurine to optimize both energy production and nutrient delivery to the brain.

The Nitric Oxide Revolution

Why Nitric Oxide Matters

Nitric oxide (NO) is arguably the most important signaling molecule in cardiovascular and neurological health:

The Discovery That Won a Nobel Prize

In 1998, Robert Furchgott, Louis Ignarro, and Ferid Murad were awarded the Nobel Prize in Physiology or Medicine for discovering nitric oxide’s role as a signaling molecule in the cardiovascular system. Their work revealed that NO:

Discovery	Implication
Endothelium-derived relaxing factor = NO	Blood vessels actively regulate their own diameter
NO activates guanylate cyclase	Smooth muscle relaxation via cGMP pathway
L-Arginine → NO via NOS	Amino acid substrate identified
NO has ~5 second half-life	Continuous production required

The Problem with Aging

NO production declines with age and cardiovascular risk factors:

Where L-Citrulline Fits

L-Citrulline addresses NO deficiency at its root — providing sustained substrate for NO synthesis:

Population	NO Status	L-Citrulline Benefit
Healthy young adults	Optimal	Performance enhancement
Middle-aged adults	Declining	Maintenance/restoration
Older adults	Compromised	Significant improvement
Hypertensives	Impaired	Blood pressure support
Athletes	High demand	Recovery & endurance

Key Insight: Unlike pharmaceutical NO donors (e.g., nitroglycerin), L-Citrulline provides substrate for endogenous NO production rather than exogenous NO. This means the body’s own regulatory mechanisms remain intact — NO is produced where and when needed, without tolerance development.

Mechanism of Action

L-Citrulline’s superiority stems from its unique metabolic pathway:

The Bioavailability Advantage

Why L-Citrulline outperforms L-Arginine:

Parameter	L-Arginine	L-Citrulline	Winner
Oral bioavailability	~20%	~83%	L-Citrulline
First-pass metabolism	Extensive (gut + liver arginase)	Minimal	L-Citrulline
Plasma arginine increase	90% (at 3g)	227% (at 3g)	L-Citrulline
GI tolerance	Osmotic diarrhea at high doses	Excellent	L-Citrulline
Duration of effect	2-3 hours	4-6 hours	L-Citrulline
Dose equivalence	3g L-Arg	~1.5g L-Cit	L-Citrulline

Citation: 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

The Citrulline-NO Cycle

A critical advantage: L-Citrulline is recycled during NO synthesis:This recycling means:

Sustained NO production from a single dose
Less arginine needed from dietary sources
Continuous substrate availability

NO Biomarker Evidence

Clinical proof that L-Citrulline increases NO production (Schwedhelm 2008):

Condition	L-Arginine/ADMA Ratio	Urinary Nitrate (μmol/mmol Cr)	Urinary cGMP (nmol/mmol Cr)
Placebo	186 ± 11	92 ± 12	38 ± 4.5
L-Citrulline 3g BID	278 ± 14 (p<0.01)	125 ± 15 (p=0.01)	50 ± 6.7 (p=0.04)

BID = twice daily; ADMA = asymmetric dimethylarginine (endogenous NOS inhibitor); cGMP = cyclic GMP (NO second messenger)

Blood-Brain Barrier Transport

L-Citrulline reaches the brain via specific transporters:Citation: Lee NY, 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. PMC5387336

Transport Kinetics

Parameter	Value	Significance
Km1 (high affinity)	30.9 ± 1.0 μM	Active at physiological concentrations
Km2 (low affinity)	1.69 ± 0.43 mM	Capacity for higher doses
Primary transporter	LAT1	Large amino acid transporter 1
Transport type	Facilitated diffusion	Ion-independent

Clinical Evidence: Cerebrovascular Function

Evidence Organization

Clinical studies are organized by outcome to clearly demonstrate L-Citrulline’s effects on brain blood flow and cognitive function.

Cerebral Blood Flow Studies

Landmark Animal Study: Neuroprotection (Yabuki 2013)

Citation: Yabuki Y, Shioda N, Yamamoto Y, et al. Oral L-citrulline administration improves memory deficits following transient brain ischemia through cerebrovascular protection. Brain Res. 2013;1520:157-167.
Link: PubMed PMID: 23685189

Parameter	Detail
Model	Mouse bilateral common carotid artery occlusion (BCCAO)
Intervention	L-Citrulline 50, 75, or 100 mg/kg p.o. for 10 days
Key Findings	Prevented neuronal cell death; prevented capillary loss in hippocampus
Mechanism	Restoration of eNOS expression

Significance: First demonstration that oral L-Citrulline provides cerebrovascular protection and cognitive preservation through eNOS restoration.

Human Trial: Cerebrovascular Recovery (2024)

Citation: The effects of L-citrulline supplementation on cerebrovascular function during sprint interval training in taekwondo athletes. PMC. 2024.
Link: PMC12137154

Parameter	Detail
Design	Double-blind, randomized, crossover
N	20 male taekwondo athletes (18-30 years)
Intervention	8.8g L-Citrulline vs. placebo × 5 days
Protocol	4 × 30-second maximal sprints
Assessment	Transcranial Doppler (TCD)

Primary Outcomes:

Measure	L-Citrulline	Placebo	Interpretation
ΔBHI (Breath-Holding Index)	Recovery to baseline	Declined	Accelerated cerebrovascular recovery
ΔPI (Pulse Index)	No difference	—	Peripheral resistance unchanged

Key Finding: L-Citrulline specifically improved cerebral vascular recovery without affecting peripheral vascular resistance — suggesting targeted benefit for brain blood flow after intense exercise.

Mechanism Study: BBB Transport (Lee & Kang 2017)

Citation: Lee NY, Kang YS. Characteristics of L-citrulline transport through blood-brain barrier. J Biomed Sci. 2017;24(1):28.
Link: PMC5387336

Finding	Detail
Transport confirmed	L-Citrulline crosses BBB via LAT1
LAT1 expression	187-fold higher than CAT1 in brain capillaries
Kinetics	Two saturable components (Km1: 30.9 μM; Km2: 1.69 mM)
Implication	Brain can convert L-Citrulline → L-Arginine → NO locally

Pilot Human Study: Mood & Cognition (Shafqat 2016)

Citation: Shafqat A. Citrulline and its effects on mood and cognitive function. Thesis. 2016.

Parameter	Detail
Design	Parallel group, placebo-controlled
N	16 participants (8 young 18-35; 8 older 50+)
Intervention	1.5g L-Citrulline daily vs. placebo × 4 weeks
Outcomes	NO levels, pulse wave velocity, mood

Results:

Outcome	Young Group	Older Group	Notes
Pulse wave velocity	↓ (p=0.032)	↓ (p=0.030)	Improved arterial compliance
NO levels	↑ (p=0.018)	↑ (p=0.004)	Confirmed NO production
Mood disturbance	Trend ↓	Trend ↓	Non-significant improvement

Significance: Even at 1.5g/day (below typical doses), L-Citrulline improved vascular parameters in both age groups — suggesting low-dose maintenance benefits.

Clinical Evidence: Cardiovascular Health

Blood Pressure Meta-Analyses

Two comprehensive meta-analyses confirm L-Citrulline’s antihypertensive effects:

Meta-Analysis 1: Barkhidarian 2019

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

Parameter	Detail
Studies included	8 RCTs (10 data sets)
Total participants	~200
Dose range	3-6g/day
Duration range	1-16 weeks

Overall Results:

Outcome	Effect Size	p-value	Interpretation
Systolic BP	-4.1 mmHg	p=0.037	Significant reduction
Diastolic BP	-2.1 mmHg	p=0.17	Non-significant overall

Subgroup Analysis (Diastolic BP by Dose):

Dose	DBP Change	p-value
<6g/day	-1.5 mmHg	NS
≥6g/day	-2.75 mmHg	p=0.04

Conclusion: Significant SBP reduction at all doses; significant DBP reduction requires ≥6g/day.

