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Dietary supplements for improving nitric-oxide synthesis

Kiani AK, Bonetti G, Medori MC, Caruso P, Manganotti P, Fioretti F, Nodari S, Connelly ST, Bertelli M
Journal of Preventive Medicine and Hygiene 2022 Volume 63, Issue 2 Suppl 3, pages E239–E245

Bibliography

PubMed
PMID 36479475
PubMed Central
PMC9710401
DOI
10.15167/2421-4248/jpmh2022.63.2S3.2766
Funding
Funded by the Provincia Autonoma di Bolzano in the framework of LP 15/2020 (dgp 3174/2021).
Competing interests
Authors declare no conflict of interest. Several authors are affiliated with MAGI Euregio, MAGI'S LAB, and MAGISNAT — private genetic testing and research organisations — which is disclosed in the author affiliations but not flagged as a competing interest.

Study snapshot

DesignNarrative review
ModelPrimarily human clinical trial evidence (moderately trained and untrained adults, with limited data on elite athletes and older adults); some cited animal and cell-culture mechanistic work
SampleNot applicable (review of primary trials)
InterventionOral L-arginine (typically 6 g/day for 3–56 days; up to 14.2 g/day in one 6-month study); L-arginine as alpha-ketoglutarate or alpha-ketoisocaproate; oral L-citrulline (typically 6 g/day, sometimes with malate) alone or with malate; beetroot juice (typically 500 mL/day ≈ 5–9 mmol nitrate, acute to 6-day protocols); glycine propionyl-L-carnitine (4.5 g/day for 4 weeks or single dose); 2-nitroxy ethyl 2-amino-3-methylbutanoate
DurationReviewed protocols spanned acute single dose to 6 months
EndpointsPlasma nitrate and nitrite concentrations; VO₂ kinetics and oxygen cost of exercise; time to exhaustion; time-trial performance; peak power output; blood pressure; erectile function; wound healing; pregnancy blood pressure; respiratory response; muscle contractile efficiency

What the study showed, in plain terms

Your body has two independent ways to make nitric oxide. The first is enzymatic: nitric oxide synthase converts the amino acid L-arginine into nitric oxide. The second bypasses enzymes entirely: dietary nitrate (mostly from green leafy vegetables and beetroot) is reduced by bacteria on the surface of your tongue into nitrite, then further reduced in the stomach and bloodstream into nitric oxide. This 2022 review looks at the supplement options for both pathways.

On the enzymatic side, L-arginine at 6 grams per day for a few days has been shown to reduce the oxygen cost of moderate exercise and extend time to exhaustion in untrained and moderately trained adults. L-citrulline, though it isn't itself the substrate for nitric oxide synthase, has an interesting advantage: it bypasses the liver and gets converted to L-arginine in the kidneys, producing a more sustained rise in plasma L-arginine than L-arginine itself. Six grams of L-citrulline with malate for 16 days has been reported to increase muscle ATP production during exercise by roughly a third.

On the nitrate side, beetroot juice at around 500 mL per day (roughly 5–9 mmol of nitrate) reduces the oxygen cost of submaximal exercise by about 5%, blunts the oxygen "slow component" during hard exercise by around 23%, and extends time to exhaustion by roughly 19%. The review also touches on smaller subgroups of evidence for glycine propionyl-L-carnitine and 2-nitroxy ethyl 2-amino-3-methylbutanoate, on modest benefits for erectile function and pregnancy blood pressure, and on the practical point that most of the benefits associated with these supplements are more visible in moderately trained rather than elite subjects.

Key findings

  • Nitric oxide is synthesised via two independent pathways: NOS-dependent (L-arginine → NO by nNOS, iNOS, or eNOS) and NOS-independent (nitrate → nitrite → NO), with the second pathway becoming more active as tissue oxygen falls.
  • L-arginine at 6 g/day for 3 days reduced VO₂ and extended cycling time to exhaustion (approximately 707 s versus 562 s in placebo) in one reviewed trial; higher chronic doses (14.2 g/day for ~6 months) increased peak jump power in postmenopausal women.
  • L-citrulline (6 g/day for 16 days) with malate increased oxidative ATP production during finger-flexion exercise by approximately 34% and phosphocreatine recovery rate after exercise by approximately 20%.
  • A single 8 g dose of L-citrulline with malate increased bench-press repetitions to exhaustion at 80% 1RM by approximately 19%.
  • Beetroot juice (approximately 5–9 mmol nitrate/day, 3–15 days) reduced the oxygen cost of submaximal exercise by approximately 5%, reduced the VO₂ slow component by approximately 23%, extended exhaustion time by approximately 19%, and improved 4–16.1 km cycling time-trial performance by approximately 2.8%.
  • Sodium nitrate (0.1 mmol/kg/day for 3 days) significantly enhanced mitochondrial efficiency (phosphate/oxygen ratio) in healthy volunteers.
  • L-citrulline bypasses hepatic metabolism and arginase, is not degraded on first pass, and elevates plasma L-arginine more efficiently and sustainably than oral L-arginine itself, with approximately 80% catabolised to L-arginine in proximal renal tubule cells.
  • Reported side effects at higher L-arginine or L-citrulline doses (over 9 g/day) include gastrointestinal disturbances (nausea, bloating, diarrhoea, stomach pain), headache, heartburn, and palpitations; risk is elevated in cirrhosis, guanidinoacetate methyltransferase deficiency, and low blood pressure.
  • A 2006 trial (VINTAGE MI) reported that L-arginine after acute myocardial infarction was associated with worse outcomes than placebo, underscoring that these supplements are not benign in all populations.

What this study can and cannot tell us

This is a narrative review published in a supplement issue of a journal, without a described search strategy, inclusion criteria, or formal risk-of-bias assessment. Selection of primary studies appears purposive, and the review tends to summarise positive findings from small trials without applying the effect-size adjustments (for example, translating time-to-exhaustion effects into time-trial equivalents) that more rigorous syntheses now insist on.

Effect sizes reported for exercise outcomes are drawn largely from studies in moderately trained young men. The review itself notes — consistent with the broader nitrate literature — that highly trained athletes typically respond less, that older adults and women are underrepresented, and that most human evidence does not extend beyond 6 weeks of supplementation. Several claimed benefits (weight loss, common-cold prevention, memory-loss side-effect reduction) are described as lacking robust research support in the review's own conclusions.

Author affiliations include private genetic testing and research organisations (MAGI Euregio, MAGI'S LAB, MAGISNAT); the review explicitly states no conflicts of interest, but these commercial affiliations are relevant context when assessing framing choices. Safety discussion is high-level; readers making individual decisions should note the VINTAGE MI trial finding that L-arginine after myocardial infarction was associated with harm, and the reviewers' recommendation that these supplements be taken only under medical supervision when there is any relevant health condition or interacting medication.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology