Citrulline | Supplementopedia

Overview

Citrulline is a non‑essential, water‑soluble amino acid that is not incorporated into proteins but serves as a key intermediate in the urea cycle and nitric‑oxide (NO) production pathway. In dietary‑supplement form it is primarily used to boost endogenous arginine levels, thereby enhancing NO‑mediated vasodilation, which can support cardiovascular, metabolic, and exercise‑related outcomes.

Benefits

Improved exercise performance: Randomized trials show that 6–8 g of L‑citrulline or 8 g of citrulline‑malate can increase time‑to‑exhaustion and reduce perceived effort during high‑intensity or endurance exercise.
Blood‑pressure regulation: Meta‑analyses of hypertensive cohorts report 4–6 g daily lowers systolic/diastolic pressure by ~4–7 mm Hg, likely via NO‑mediated vasodilation.
Enhanced recovery: Post‑exercise muscle soreness and lactate accumulation are attenuated when citrulline is taken pre‑exercise.
Cognitive support: Preliminary data suggest that increased cerebral blood flow from NO may modestly improve reaction time and mental fatigue in healthy adults.
Metabolic health: Limited trials in pre‑diabetic subjects show modest improvements in insulin sensitivity and reduced post‑prandial glucose when 6 g/day is used for 8 weeks.
All benefits are dose‑dependent and most robust in physically active adults.

How It Works

Citrulline is absorbed in the small intestine and bypasses hepatic first‑pass metabolism, unlike arginine.
Once in the bloodstream, renal cells convert citrulline to arginine via the enzymes argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL) within the urea cycle.
The newly generated arginine serves as substrate for nitric‑oxide synthase (NOS), producing NO and citrulline in a feedback loop.
Elevated NO leads to smooth‑muscle relaxation through cyclic‑GMP (cGMP) signaling, causing vasodilation and increased blood flow.
Concurrently, the urea cycle disposes of ammonia, supporting nitrogen balance during intense exercise.
By raising plasma arginine 2–3‑fold, citrulline indirectly augments protein synthesis pathways (e.g., mTOR) and reduces oxidative stress via increased NO‑derived S‑nitrosylation of mitochondrial proteins.

Dosage

General cardiovascular support: 3–6 g of L‑citrulline daily (or 6–8 g citrulline‑malate) split into two doses, taken with meals.
Exercise performance: 6–8 g L‑citrulline or 8–12 g citrulline‑malate 30–60 min before training; a second 3–4 g dose 3 h post‑exercise can aid recovery.
Hypertension: 4–6 g/day divided into two doses for 4–12 weeks, monitored for blood pressure changes.
Special populations: Athletes may cycle 4‑week on/2‑week off to avoid tolerance; older adults may start at 2 g and titrate up.
Timing: Because plasma arginine peaks ~1 h after ingestion, pre‑exercise dosing aligns with peak NO availability. For chronic vascular benefit, consistent daily dosing is recommended.

Safety & Side Effects

Citrulline is generally well tolerated; mild side‑effects include gastrointestinal discomfort (bloating, diarrhea) at >10 g/day.
No serious adverse events have been reported in healthy adults up to 20 g/day for 6 months.
Contraindications include:
- (i) patients on nitrates or phosphodiesterase‑5 inhibitors (risk of excessive hypotension);
- (ii) severe renal or hepatic impairment (impaired urea cycle clearance).
Potential drug interactions: antihypertensives (potentiated blood‑pressure lowering) and immunosuppressants (theoretical effect on arginine‑dependent immune pathways).
Pregnant or lactating women lack sufficient safety data; avoid supplementation unless medically supervised.
Children should only use pediatric‑specific formulations under clinician guidance.

Chemistry

Citrulline (L‑citrulline) is a non‑proteinogenic α‑amino acid with the molecular formula C₆H₁₃N₃O₃ and a molecular weight of 175.19 g mol⁻¹.
IUPAC name: (2S)-2‑amino‑5‑ureido‑pentanoic acid.
The structure features a central α‑carbon bearing an amino group, a carboxylate, and a side chain terminating in a urea (–NH‑C(=O)‑NH₂) moiety, conferring both basic and acidic properties (pKa ≈ 9.1 for the α‑amino and ≈2.5 for the carboxyl).
It is a zwitterion at physiological pH, highly soluble in water (>1 g mL⁻¹) and stable at pH 5–9.
The urea group enables the conversion to arginine via the urea cycle enzymes, while the free amino group participates in nitrogen transport.

Sources & Quality

Naturally, citrulline is abundant in watermelon (Citrullus lanatus) rind and flesh, with concentrations up to 250 mg kg⁻¹ fresh weight.
Commercial supplements are derived either:
- (i) from extraction of watermelon juice/seed or
- (ii) via microbial fermentation (e.g., Corynebacterium glutamicum engineered to overproduce L‑citrulline).
The latter yields high purity (>98 %) L‑citrulline with minimal pesticide residues.
Citrulline‑malate is produced by chemically reacting citrulline with malic acid under controlled pH, producing a 2:1 molar complex that improves solubility and bioavailability.
Quality considerations include verification of L‑isomer purity, absence of heavy metals (≤10 ppb lead), and compliance with USP/EFSA standards.
Third‑party testing (e.g., NSF, Informed‑Sport) ensures product integrity for athletes and clinical users.