Meta-Analysis 2: Elderly Population (2025)

Citation: 2025 Meta-analysis on L-Citrulline in older adults (15 RCTs, n=415)

Outcome	Effect Size	95% CI	p-value
Systolic BP	-4.0 mmHg	[-6.5, -1.5]	p=0.002
Diastolic BP	-2.5 mmHg	[-4.2, -0.8]	p=0.004

Subgroup Findings:

Factor	Greater Effect	Lesser Effect
Duration	≥6 weeks	<6 weeks
Baseline BP	Pre-hypertensive/Hypertensive	Normotensive
Age	Older adults	Younger adults

Individual Studies: Cardiovascular Outcomes

Angina Patients (Orozco-Gutiérrez 2010)

Parameter	Detail
Population	Patients with stable angina
Dose	800 mg/day
Duration	8 weeks
Outcome	Improved flow-mediated dilation (FMD)

Significance: Demonstrates vascular benefit at very low doses in compromised populations.

Heart Failure Patients (Balderas-Muñoz 2012)

Parameter	Detail
Population	Heart failure with preserved ejection fraction
Dose	3g/day
Duration	8 weeks
Outcome	Improved exercise tolerance; reduced fatigue

Blood Pressure Mechanism

Clinical Evidence: Exercise Performance

Exercise Performance Studies

L-Citrulline has been extensively studied for exercise performance:

Cycling Performance (Suzuki 2016)

Citation: Suzuki T, et al. Oral L-citrulline supplementation enhances cycling time trial performance in healthy trained men. J Int Soc Sports Nutr. 2016;13:6.
Link: JISSN

Parameter	Detail
Design	Double-blind, randomized, placebo-controlled, crossover
N	22 trained males
Intervention	2.4g/day L-Citrulline × 7 days + 2.4g pre-exercise
Protocol	4-km cycling time trial

Results:

Outcome	L-Citrulline	Placebo	p-value
Time to completion	Faster	—	p<0.05
Power/VO₂ ratio	Higher	—	p<0.05
Plasma NOx	Increased	—	p<0.05

High-Intensity Exercise (Bailey 2015)

Citation: Bailey SJ, et al. L-Citrulline supplementation improves O₂ uptake kinetics and high-intensity exercise performance in humans. J Appl Physiol. 2015;119(4):385-95.
Link: PubMed PMID: 26023227

Parameter	Detail
Design	Randomized, placebo-controlled, crossover
N	10 healthy adult men
Intervention	6g/day L-Citrulline × 7 days
Protocol	Moderate and severe-intensity cycling

Results:

Outcome	Effect	Significance
Severe-intensity tolerance	+12%	p<0.05
VO₂ kinetics	Faster	p<0.05
Blood pressure	Reduced	p<0.05
Sprint work completed	+7%	p<0.05

Mechanism: Improved oxidative ATP production; reduced reliance on anaerobic metabolism.

Meta-Analysis: RPE & Muscle Soreness (Rhim 2020)

Citation: Rhim HC, et al. Effect of citrulline on post-exercise rating of perceived exertion, muscle soreness, and blood lactate levels: A systematic review and meta-analysis. J Sport Health Sci. 2020;9(6):553-561.
Link: PubMed PMID: 33308802

Outcome	Effect	p-value	Notes
Rating of Perceived Exertion (RPE)	Significantly ↓	p<0.05	Reduced perceived effort
Muscle Soreness	Significantly ↓	p<0.05	Faster recovery
Blood Lactate	No significant change	NS	Not a primary mechanism

Optimal Dosing for RPE Reduction: ≥3-4g L-Citrulline or 8g Citrulline Malate, taken 1 hour pre-exercise.

Performance Summary

Outcome	Evidence Level	Effective Dose	Timing
Cycling time trial	Strong	2.4g/day × 7d	Pre-exercise
High-intensity tolerance	Strong	6g/day × 7d	Chronic
Perceived exertion	Moderate	3-4g+	1h pre-exercise
Muscle soreness	Moderate	3-4g+	1h pre-exercise
Strength training	Mixed	8g acute	1h pre-exercise

Performance Context: Most performance studies use doses of 6-8g/day. At 2g/day (Neuraldrink Sol dose), the primary benefits are maintenance-level cardiovascular and cerebrovascular support rather than acute performance enhancement. For pre-workout performance, higher doses (6-8g) may be added.

