The AtlasAmino acidsPositively charged

ArginineArg · R

The substrate for nitric oxide, the hinge of the urea cycle and the start of creatine, and the supplement whose own first pass through the gut undoes most of what is claimed for it.

Status Reference · not yet an episodeSources 49Reviewed October 2026

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Skeletal formula — every corner and every line end is a carbon, and the hydrogens on carbon are left implied.

Molecule · Arg · 12 heavy atoms

Arginine

C₆H₁₄N₄O₂174.20 g/mol

The substrate for nitric oxide, the hinge of the urea cycle and the start of creatine, and the supplement whose own first pass through the gut undoes most of what is claimed for it.

Built fromthe charted ones open their own entry

C6CarbonH14Hydrogen N4Nitrogen O2Oxygen

Codes: Arg · R
Formula: C₆H₁₄N₄O₂
Molar mass: 174.20 g/mol
Systematic name: (2S)-2-amino-5-(diaminomethylideneamino)pentanoic acid
Side chain: 3-Guanidinopropyl: three carbons ending in a guanidinium group; always positively charged.
Class: Positively charged
In the diet: Conditionally essential
Carbon skeleton: Glucogenic
pKa: α-COOH 2.17 · α-NH₃⁺ 9.04 · side chain 12.48
Isoelectric point: pH 10.76
Hydropathy: -4.5 (Kyte–Doolittle)
Codons: CGU CGC CGA CGG AGA AGG
Main transporters: SLC7A7 (y⁺LAT1, with CD98), SLC3A1, SLC7A9 (rBAT, b⁰,⁺AT)

pKa and isoelectric point: Nelson and Cox, Lehninger Principles of Biochemistry, table of amino acid properties (free amino acid, 25 °C). Hydropathy: Kyte and Doolittle, J Mol Biol 1982. Essentiality: Reeds, J Nutr 2000. Formula and mass computed from the structure.

In brief

What it is

An amino acid whose side chain ends in a guanidinium group, the most strongly basic group in any amino acid: always positively charged, even buried inside a protein ¹. The body makes it, mostly from citrulline in the kidney ².

Why it matters

Arginine is the only substrate of the nitric oxide synthases, a step in the urea cycle, and the source of creatine, polyamines and agmatine ^3,4,5. That is why it is sold for blood pressure, erections and exercise, and why it disappoints: a large share of what is swallowed is used up by the gut and liver before it reaches the body ^6,7.

Where it runs short

Arginine is conditionally essential: adults make enough, but the newborn, and people with urea cycle disorders or lysinuric protein intolerance, may not ^8,9,10.

Where it turns

Inherited arginase 1 deficiency leaves arginine high from birth and causes a slowly progressive spastic weakness of the legs, unlike the other urea cycle disorders ^11,12.

The paradox: the body is rarely short of arginine, and the supplement rarely arrives.

The molecule

Arginine’s side chain is three carbons ending in a guanidinium group, a carbon bonded to three nitrogens that shares its positive charge across all of them. Textbooks give its pKa as about 12.5, but a 2015 NMR study measured 13.8, high enough that arginine stays charged even when buried in the core of a protein ¹.

Charge · pHArginine carries a full positive charge at the pH of blood.

Move across the chart to read the charge at any pH.

Computed from its pKa values (α-carboxyl 2.17, α-amino 9.04, side chain 12.48) by the Henderson–Hasselbalch equation, for the free amino acid in water at 25 °C. Inside a folded protein the same groups can shift by a unit or more. The faint lines are the other amino acids.

HydropathyArginine scores -4.5: the most water-loving of the twenty.

Kyte–Doolittle hydropathy index: positive values avoid water and tend to be buried inside a folded protein, negative values sit on its surface. Each letter is an amino acid; choose one to open it.

The genetic codeArginine has 6 codons. The code is redundant, so most single-letter changes at the third position still write arginine.

The 64 codons of the standard genetic code. Codons for arginine are marked.
1st ↓ 2nd →	U	C	A	G	3rd
U	UUUPhe	UCUSer	UAUTyr	UGUCys	U
	UUCPhe	UCCSer	UACTyr	UGCCys	C
	UUALeu	UCASer	UAAStop	UGAStop	A
	UUGLeu	UCGSer	UAGStop	UGGTrp	G
C	CUULeu	CCUPro	CAUHis	CGUArg	U
	CUCLeu	CCCPro	CACHis	CGCArg	C
	CUALeu	CCAPro	CAAGln	CGAArg	A
	CUGLeu	CCGPro	CAGGln	CGGArg	G
A	AUUIle	ACUThr	AAUAsn	AGUSer	U
	AUCIle	ACCThr	AACAsn	AGCSer	C
	AUAIle	ACAThr	AAALys	AGAArg	A
	AUGMet	ACGThr	AAGLys	AGGArg	G
G	GUUVal	GCUAla	GAUAsp	GGUGly	U
	GUCVal	GCCAla	GACAsp	GGCGly	C
	GUAVal	GCAAla	GAAGlu	GGAGly	A
	GUGVal	GCGAla	GAGGlu	GGGGly	G

Where it comes from

Adults make arginine. The small intestine makes citrulline from glutamine, and the kidney turns that citrulline into arginine and releases it, an intestinal–renal axis ^2,13.

Because of that, arginine is conditionally essential, needed in the diet only when synthesis cannot keep up: in newborns, and in strict carnivores, birds and fish ⁸. In people with urea cycle disorders, arginine itself becomes part of the treatment ⁹.

Conditionally essentialMade from citrulline that the gut produces and the kidney converts, so adults do not need it in the diet; it is considered conditionally essential in newborns and in several animal species ^2,8.

How much

No requirement is set for healthy adults, who make their own ^2,8.

Where it is in food

Protein foods generally; but much of the arginine in a meal or a capsule is used by the gut and liver on first pass ⁶.

In the bottle · fermentedMade by fermentation in Corynebacterium glutamicum; strains used for feed-grade arginine in Europe are not genetically modified and the product is at least 98% pure ^8,14.

What the body does with it

Nitric oxide is made only from arginine. Endothelial nitric oxide relaxes blood vessels, neuronal nitric oxide signals in the brain and triggers erection, and inducible nitric oxide is a weapon of immune cells ³. In healthy adults, about 16% of the nitrate the body makes each day came from dietary arginine on its first pass through the gut and liver ¹⁵.

Arginine is also the last amino acid of the urea cycle: arginase splits it into urea, which is excreted, and ornithine, which goes round again ⁹. Argininosuccinate lyase, which makes arginine in that cycle, turned out to be needed for nitric oxide production as well; in people with its deficiency, a nitric oxide donor restored blood vessel responses ¹⁶.

Creatine synthesis begins by transferring arginine’s guanidino group to glycine. It is a large drain on arginine, glycine and methionine, and vegetarians get almost no creatine from their diet, so they make all of it ⁵.

Methylated arginines in proteins are released as asymmetric dimethylarginine when those proteins are broken down. It blocks nitric oxide synthase, more than 10 mg of it is excreted daily, and it accumulates when the kidneys fail ^4,17.

Giving the enzyme that destroys arginine is now a treatment. In arginase 1 deficiency the enzyme at the end of the urea cycle is missing, arginine accumulates, and dietary protein restriction rarely prevents the spasticity and loss of mobility that follow. Pegzilarginase is recombinant human arginase given weekly: across two open-label extension studies, 37 of 39 evaluable participants met a composite response or maxed out a motor domain, six-minute walk distance improved by 19%, spasticity improved in 21 of 25 with 12 reaching no spasticity at all, and plasma arginine stayed controlled for up to five years ¹⁸. A 2026 phase 3 study extended it to children under two — three of them, which for this disease is a trial ¹⁹.

In three sentences each

The only source of nitric oxide

Three nitric oxide synthases split arginine with oxygen into nitric oxide and citrulline, using NADPH, FAD, FMN and tetrahydrobiopterin; nerve-derived nitric oxide is what drugs like sildenafil depend on ³.

Swallowed, mostly intercepted

In adults about 38% of dietary arginine was taken up by the gut and liver on first pass ⁶. Oral citrulline, which the kidney turns into arginine, raised blood arginine more than the same dose of arginine did ⁷.

A natural brake

Asymmetric dimethylarginine, released when methylated proteins are broken down, blocks nitric oxide synthase; it accumulates in kidney failure and higher levels predict cardiovascular events ^17,20.

How it is made, moved and broken down

Arginine’s products include nitric oxide, urea, creatine, polyamines, proline, glutamate and agmatine ⁴. Because so many pathways compete for it, a ratio of arginine to ornithine and citrulline was proposed as a measure of how available it is; in 1,010 people, a low ratio predicted cardiovascular events ²¹.

Carbon skeleton · glucogenicArginase splits it into ornithine and urea; ornithine can go on to glutamate, proline and polyamines ⁴.

Made in the kidneyFrom citrulline the intestine releases ².

Citrulline + aspartate
Argininosuccinate synthetaseASS1 · ATP
Argininosuccinate
Argininosuccinate lyaseASL
Arginine + fumarate

Where it goesCompeting fates ^3,4,5.

Arginine
Nitric oxide synthaseNOS1, NOS2, NOS3 · BH4, NADPH, O₂
Nitric oxide + citrulline
ArginaseARG1, ARG2 · manganese
Ornithine + urea
Arginine:glycine amidinotransferaseGATM
Guanidinoacetate → creatine

How it crosses membranes

SLC7A7 · y⁺LAT1, with CD98the blood side of gut and kidney cells — exports arginine with lysine and ornithine; lost in lysinuric protein intolerance ¹⁰
SLC3A1, SLC7A9 · rBAT, b⁰,⁺ATkidney and gut lumen — reclaims arginine with cystine; mutations cause cystinuria ²²

Where it matters most

Kidney: Makes the body’s arginine from intestinal citrulline ².
Liver: Runs the urea cycle, in which arginase splits arginine into urea and ornithine ⁹.
Blood vessels: Endothelial nitric oxide synthase makes the nitric oxide that relaxes them ³.
Gut: Takes up a large share of swallowed arginine before it reaches the circulation ⁶.
Muscle and brain: Use creatine made from arginine and glycine; inherited defects of its synthesis are treatable with oral creatine ^5,23.

When it goes wrong

Inherited

Arginase 1 deficiency

ARG1 · autosomal recessive

Persistently high arginine drives a progressive spastic diplegia, developmental delay and seizures; across 157 reported cases the mean age at diagnosis was 6.4 years ^11,12,24. In the PEACE trial, pegzilarginase, an enzyme that breaks down arginine, lowered plasma arginine from 354 to 86 µmol/L against almost no change on placebo ²⁵.

How it is foundPlasma arginine, then ARG1 sequencing; it is often first mistaken for hereditary spastic paraplegia ^12,24.

Inherited

Urea cycle disorders

ASS1, ASL, OTC and others · mostly recessive; OTC X-linked

About one birth in 35,000; half present as newborns with high ammonia. Arginine, or citrulline, is given in several of them to keep the cycle turning ⁹.

How it is foundAmmonia, plasma amino acids and urinary orotic acid, then genetic testing ⁹.

Drug

Arginine after a heart attack

In VINTAGE MI, arginine 3 g three times a day did not improve vascular stiffness or heart function, and there were six deaths on arginine against none on placebo; the trial stopped enrolling ²⁶.

Biomarker

ADMA and cardiovascular risk

Across 22 prospective studies and nearly 20,000 people, higher ADMA predicted heart disease and stroke ²⁰. Statins lowered it modestly in a meta-analysis ²⁷.

How it is foundMass spectrometry; immunoassays disagree ²⁸.

Drug

Arginine deprivation in cancer

ASS1

Tumors that lack argininosuccinate synthetase cannot make arginine. Pegargiminase with chemotherapy lengthened survival in 249 people with mesothelioma, with more serious side effects ²⁹; in 635 people with liver cancer it had no effect ³⁰.

How it is foundASS1 status of the tumor, in trials.

Drug

MELAS

MT-TL1 · mitochondrial

Arginine is widely given for the stroke-like episodes of this mitochondrial disease, but a 2022 systematic review found no randomized trial and no demonstrable benefit ³¹.

How it is measured

Plasma arginine is measured in the amino acid panel and, for arginase 1 deficiency, as the treatment target ²⁵. ADMA is measured in research, but immunoassays and mass spectrometry give different numbers, with immunoassay reading about a third higher in kidney disease ²⁸. Creatine and guanidinoacetate in plasma and urine diagnose the creatine synthesis disorders ³².

Plasma argininePart of the amino acid panel; high in arginase 1 deficiency and the target of its treatment ^12,25.Raised in 82% of reported arginase 1 deficiency cases ¹².Arginine and ornithine change in the tube if the sample waits; prompt processing matters ³³.
ADMAAsymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase ¹⁷.Research; not a routine clinical test.In 22 prospective studies, people in the top third had 42% more cardiovascular events than the bottom third ²⁰.Immunoassay and mass spectrometry disagree badly, especially in advanced kidney disease, so values are not comparable across methods ²⁸.
Arginine stimulation testArginine infused to provoke growth hormone release, in testing children for growth hormone deficiency ³⁴.Accepted by consensus for children, alongside the glucagon test ³⁴.

Food, supplements and the evidence

Establishedreplicated in people, for a named outcome

Arginine is part of the treatment of several urea cycle disorders ⁹.
Arginine infusion is a standard stimulus for testing growth hormone in children ³⁴.

Uncertainsmall, short, mixed, surrogate or preclinical

Blood pressure: eleven small trials of 4 to 24 g a day found a fall of about 5 mmHg systolic ³⁵.
Erectile dysfunction: pooled trials in mild to moderate cases found benefit, more with a PDE5 inhibitor than alone; adverse effects were more common on arginine ^36,37.
Preventing necrotizing enterocolitis in preterm babies: three trials in 285 infants showed fewer cases, not enough to change practice ³⁸.
Sickle cell disease: four trials suggested less pain and fewer crises ³⁹.
Blood pressure, re-measured properly. The older trials used clinic readings; a 2026 meta-analysis restricted to ambulatory monitoring pooled five randomized trials and 202 participants and found 24-hour systolic pressure down 4.23 mmHg (95% CI −5.87 to −2.58) and diastolic down 3.04, with the largest effect at night (systolic −5.70) ⁴⁰. Five trials is a thin base for a confident number, and 24-hour monitoring is the right way to measure it.
Pre-eclampsia, where the effect size is large and the evidence quality is not. Across 20 randomized trials in 2,028 pregnant women, L-arginine in prevention trials was associated with less pre-eclampsia (RR 0.52, 95% CI 0.35 to 0.78) and less severe pre-eclampsia (RR 0.23, 95% CI 0.09 to 0.55), and in treatment trials with lower systolic pressure and less fetal growth restriction. Every one of those estimates is rated low or very low certainty, eight of the trials were at high risk of bias and 12 raised concerns, and the single citrulline study found nothing ⁴¹.
Breathlessness in COPD. 150 stable patients took L-arginine 1.66 g with liposomal vitamin C twice daily or placebo for four weeks, and reported better dyspnoea and daily activity scores, with more patients reaching the minimal clinically important difference ⁴². The endpoints are all self-reported and the trial was single-blind, which is exactly the combination that most needs replicating before it becomes advice.

Sold asthe claim on the label, against the evidence

“Arginine boosts nitric oxide and performance.” Much of an oral dose is eliminated before it reaches the circulation, citrulline raises blood arginine more than arginine does, and a widely cited positive meta-analysis of athletic performance was later criticised for errors that distorted its pooled effect ^6,7,43,44.
The pump, measured three more times. Sixteen trained men took 3.2 to 9.6 g a day for four days: no difference in repetitions, volume load or fatigue, no difference in plasma nitric oxide, and a brachial artery that was wider for one minute after exercise and no wider at any other point ⁴⁵. Forty-six trained men given arginine WITH citrulline malate — the combination sold as synergistic — showed no improvement across a Wingate test, a CrossFit workout or a step test, apart from reaching peak power sooner ⁴⁶. And 43 trained adults given citrulline or citrulline malate improved on none of ten neuromuscular measures ⁴⁷. Three trials, three designs, one answer.
“Arginine for the aging cardiovascular system.” A 2026 mechanistic review puts the position plainly: the pathway is right, endothelial function does improve, the hard endpoints do not follow, and randomized trials in advanced cardiovascular disease have reported worsened endothelial and cardiac function and increased mortality. Its authors — who study this pathway — conclude that chronic supplementation should be implemented carefully or avoided in advanced cardiovascular disease and in the elderly, which is the population it is marketed to ⁴⁸.

What is strange about it

In the VINTAGE MI trial, 153 people recovering from a heart attack took arginine or placebo for six months. Six died on arginine and none on placebo, and the trial was stopped ²⁶.

Some tumors cannot make their own arginine. An enzyme that destroys arginine in the blood, pegargiminase, added to chemotherapy for mesothelioma, extended median survival from 7.7 to 9.3 months ²⁹; the same approach in liver cancer did nothing ³⁰.

Of the urea cycle disorders, arginase 1 deficiency is the odd one out: babies are healthy at birth, high ammonia is uncommon, and the disease shows itself years later as stiff legs, often first diagnosed as hereditary spastic paraplegia ^11,12,24.

