L-Citrulline | Supplementopedia

Overview

L‑Citrulline is a non‑essential, conditionally essential α‑amino acid that is not incorporated into proteins but serves as a metabolic precursor to L‑arginine and nitric‑oxide (NO) production. It is most commonly taken as a dietary supplement to support vascular function, exercise performance, and overall metabolic health.

Benefits

Enhanced aerobic performance: Randomized trials show 6–8 g of L‑citrulline or 3 g of its more bioavailable form, citrulline malate, improve time‑to‑exhaustion and reduce perceived exertion during cycling or running (e.g., Pérez‑Guisado 2020).
Blood pressure reduction: Meta‑analyses of hypertensive adults report a mean systolic drop of 4–6 mm Hg after 4–12 weeks of 3–6 g daily (Schwedhelm 2018).
Endothelial function: Increased flow‑mediated dilation (FMD) has been documented after 2 weeks of 5 g daily supplementation in middle‑aged adults.
Recovery & muscle soreness: Citrulline malate (6‑8 g) attenuates delayed‑onset muscle soreness and improves recovery of muscle power after intense resistance training (Wax 2015).
Potential cognitive benefits: Early pilot data suggest modest improvements in executive function under acute stress, likely mediated by enhanced cerebral blood flow, though larger trials are needed.

How It Works

Process: After oral ingestion, L‑citrulline is absorbed via the small‑intestine and bypasses hepatic first‑pass metabolism, entering the systemic circulation where it is taken up by the kidneys.
Pathway:
- It is converted to L‑arginine via the urea cycle enzymes argininosuccinate synthase and argininosuccinate lyase.
- Elevated plasma L‑arginine fuels endothelial nitric‑oxide synthase (eNOS), increasing NO synthesis.
- NO activates soluble guanylate cyclase in vascular smooth muscle, raising cyclic‑GMP levels, which cause vasodilation and improve blood flow.
- The same pathway enhances nutrient delivery to skeletal muscle, facilitating ATP regeneration and reducing ammonia accumulation during high-intensity exercise.
- The conversion of L‑citrulline to L‑arginine raises plasma arginine faster than direct arginine supplementation because citrulline avoids intestinal degradation by arginase.

Dosage

General health/vascular support: 3–6 g of pure L‑citrulline or 6–8 g of citrulline‑malate per day, divided into two doses (morning & pre‑exercise).
Performance & recovery: 8 g citrulline‑malate 30‑60 min before training; 6 g is effective for most athletes.
Hypertension/vascular health: 3–5 g of pure L‑citrulline daily, taken with food to improve tolerability.
Special populations: Lower doses (1–2 g) may be used for older adults or those with renal impairment.
Loading is not required: Steady daily intake maintains plasma arginine elevations for >6 h. Adjust dose upward only if tolerated and under professional guidance.

Safety & Side Effects

L‑citrulline is well‑tolerated at ≤12 g/day.
Reported adverse events are mild: gastrointestinal discomfort, bloating, or diarrhea in <5 % of users.
Contraindications:
- Severe renal impairment (eGFR <30 mL/min/1.73 m²) because citrulline is cleared renally.
- Patients on nitric‑oxide donors (e.g., nitroglycerin) or phosphodiesterase‑5 inhibitors should monitor blood pressure for additive hypotension.
No significant drug‑enzyme interactions have been identified, but concurrent use with antihypertensives may amplify blood-pressure-lowering effects.
Pregnant or lactating women lack sufficient safety data; a precautionary approach (≤3 g/day) is advised.
Children under 12 years should avoid supplementation unless directed by a physician.

Chemistry

L‑Citrulline (L‑2‑amino‑5‑ureidopentanoic acid) is a non‑proteinogenic α‑amino acid with the molecular formula C₆H₁₃N₃O₃ and a molecular weight of 175.19 g/mol.
Its IUPAC name is (2S)-2‑amino‑5‑ureido‑pentanoic acid.
The molecule contains a standard α‑amino acid backbone, a carboxyl group, and a side‑chain ureido (‑NH‑C(=O)‑NH₂) moiety, which confers high polarity and water solubility (≈10 g/100 mL at 25 °C).
The L‑enantiomer is the biologically active form; the D‑form is not naturally occurring and lacks metabolic conversion to L‑arginine.
Its pKa values are ~2.0 (carboxyl), ~9.1 (α‑amino), and ~12.5 (ureido), influencing its absorption and distribution.

Sources & Quality

Commercial L‑citrulline is primarily produced by microbial fermentation of glucose using engineered Corynebacterium or E. coli strains, yielding a high‑purity (>99 %) product.
Natural dietary sources contain low amounts of citrulline: watermelon (Citrullus lanatus) provides ~150 mg per 100 g fresh fruit; other sources include cucumbers, gourds, and some melons.
For supplements, the amino acid is isolated as a crystalline powder or combined with malic acid (citrulline‑malate) to improve solubility and taste.
Quality considerations include verification of ≥99 % purity, absence of heavy metals or residual solvents, and compliance with GMP or USP standards.
Third‑party testing (e.g., NSF, Informed‑Choice) is recommended to ensure product integrity and accurate labeling.