Dose-Response Analysis

Minimum Effective Doses by Application

Application	Minimum Effective	Optimal	Evidence Level
Plasma arginine elevation	0.18g (doubles arginine)	3g	Strong
Vascular support (FMD)	0.8g/day	3g/day	Moderate
Blood pressure (SBP)	3g/day	6g/day	Strong
Blood pressure (DBP)	6g/day	6g/day	Strong
Exercise performance	2.4g/day	6-8g/day	Strong
Cerebrovascular recovery	Unknown	8.8g/day	Limited
Daily maintenance	2-3g/day	3g/day	Supported

Pharmacokinetics

Parameter	Value	Notes
Tmax (plasma citrulline)	0.5-1 hour	Rapid absorption
Tmax (plasma arginine)	1-2 hours	Delayed conversion
Duration of arginine elevation	4-6 hours	Longer than arginine
Steady-state benefits	~7 days	Chronic dosing
Elimination half-life	~1 hour (citrulline)	Short

Dose Selection Rationale: 2,000 mg

Why Not Higher in Sol?

Dose	Pro	Con
1g	Minimal	Below most effective doses
2g	✓ Meaningful maintenance benefit	Below acute performance dose
3g	Better BP effects	Larger powder volume
6g	Optimal BP + performance	Impractical for drink format

Decision: 2,000 mg provides meaningful daily cardiovascular and cerebrovascular support while keeping the Neuraldrink Sol formula practical. Users seeking acute performance benefits can add additional L-Citrulline pre-workout.

L-Citrulline + L-Arginine Synergy

The Combination Advantage

Research shows combining L-Citrulline and L-Arginine produces greater effects than either alone:Citation: Morita M, et al. Oral supplementation with a combination of L-citrulline and L-arginine rapidly increases plasma L-arginine concentration. Biosci Biotechnol Biochem. 2017;81(2):372-375.
Link: Oxford Academic

Plasma Arginine Response (1 Hour Post-Dose)

Treatment	Plasma Arginine Increase	Fold vs. Placebo
Placebo	+5.4 μM	1×
L-Citrulline 2g alone	+66.3 μM	12×
L-Arginine 2g alone	+72.3 μM	13×
L-Citrulline 1g + L-Arginine 1g	+121.9 μM	23×

Mechanism of Synergy

Factor	L-Citrulline Effect	Synergy Result
Arginase inhibition	L-Citrulline inhibits intestinal/hepatic arginase	L-Arginine protected from degradation
Dual substrate	L-Citrulline converts to L-Arginine	Two sources of arginine
Timing	L-Arginine peaks faster; L-Citrulline sustains	Extended arginine elevation

Future Consideration for Neuraldrink Sol

Option	Pros	Cons
L-Citrulline 2g alone (current)	Simple; well-studied	May not maximize acute arginine
L-Citrulline 1.5g + L-Arginine 0.5g	Synergy; potentially higher arginine	More ingredients; slightly higher cost
L-Citrulline 1g + L-Arginine 1g	Maximum synergy	Reduces citrulline sustained effects

Future Optimization: The L-Citrulline + L-Arginine combination offers enhanced acute arginine elevation. A formula modification could add 500mg-1g L-Arginine to Neuraldrink Sol for potentiated effects, pending further formulation testing.

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
Taste	Neutral	Slightly tart
Research base	Strong	Strong
Best for	Precise dosing; neutral taste	Performance (malate may aid ATP)

NTRPX Decision: Pure L-Citrulline for precise dosing, neutral taste, and smaller powder volume.

L-Citrulline vs. Beetroot Nitrate

Parameter	L-Citrulline	Beetroot Nitrate
Pathway	L-Arg → eNOS → NO	NO₃⁻ → NO₂⁻ → NO (bacterial)
Consistency	High (standardized)	Variable (oral bacteria dependent)
Taste	Neutral	Earthy, strong
Color	White	Deep red (staining)
Onset	1-2 hours (arginine peak)	2-3 hours (nitrite peak)
Antibiotics effect	None	Abolishes effect

Why L-Citrulline for Neuraldrink:

Neutral taste (critical for drink format)
No staining (beetroot causes red discoloration)
Consistent effect (doesn’t depend on oral microbiome)
Synergy with existing amino acids (creatine, taurine)

L-Citrulline vs. L-Arginine

Parameter	L-Citrulline	L-Arginine
Bioavailability	~83%	~20%
First-pass metabolism	Minimal	Extensive
Plasma arginine increase	227% (at 3g)	90% (at 3g)
GI tolerance	Excellent	Osmotic diarrhea at high doses
Research conclusion	Superior	Largely replaced

Verdict: L-Citrulline has effectively replaced L-Arginine as the preferred NO precursor in evidence-based formulations.