The arginine story in sickle cell disease is the clearest example of why a failed trial is worth reading. 108 children aged 3 to 21 admitted with vaso-occlusive pain were randomized to standard-dose intravenous arginine, a loading dose, or placebo, with total parenteral opioid use as the primary endpoint. It missed: opioid use, time to crisis resolution, pain scores and patient-reported outcomes were the same across arms. What the trial established instead is that the deficiency is real — arginine was low at presentation in 79% of the children, mean 50 µmol/L — that arginine bioavailability at presentation predicted how long the crisis lasted in the placebo arm (r = −0.39) and stopped predicting it once arginine was given, that platelet mitochondrial activity rose and protein carbonyls fell on arginine and not on placebo, and that the opioid-sparing effect reached significance in the children whose arginine was lowest ⁴⁹. A negative trial that names the subgroup it should have enrolled is a better document than a positive one that cannot explain itself.

Where it connects

In the Atlas

LysLysinePositively charged GlyGlycineNonpolar, aliphatic GlnGlutaminePolar, uncharged ProProlineNonpolar, aliphatic NNitrogenElement

Topics on the map

On the map

A star in Conditional amino acids, one of 14. The substrate for nitric oxide, and mostly destroyed in the gut and liver before it arrives — which is why the supplement disappoints and its precursor does not.

Find it on the map

Sources

49 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.

