By Dr. Gavin McAuley | EMPOWERVIDA
THE SHORT ANSWER
You can, but citrulline alone is actually more effective than arginine for raising blood arginine levels. This sounds paradoxical, but L-citrulline bypasses first-pass liver metabolism and is converted to arginine in the kidneys, producing a more sustained and higher peak plasma arginine level than oral arginine itself. Taking both is not harmful, but citrulline alone is the more efficient strategy for nitric oxide production.
The Arginine Paradox
When you take oral L-arginine, approximately 40% is broken down by the enzyme arginase in the gut wall and liver during first-pass metabolism before it ever reaches systemic circulation. This means that a 6g dose of arginine delivers roughly 3.6g to your bloodstream. L-citrulline, by contrast, passes through the gut and liver untouched (neither organ has significant citrullinase activity) and is then converted to arginine by the enzyme argininosuccinate synthase in the kidneys. This renal conversion provides a sustained release of arginine directly into the bloodstream, bypassing the hepatic destruction.
A study in the British Journal of Clinical Pharmacology demonstrated that oral citrulline supplementation produced higher peak plasma arginine levels and a longer duration of elevated arginine than an equivalent dose of oral arginine. This is why citrulline has largely replaced arginine in evidence-based nitric oxide protocols.
Nitric Oxide and Why It Matters
The ultimate goal of both supplements is to increase nitric oxide (NO) production via endothelial nitric oxide synthase (eNOS). NO is a gaseous signalling molecule that relaxes vascular smooth muscle, dilating blood vessels to improve blood flow. The benefits extend across multiple domains: cardiovascular health (lower blood pressure, reduced arterial stiffness), exercise performance (improved oxygen delivery to working muscles, reduced fatigue), erectile function (NO is the primary mediator of erection), and potentially cognitive function (cerebral blood flow).
When to Use Each (or Both)
Citrulline alone (preferred): For general cardiovascular health, exercise performance, and sustained NO production. This is the more pharmacologically rational approach.
Arginine alone: For acute, short-term NO elevation (e.g., pre-workout within 30-60 minutes). Arginine produces a faster but shorter spike in plasma levels.
Both together: Some athletes use a combination for both immediate (arginine) and sustained (citrulline) NO elevation around training. This is reasonable but not necessary for most people.
Dosing and Timing
L-Citrulline: 3,000-6,000mg daily. For exercise performance, take 60 minutes pre-workout. For cardiovascular health, split into 2 doses (morning and evening). Use L-citrulline, not citrulline malate, unless you specifically want the malic acid for Krebs cycle support (in which case, citrulline malate at a 2:1 ratio, so 6-8g to get 4-5g citrulline).
L-Arginine (if used): 3,000-6,000mg, 30-60 minutes before desired effect. Take on an empty stomach for best absorption as it competes with other amino acids for transport.
Cofactors: Ensure adequate folate, B12, and BH4 (tetrahydrobiopterin) status. eNOS requires these cofactors. Without them, eNOS "uncouples" and produces superoxide (a damaging free radical) instead of NO.
Safety Considerations
Blood pressure medications: Both supplements lower blood pressure via vasodilation. If you take antihypertensives (especially PDE5 inhibitors like sildenafil, or nitrates), the combination can cause excessive hypotension. Discuss with your prescriber.
Post-heart attack: Arginine supplementation was associated with increased mortality in post-MI patients in one JAMA study. Citrulline has not been similarly studied. Avoid both after a heart attack without cardiologist approval.
Herpes: Arginine (but not citrulline) can trigger herpes outbreaks by providing substrate for viral replication. If you manage HSV, citrulline is the safer choice.
GI effects: High-dose arginine can cause diarrhoea and nausea. Citrulline is generally better tolerated.
An Educational Perspective: Educational frameworks often suggest citrulline over arginine in almost every scenario. The pharmacokinetics are simply superior. For patients wanting cardiovascular support or improved exercise performance, L-citrulline 3-6g daily is my standard recommendation. For patients who insist on arginine (often because of marketing), It is important to understand the first-pass metabolism issue and suggest they consider citrulline instead. The one exception is patients wanting a rapid pre-event effect, where a combination of arginine (immediate) plus citrulline (sustained) can be justified.
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Medical Disclaimer: This article is for educational purposes only. Do not combine with nitrate medications or PDE5 inhibitors without medical supervision. Avoid supplementation after myocardial infarction.