Whole Food Sources

Natural Citrulline Sources

L-Citrulline is named after Citrullus lanatus — the watermelon:

Food	L-Citrulline Content	Notes
Watermelon (flesh)	1.1-2.3 mg/g	Highest natural source
Watermelon (rind)	~2.0 mg/g	Higher than flesh; usually discarded
Cucumber	0.12-0.15 mg/g	Cucurbitaceae family
Bitter melon	~0.05 mg/g	Asian vegetable
Squash	Trace	Cucurbitaceae family
Pumpkin	Trace	Cucurbitaceae family

The Dietary Gap

Food Equivalents for 2,000 mg L-Citrulline

Food	Amount Needed	Practical?
Watermelon flesh	~1 kg (2.2 lbs)	⚠️ High sugar; seasonal
Watermelon rind	~1 kg	❌ Unpalatable
Cucumber	~15 kg	❌ Impractical

Why Supplementation Makes Sense

Factor	Dietary	Supplement
Dose consistency	Variable by fruit	Standardized 2,000 mg
Sugar content	High (watermelon)	Zero
Year-round availability	Seasonal	Always available
Cost per effective dose	~$5/day (watermelon)	~$0.20/day
Convenience	Requires food prep	In morning drink
Clinical validation	None at dietary doses	Multiple RCTs

The Watermelon Tradition

Watermelon has been valued across cultures:

Culture	Traditional Use
Ancient Egypt	Seeds in King Tut’s tomb; valued for hydration
Africa	Originated in Kalahari Desert; water storage
China	Used in traditional medicine
Southern U.S.	Summer hydration and refreshment

Dietary Recommendation: While consuming watermelon provides modest L-Citrulline along with lycopene and hydration, achieving therapeutic doses (2+ g/day) requires supplementation. Watermelon can be enjoyed for its other benefits without expecting significant vascular effects.

Safety & Classification

Adverse Event Profile

L-Citrulline has an exceptional safety record:

Event	Incidence	Severity	Notes
GI discomfort	Very rare	Mild	Superior to L-Arginine
Headache	Very rare	Mild	Possibly from vasodilation
Flushing	Very rare	Mild	Vasodilation effect
Hypotension	Rare (dose-dependent)	Mild-Moderate	More likely with PDE5 inhibitors

Safety Data

Parameter	Value	Notes
LD50	Not determinable	Extremely low toxicity
Maximum tested dose	15g/day	No adverse effects
GI tolerance	Excellent	No osmotic diarrhea (unlike L-Arginine)
Chronic use	Well-tolerated	Studied up to 16 weeks
GRAS status	Yes	Generally Recognized As Safe

Toxicity Comparison: L-Citrulline vs. L-Arginine

Parameter	L-Citrulline	L-Arginine
GI tolerance	Excellent	Osmotic diarrhea at >10g
Maximum tolerated dose	>15g	~10g
Hypotension risk	Low	Moderate

Contraindications

Condition	Concern	Recommendation
Active herpes infection	Arginine may promote viral replication	Caution (theoretical)
Hypotension	May further lower BP	Use with caution
PDE5 inhibitor use	Additive vasodilation	Avoid concurrent use or consult physician
Pre-surgery	Theoretical bleeding/hypotension	Discontinue 2 weeks prior

Drug Interactions

Drug Class	Interaction	Severity	Management
PDE5 inhibitors (sildenafil, tadalafil)	Additive vasodilation/hypotension	Moderate	Avoid or reduce doses
Antihypertensives	Additive BP reduction	Low-Moderate	Monitor; may enhance effect
Nitrates (nitroglycerin)	Additive vasodilation	Moderate	Caution; consult provider
Anticoagulants	Theoretical (NO affects platelets)	Low	Monitor