1
Fitch CA, Platzer G, Okon M, et al. Arginine: its pKa value revisited.Protein Sci · 2015 · 24(5):752–761doi:10.1002/pro.2647 · PMID 25808204
pKa 13.8, not about 12; always charged.
2
van de Poll MCG, Soeters PB, Deutz NEP, et al. Renal metabolism of amino acids: its role in interorgan amino acid exchange.Am J Clin Nutr · 2004 · 79(2):185–197doi:10.1093/ajcn/79.2.185 · PMID 14749222
Kidney makes arginine from intestinal citrulline.
3
Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function.Eur Heart J · 2012 · 33(7):829–837doi:10.1093/eurheartj/ehr304 · PMID 21890489
Three isoforms; cofactors; nNOS and erection.
4
Morris SM. Arginine metabolism revisited.J Nutr · 2016 · 146(12):2579S–2586Sdoi:10.3945/jn.115.226621 · PMID 27934648
The many products of arginine.
5
Brosnan JT, Brosnan ME. Creatine: endogenous metabolite, dietary, and therapeutic supplement.Annu Rev Nutr · 2007 · 27:241–261doi:10.1146/annurev.nutr.27.061406.093621 · PMID 17430086
Creatine synthesis drains arginine, glycine and methionine.
6
Castillo L, Chapman TE, Yu YM, et al. Dietary arginine uptake by the splanchnic region in adult humans.Am J Physiol · 1993 · 265(4 Pt 1):E532–E539doi:10.1152/ajpendo.1993.265.4.E532 · PMID 8238326
About 38% first-pass uptake; small tracer studies.
7
Schwedhelm E, Maas R, Freese R, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism.Br J Clin Pharmacol · 2008 · 65(1):51–59doi:10.1111/j.1365-2125.2007.02990.x · PMID 17662090
20 volunteers; citrulline raised arginine more; no change in vessel function.
8
EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP); Bampidis V, Azimonti G, et al. Assessment of the application for renewal of authorisation of L-arginine produced by fermentation using Corynebacterium glutamicum NITE SD 00285 for all animal species.EFSA J · 2019 · 17(6):e05720doi:10.2903/j.efsa.2019.5720 · PMID 32626342
Conditionally essential in neonates and some species; strain and purity.
9
Häberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: first revision.J Inherit Metab Dis · 2019 · 42(6):1192–1230doi:10.1002/jimd.12100 · PMID 30982989
Incidence about 1 in 35,000.
10
Torrents D, Mykkänen J, Pineda M, et al. Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene.Nat Genet · 1999 · 21(3):293–296doi:10.1038/6809 · PMID 10080182
The dibasic amino acid exporter.
11
Diaz GA, Bechter M, Cederbaum SD. The role and control of arginine levels in arginase 1 deficiency.J Inherit Metab Dis · 2023 · 46(1):3–14doi:10.1002/jimd.12564 · PMID 36175366
Arginine as the main driver of disease. One author from the drug’s developer.
12
Bin Sawad A, Pothukuchy A, Badeaux M, et al. Natural history of arginase 1 deficiency and the unmet needs of patients: a systematic review of case reports.JIMD Rep · 2022 · 63(4):330–340doi:10.1002/jmd2.12283 · PMID 35822089
157 patients; diagnosis at a mean 6.4 years.
13
Marini JC, Agarwal U, Robinson JL, et al. The intestinal-renal axis for arginine synthesis is present and functional in the neonatal pig.Am J Physiol Endocrinol Metab · 2017 · 313(2):E233–E242doi:10.1152/ajpendo.00055.2017 · PMID 28611027
Pigs; the axis exists in the newborn.
14
Jiang Y, Sheng Q, Wu XY, et al. L-arginine production in Corynebacterium glutamicum: manipulation and optimization of the metabolic process.Crit Rev Biotechnol · 2021 · 41(2):172–185doi:10.1080/07388551.2020.1844625 · PMID 33153325
Industrial fermentation.
15
Castillo L, deRojas TC, Chapman TE, et al. Splanchnic metabolism of dietary arginine in relation to nitric oxide synthesis in normal adult man.Proc Natl Acad Sci U S A · 1993 · 90(1):193–197doi:10.1073/pnas.90.1.193 · PMID 8419922
About 16% of daily nitrate from first-pass dietary arginine.
16
Erez A, Nagamani SCS, Shchelochkov OA, et al. Requirement of argininosuccinate lyase for systemic nitric oxide production.Nat Med · 2011 · 17(12):1619–1626doi:10.1038/nm.2544 · PMID 22081021
ASL is part of the NOS complex; NO donor helped patients’ vessels.
17
Vallance P, Leone A, Calver A, et al. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.Lancet · 1992 · 339(8793):572–575doi:10.1016/0140-6736(92)90865-z · PMID 1347093
ADMA discovered; accumulates in kidney failure.
18
McNutt M, Rutsch F, Russo RS, et al. Long-term efficacy and tolerability of pegzilarginase in arginase 1 deficiency: results of two international multicentre open-label extension studies.J Inherit Metab Dis · 2025 · 48(4):e70066doi:10.1002/jimd.70066 · PMID 40714964
The enzyme that destroys arginine, given as a drug to people who cannot destroy it themselves.
19
Ghosh A, Baghdasaryan A, Pinto PL, Rudebeck M. Efficacy and safety of pegzilarginase in patients below 2 years of age with arginase 1 deficiency: a phase 3, open-label, multi-centre study.EClinicalMedicine · 2026 · 97:104021doi:10.1016/j.eclinm.2026.104021 · PMID 42404437
Three infants. For a disorder this rare that is a phase 3 trial, and it is worth saying so.
20