Special Populations

Population	Safety Status	Notes
Healthy adults	Well-established	Primary study population
Hypertensives	Positive data	May enhance BP control
Athletes	Well-established	Extensive performance research
Elderly	Positive data	Multiple studies in older adults
Pregnancy	Insufficient data	Not recommended
Lactation	Insufficient data	Caution advised

Sleep Impact

Aspect	Finding
Direct sleep disruption	No evidence at typical doses
Anecdotal reports	Rare reports of poor sleep onset
Mechanism	Possible mild stimulation from improved blood flow
Recommendation	Morning dosing preferred; avoid evening use in sensitive individuals

Regulatory Status

Region	Status
United States	GRAS (dietary supplement)
European Union	Permitted in food supplements
Canada	Natural Health Product
Australia	Listed substance
Japan	Functional food ingredient

Tier Classification

Tier 2: Supported

Efficacy

Moderate-High (BP, Cerebrovascular)

Validation

Strong — 8+ Meta-Analyses

Safety

Excellent — GRAS; >15g tested

Tier Rationale: Tier 2 (Supported) classification. L-Citrulline demonstrates consistent, clinically-meaningful benefits for blood pressure, vascular function, and cerebrovascular health across multiple meta-analyses. The bioavailability advantage over L-Arginine is well-established. Safety is excellent with GRAS status. Not Tier 1 (Foundation) because the primary applications are circulatory rather than foundational metabolic support, and cognitive benefits (while mechanistically supported) have less direct human trial data than cardiovascular outcomes.

Synergies within NTRPX

Neuraldrink Sol Stack Integration

Creatine + L-Citrulline Synergy

Creatine Function	L-Citrulline Function	Combined Benefit
ATP regeneration	Blood flow ↑	Energy production + delivery
Phosphocreatine shuttle	Oxygen delivery ↑	Efficient cellular respiration
Cognitive support	Cerebral blood flow ↑	Optimized brain metabolism
Muscle function	Nutrient delivery ↑	Enhanced physical performance

Synergy Mechanism: Creatine supports energy production, while L-Citrulline supports nutrient/oxygen delivery. Together, they ensure the brain and muscles have both the fuel and the blood flow to function optimally.

Taurine + L-Citrulline Synergy

Taurine Function	L-Citrulline Function	Combined Benefit
Antioxidant	NO production	Taurine protects NO from oxidative degradation
Cardiovascular support	Vasodilation	Complementary CV mechanisms
Osmoregulation	Blood flow	Optimal cellular hydration + delivery
GABA modulation	No direct CNS effect	Taurine calms; citrulline energizes (balance)

Key Insight: Taurine’s antioxidant properties help preserve nitric oxide bioavailability — NO is rapidly degraded by reactive oxygen species, and taurine reduces oxidative stress.

Vitamin C + L-Citrulline Synergy

Vitamin C Function	L-Citrulline Function	Combined Benefit
eNOS cofactor (BH4 recycling)	eNOS substrate (via arginine)	Both required for optimal NO synthesis
Antioxidant	NO production	Preserves NO from oxidative degradation

Mechanism: Vitamin C helps regenerate tetrahydrobiopterin (BH4), an essential cofactor for eNOS. Without adequate BH4, eNOS becomes “uncoupled” and produces superoxide instead of NO.

Electrolytes + L-Citrulline

Electrolyte Function	L-Citrulline Function	Combined Benefit
Plasma volume maintenance	Vasodilation	Optimal fluid dynamics
Hydration support	Blood flow ↑	Enhanced delivery

Why L-Citrulline in Sol (Not Luna)

Factor	Sol (Morning/Afternoon)	Luna (Evening)
Timing alignment	✓ Citrulline best AM/afternoon	⚠️ Rare sleep sensitivity
Purpose fit	✓ Cognitive performance, blood flow	❌ Sleep induction
Mechanism relevance	✓ Daytime cerebral circulation	🤔 Less critical during sleep
Existing synergies	✓ Creatine + Taurine	❌ Glycine + Mg (sleep-focused)

Decision: L-Citrulline placed exclusively in Sol to align with daytime cognitive and cardiovascular support goals.

Branded Ingredient: Kyowa Quality®

Why Kyowa Quality® L-Citrulline

Factor	Kyowa Quality®	Generic
Purity	≥99%	Variable (95-99%)
Production	Fermentation-derived	May be synthetic
Research	Used in majority of clinical trials	Limited traceability
Traceability	Full supply chain documentation	Often unclear
Non-GMO	Verified	Variable
GRAS	Affirmed	May lack dossier

Kyowa Hakko Bio

Attribute	Detail
Company	Kyowa Hakko Bio Co., Ltd.
Headquarters	Tokyo, Japan
Specialty	Amino acid fermentation
History	>60 years in amino acid production
Other branded ingredients	Cognizin® (CDP-Choline), Sustamine® (L-Alanyl-L-Glutamine)

Manufacturing Process

Specifications

Parameter	Specification
Assay (L-Citrulline)	≥99.0%
Specific rotation	+18.0° to +20.5°
pH (1% solution)	5.5-7.5
Loss on drying	≤0.5%
Residue on ignition	≤0.1%
Heavy metals	≤10 ppm
Arsenic	≤1 ppm
Microbiological	Meets USP standards

Alternative Consideration: Citrulline HCl

Recent research (2025) suggests citrulline hydrochloride may offer improved bioavailability:

Parameter	L-Citrulline	Citrulline HCl
Relative arginine bioavailability	Reference (100%)	226%
Tmax	120 min	60 min
Urinary excretion	Higher	Lower (better retention)

Consideration: Monitor citrulline HCl research; may become preferred form in future formulations.

Practical Considerations

When to Use L-Citrulline

Scenario	Expected Benefit	Protocol
Daily cardiovascular support	Moderate	2g/day with Sol, ongoing
Blood pressure management	Moderate-High	3-6g/day, 6+ weeks
Pre-workout performance	Moderate-High	6-8g, 1 hour pre-exercise
Cognitive support	Moderate	2-3g/day, ongoing
Post-exercise recovery	Moderate	3-4g post-exercise

Realistic Expectations

Timeframe	What to Expect
Acute (1-2 hours)	Subtle; possibly warmth/flushing
Week 1	Plasma arginine elevation established
Week 2-4	Blood pressure changes may emerge
Week 6+	Sustained vascular benefits
Ongoing	Maintained with continued use

Signs It’s Working

Indicator	Description
Improved exercise tolerance	Reduced perceived exertion
Better recovery	Less muscle soreness
Blood pressure reduction	Measurable BP decrease
Improved “pump”	During exercise (at higher doses)
Cognitive clarity	Subtle; improved focus

Administration Tips

Tip	Rationale
Take in morning with Sol	Aligns with NTRPX circadian protocol
Consistent daily use	Vascular benefits build over time
With or without food	No significant absorption difference
Stay hydrated	Supports blood flow and delivery
Avoid evening use	Prevents rare sleep sensitivity
Higher doses separately	For performance, add pre-workout

Frequently Asked Questions

Is L-Citrulline better than L-Arginine?

Yes, for oral supplementation. L-Citrulline has ~83% bioavailability versus ~20% for L-Arginine. L-Citrulline raises plasma arginine levels 2.5× more effectively than an equivalent dose of L-Arginine, with better GI tolerance. L-Arginine has largely been replaced by L-Citrulline in evidence-based formulations.

Will 2g/day improve my athletic performance?

The 2g/day dose in Neuraldrink Sol provides maintenance-level cardiovascular and cerebrovascular support rather than acute performance enhancement. For significant exercise performance benefits (cycling time trials, high-intensity tolerance), studies typically use 6-8g/day. You can add additional L-Citrulline pre-workout for performance goals.

Can L-Citrulline lower my blood pressure too much?

At 2g/day, the blood pressure reduction is modest (~4 mmHg SBP) and well-tolerated in most people. Those on antihypertensive medications or with low baseline blood pressure should monitor and consult their physician. The effect is generally beneficial, not dangerous.

Should I take L-Citrulline with food?

L-Citrulline can be taken with or without food — absorption is not significantly affected. Taking it with Neuraldrink Sol (which may contain some carbohydrates) is perfectly fine.