Willeit P, Freitag DF, Laukkanen JA, et al. Asymmetric dimethylarginine and cardiovascular risk: systematic review and meta-analysis of 22 prospective studies.J Am Heart Assoc · 2015 · 4(6):e001833doi:10.1161/JAHA.115.001833 · PMID 26021436
19,842 people; top third against bottom, RR 1.42.
21
Tang WHW, Wang Z, Cho L, et al. Diminished global arginine bioavailability and increased arginine catabolism as metabolic profile of increased cardiovascular risk.J Am Coll Cardiol · 2009 · 53(22):2061–2067doi:10.1016/j.jacc.2009.02.036 · PMID 19477356
1,010 people; low arginine ratio, hazard ratio 1.98.
22
Servais A, Thomas K, Dello Strologo L, et al. Cystinuria: clinical practice recommendation.Kidney Int · 2021 · 99(1):48–58doi:10.1016/j.kint.2020.06.035 · PMID 32918941
The basic amino acid transporter of the kidney.
23
Fernandes-Pires G, Azevedo MD, Lanzillo M, et al. Rescue of myocytes and locomotion through AAV-driven intracisternal gene therapy in a rat model of creatine transporter deficiency.Mol Ther Methods Clin Dev · 2024 · 32(2):101251doi:10.1016/j.omtm.2024.101251 · PMID 38745894
Creatine synthesis defects treatable with creatine; transporter deficiency not. Rat study.
24
McNutt MC, Foreman N, Gotway G. Arginase 1 deficiency in patients initially diagnosed with hereditary spastic paraplegia.Mov Disord Clin Pract · 2023 · 10(1):109–114doi:10.1002/mdc3.13612 · PMID 36698992
Misdiagnosis as hereditary spastic paraplegia.
25
Sanchez Russo R, Gasperini S, Bubb G, et al. Efficacy and safety of pegzilarginase in arginase 1 deficiency (PEACE): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial.EClinicalMedicine · 2024 · 68:102405doi:10.1016/j.eclinm.2023.102405 · PMID 38292042
32 patients; arginine normalized in 90.5%.
26
Schulman SP, Becker LC, Kass DA, et al. L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial.JAMA · 2006 · 295(1):58–64doi:10.1001/jama.295.1.58 · PMID 16391217
153 patients; six deaths on arginine, none on placebo.
27
Zinellu A, Mangoni AA. An updated systematic review and meta-analysis of the effect of statins on asymmetric dimethylarginine.Nitric Oxide · 2022 · 120:26–37doi:10.1016/j.niox.2022.01.001 · PMID 35032642
23 studies; modest fall.
28
Pecchini P, Malberti F, Mieth M, et al. Measuring asymmetric dimethylarginine (ADMA) in CKD: a comparison between enzyme-linked immunosorbent assay and liquid chromatography-electrospray tandem mass spectrometry.J Nephrol · 2012 · 25(6):1016–1022doi:10.5301/jn.5000085 · PMID 22322824
126 patients; ELISA 0.78 against 0.59 µmol/L by mass spectrometry.
29
Szlosarek PW, Creelan BC, Sarkodie T, et al. Pegargiminase plus first-line chemotherapy in patients with nonepithelioid pleural mesothelioma: the ATOMIC-Meso randomized clinical trial.JAMA Oncol · 2024 · 10(4):475–483doi:10.1001/jamaoncol.2023.6789 · PMID 38358753
249 patients; median survival 9.3 against 7.7 months. Manufacturer-sponsored.
30
Abou-Alfa GK, Qin S, Ryoo BY, et al. Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma.Ann Oncol · 2018 · 29(6):1402–1408doi:10.1093/annonc/mdy101 · PMID 29659672
635 patients; no survival difference.
31
Stefanetti RJ, Ng YS, Errington L, et al. L-arginine in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes: a systematic review.Neurology · 2022 · 98(23):e2318–e2328doi:10.1212/WNL.0000000000200299 · PMID 35428733
37 articles, no randomized trials; no demonstrable benefit.
32
Liu N, Sun Q. Laboratory diagnosis of cerebral creatine deficiency syndromes by determining creatine and guanidinoacetate in plasma and urine.Methods Mol Biol · 2022 · 2546:129–140doi:10.1007/978-1-0716-2565-1_12 · PMID 36127584
The diagnostic method.
33
Xia T, Gao S, Shu C, et al. Analysis of amino acids in human blood using UHPLC-MS/MS: potential interferences of storage time and vacutainer tube in pre-analytical procedure.Clin Biochem · 2016 · 49(18):1372–1378doi:10.1016/j.clinbiochem.2016.09.018 · PMID 27693603
Storage and tube effects on plasma amino acids.
34
Arlien-Søborg MC, Radovick S, Boguszewski MCS, et al. Consensus and controversies about diagnosing GH deficiency: a Delphi survey by the GH research society.Pituitary · 2025 · 28(3):57doi:10.1007/s11102-025-01526-z · PMID 40335774
Arginine and glucagon tests accepted in children.
35
Dong JY, Qin LQ, Zhang Z, et al. Effect of oral L-arginine supplementation on blood pressure: a meta-analysis of randomized, double-blind, placebo-controlled trials.Am Heart J · 2011 · 162(6):959–965doi:10.1016/j.ahj.2011.09.012 · PMID 22137067
11 trials, 387 people; systolic −5.4 mmHg.
36
Rhim HC, Kim MS, Park YJ, et al. The potential role of arginine supplements on erectile dysfunction: a systemic review and meta-analysis.J Sex Med · 2019 · 16(2):223–234doi:10.1016/j.jsxm.2018.12.002 · PMID 30770070
10 trials, 540 men; adverse effects 8.3% against 2.3%.
37
Barbonetti A, Tienforti D, Antolini F, et al. Nutraceutical interventions for erectile dysfunction: a systematic review and network meta-analysis.J Sex Med · 2024 · 21(11):1054–1063doi:10.1093/jsxmed/qdae123 · PMID 39279185
15 trials; best with tadalafil.
38
Shah PS, Shah VS, Kelly LE. Arginine supplementation for prevention of necrotising enterocolitis in preterm infants.Cochrane Database Syst Rev · 2017 · 4(4):CD004339doi:10.1002/14651858.CD004339.pub4 · PMID 28399330
Three trials, 285 infants; RR 0.38; not enough for a recommendation.
39
Orsi BC, Gorski D, Krul NE, et al. The effects of nutritional supplementation for children and adolescents with sickle cell disease: a systematic review and meta-analyses.Clin Nutr · 2025 · 47:157–168doi:10.1016/j.clnu.2025.02.016 · PMID 40022955
Four arginine trials among 20.
40
Shi Y, Liu Y, Zhou Z, Xu S, Luo P. Reassessment of the effect of oral l-arginine on blood pressure: a systematic review and meta-analysis based on ambulatory blood pressure monitoring.Nitric Oxide · 2026 · 164:60–68doi:10.1016/j.niox.2026.07.004 · PMID 42520885
Only five trials and 202 people, but measured over 24 hours rather than in a clinic chair.
41
Makama M, McDougall ARA, Cao J, et al. L-arginine and L-citrulline for prevention and treatment of pre-eclampsia: a systematic review and meta-analysis.BJOG · 2025 · 132(6):698–708doi:10.1111/1471-0528.18070 · PMID 39800868
2,028 women across 20 randomized trials — and eight of those trials at high risk of bias, which is why the certainty is low.
42
Radovanovic D, Signorello JC, Fuccia G, et al. Impact of L-arginine and liposomal vitamin C supplementation on quality of life and daily life activities in patients with COPD: a randomized, multicenter, single blind, placebo-controlled trial (ILDA study).Eur J Intern Med · 2025 · 136:107–116doi:10.1016/j.ejim.2025.04.039 · PMID 40316462
150 patients, four weeks, patient-reported endpoints — and single-blind, which is the limitation that matters for those endpoints.
43
Viribay A, Burgos J, Fernández-Landa J, et al. Effects of arginine supplementation on athletic performance based on energy metabolism: a systematic review and meta-analysis.Nutrients · 2020 · 12(5):1300doi:10.3390/nu12051300 · PMID 32370176
Positive pooled effect with very high heterogeneity.
44
Trexler ET. Common errors in sports nutrition meta-analyses lead to distortion of pooled effect estimates.Nutrients · 2025 · 17(14):2375doi:10.3390/nu17142375 · PMID 40733000
Commentary identifying errors in the arginine meta-analysis.
45
Borges CC, Alves da Silva W, de Sá Filho AS, et al. Effect of arginine supplementation on vasodilation and muscular performance in young men: a randomized, double-blind, crossover study.Int J Sport Nutr Exerc Metab · 2025 · 36(1):1–12doi:10.1123/ijsnem.2025-0125 · PMID 41248623
The artery widened for a minute after exercise. Nothing else moved, including nitric oxide.
46
Selvaraj S, Petridis L, Majtényi H, et al. Acute effects of combined supplementation of L-arginine and citrulline malate on aerobic, anaerobic, and CrossFit exercise performance.Sci Rep · 2025 · 15(1):33067doi:10.1038/s41598-025-16374-x · PMID 41006371
The two ingredients that are supposed to work together, given together, across three different tests.
47
Martín-Olmedo JJ, Miras-Moreno S, Cuadra-Montes K, et al. Malate or not? Acute effects of L-citrulline versus citrulline malate on neuromuscular performance in young, trained adults: a randomized, double-blind, placebo-controlled crossover trial.Int J Sport Nutr Exerc Metab · 2025 · 35(2):89–98doi:10.1123/ijsnem.2024-0006 · PMID 39662304
43 trained adults, both forms against placebo, and ten outcomes that all came back the same.
48
Yang Z, Ming XF, Potenza DM. The Janus face of L-arginine supplementation in cardiovascular health and aging: exploration of underlying mechanisms.Front Aging · 2026 · 7:1880662doi:10.3389/fragi.2026.1880662 · PMID 42534924
The mechanism works, the endpoints do not follow, and in advanced disease the trials reported harm. Written by people who study the pathway.
49
Morris CR, Hatabah D, Korman R, et al. Arginine therapy for pain in sickle cell disease: a phase-2 randomized, placebo-controlled trial.Am J Hematol · 2025 · 100(7):1119–1131doi:10.1002/ajh.27692 · PMID 40270092
108 children randomized across three arms. It missed its primary endpoint, and what it found instead is the interesting part.

This is education, not medical advice. Nothing on this page is written with knowledge of your history, your medications or your risks, and nothing here is a dose. Do not start or stop any treatment on the basis of it — talk to your own physician. Read the full medical disclaimer.

In brief

The molecule

Where it comes from

What the body does with it

The only source of nitric oxide

Swallowed, mostly intercepted

A natural brake

How it is made, moved and broken down

Where it matters most

When it goes wrong

Arginase 1 deficiency

Urea cycle disorders

Arginine after a heart attack

ADMA and cardiovascular risk

Arginine deprivation in cancer

MELAS

How it is measured

Food, supplements and the evidence

What is strange about it

Where it connects

Sources

Every source, in your inbox.