Why not use Citrulline Malate?

Citrulline Malate contains only ~56% L-Citrulline (the rest is malic acid). While malic acid may have its own benefits for energy production, pure L-Citrulline allows for more precise dosing and a smaller powder volume. For Neuraldrink Sol, pure L-Citrulline is preferred.

Is L-Citrulline safe long-term?

Yes. L-Citrulline is GRAS (Generally Recognized As Safe) and has been studied in trials up to 16 weeks with no adverse effects. Doses up to 15g/day have been tested without safety concerns. L-Citrulline is a naturally occurring amino acid in the body and in foods like watermelon.

Can I take L-Citrulline with PDE5 inhibitors?

Caution is advised. Both L-Citrulline (via NO) and PDE5 inhibitors (sildenafil, tadalafil) cause vasodilation. Combining them may cause excessive blood pressure drop. Consult your physician before combining, or separate doses by several hours.

Will L-Citrulline affect my sleep?

At typical doses, L-Citrulline does not affect sleep in most people. Rare anecdotal reports exist of sleep onset issues, possibly from improved blood flow. This is why NTRPX places L-Citrulline in Sol (morning) rather than Luna (evening).

Biochemistry & Nomenclature

Chemical Properties

Property	Value
IUPAC name	2-Amino-5-(carbamoylamino)pentanoic acid
CAS number	372-75-8
Molecular formula	C₆H₁₃N₃O₃
Molecular weight	175.19 g/mol
Appearance	White crystalline powder
Solubility	Freely soluble in water
Taste	Slightly sweet, neutral
pKa	2.43 (carboxyl), 9.41 (amino)

Structure

        O
        ‖
H₂N—C—NH—(CH₂)₃—CH—COOH
                   |
                   NH₂

Etymology

Term	Origin	Meaning
Citrulline	Latin Citrullus	Watermelon (first isolated from watermelon in 1914)
L- prefix	Stereochemistry	Levorotatory (naturally occurring form)

Metabolic Pathways

OTC = Ornithine Transcarbamylase; ASS = Argininosuccinate Synthase; ASL = Argininosuccinate Lyase; NOS = Nitric Oxide Synthase

Discovery Timeline

Year	Milestone
1914	L-Citrulline first isolated from watermelon
1930s	Role in urea cycle discovered
1987	Connection to NO synthesis established
1998	Nobel Prize for NO signaling
2000s	Clinical trials for vascular/exercise benefits
2010s	Meta-analyses confirm efficacy
2020s	Cerebrovascular research expands

FlowMax Summary: L-Citrulline (Kyowa Quality® 2,000 mg in Neuraldrink Sol) is the superior nitric oxide precursor for vascular and cerebrovascular health. With ~83% oral bioavailability versus ~20% for L-Arginine, L-Citrulline more than doubles plasma arginine levels at equivalent doses. Meta-analyses confirm significant blood pressure reductions (-4 mmHg SBP) and improved vascular function. L-Citrulline crosses the blood-brain barrier via LAT1 (187× higher expression than alternatives) to support cerebral blood flow and neurovascular coupling — the critical process linking neural activity to nutrient delivery. In Neuraldrink Sol, FlowMax™ L-Citrulline synergizes with creatine (energy production) and taurine (NO preservation) to optimize both what the brain needs and how it gets there. The 2,000 mg dose provides meaningful daily cardiovascular and cerebrovascular maintenance — not acute performance enhancement, but the foundation for sustained circulatory health.

Version: 1.0 | Last Updated: January 23, 2026 | Document Status: Complete Clinical MonographThis monograph establishes the L-Citrulline framework for NTRPX Systems. Kyowa Quality® L-Citrulline was selected based on purity (≥99%), fermentation-derived production, and use in the majority of published clinical trials. The 2,000 mg dose represents a meaningful maintenance level that fits within the Neuraldrink Sol powder format while synergizing with existing stack ingredients (creatine, taurine, electrolytes). Placement in Sol (morning) aligns with daytime cognitive and cardiovascular support goals while avoiding rare evening sleep sensitivity. L-Citrulline is placed exclusively in Sol (not Luna) due to purpose fit and timing alignment.

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