Some of the most popular supplements today are the so called pre-workout nitric oxide (NO) boosters [1, 2]. These contain a panoply of ingredients, but one the main ones is arginine. The rationale goes that L-arginine is a precursor to nitric oxide (NO) and NO is a potent vasodilator [3, 4] Theoretically this would increase blood flow and nutrient/oxygen delivery to exercising muscles and thereby boost performance, as well as recovery.
While it is true that L-arginine supplementation mat be beneficial for various clinical populations (see below), studies in healthy adults have not unequivocally supported the marketing hype surrounding arginine supplementation and nitric oxide boosters [1, 5, 6]. Here’s why…
Some reasons explaining the inefficacy of arginine supplementation and arginine based “nitric oxide boosters”
Many pre-workout NO boosting supplements rely on the arginine-NO pathway – and a lot of theoretical assumptions. Some reason for the conflicting findings on arginine supplementation are that studies have used different routes of administration (oral vs. intravenous), various forms of L-arginine, varying exercise testing protocols, different subjects (trained vs. untrained, young vs. elderly), and supplement cocktails containing other substances (eg. creatine, beta-alanine, caffeine, carbs etc) which do have performance enhancing effects on their own.
The rationale for L-arginine supplementation is based largely on research using intravenous L-arginine, often at a high dose of 30 g. This has no practical relevance since most, if not all, supplements are taken orally, and in lower doses. In a direct head-to-head comparison of oral and intravenous L-arginine administration, no effect on vasodilatation (widening of blood vessels) or blood flow was found after oral L-arginine supplementation . One reason for this could be the extensive elimination of orally ingested L-arginine due to intestinal arginase activity and its low bioavailability . To circumvent the low bioavailability one would have to ingest a very large dose of L-arginine, which not only has an unpleasant taste, but also can cause gastric problems .
The Arginine Paradox
The arginine-NO pathway is controlled by an enzyme called eNOS (endothelial nitric oxide synthase) , which converts arginine into NO. The important thing to know is that even in people not taking any arginine supplements, blood level of arginine are already high enough to saturate eNOS. And when an enzyme is saturated with substrate (in this case L-arginine) more substrate won’t have an effect on a reaction. Therefore, if you’re healthy, when you supplement L-arginine (even in large doses) you won’t get more NO from the arginine-NO pathway, simply because L-arginine is not rate-limiting for eNOS.
However, the story is different in clinical conditions like e.g. high blood pressure [12, 13], elevated or abnormal cholesterol levels [14, 15], heart disease , insulin resistance , diabetes [18, 19] and in the elderly [13, 20, 21]. In those circumstances arginine supplementation may exert beneficial effects, possibly, at least in part, due to increased NO production . Thus, it appears that L-arginine may become a limiting factor for NO synthesis in clinical conditions, but not for healthy individuals.
The term “L-arginine paradox” refers to these specific situations in which L-arginine supplementation indeed does stimulate eNOS activity and NO production, even when blood arginine levels are within the normal range.
One explanation for the L-arginine paradox is the presence of high levels of ADMA (asymmetric dimethylarginine), which is an inhibitor of eNOS [10, 22-24]. ADMA is produced as part of the body’s normal metabolism [25-27], but in clinical conditions ADMA levels are elevated several-fold . In the presence of elevated blood levels of ADMA, eNOS activity is impaired, with a consequent reduced NO production.
How L-arginine supplementation works in the context of elevated ADMA levels
Because ADMA displaces L-arginine and thereby reduces L-arginine availability for eNOS, the ratio of L-arginine to ADMA determines how much of the L-arginine floating around in the blood that will be available for eNOS to use for NO production [28, 29]. In conditions with elevated ADMA levels, L-arginine supplementation will antagonize ADMA by increasing the L-arginine/ADMA ratio, and thereby elevate the availability of L-arginine for eNOS, thus increase NO production . This is supported by studies showing that L-arginine supplementation reverses endothelial (blood vessel) dysfunction caused by high ADMA levels in clinical populations [20, 31-33], and that there exists a direct correlation between the change in L-arginine/ADMA ratio and the change in blood flow mediated dilation (vasodilatation) .
How to combat elevated ADMA levels
The importance of ADMA is underscored by the fact that it is considered a novel cardiovascular risk factor [22, 33, 34]. ADMA seems to mediate the negative effects of many risk factors on the eNOS pathway. Therefore, blood ADMA levels have been suggested to be an “Über marker”, or an overall risk factor that reflects the summative effect of multiple risk factors on endothelial and cardiovascular health .
Because of this, drug companies are fervently trying to develop drugs that lower ADMA levels. As of this writing there is no ADMA specific drug available. The strongest candidate as an ADMA specific drug is DDAH, the enzyme that naturally breaks down ADMA [27, 35, 36], and whose activity is also impaired in the above mentioned clinical conditions.
DDAH boosting drugs are still in the pre-clinical research phase, and it will likely take many years before they, or any other ADMA lowering drugs, enter the market. However, several well known drugs used for diabetes (metformin, rosiglitazone) and high blood pressure (ACE inhibitors, angiotensin receptor antagonists) have been shown to lower ADMA levels [37-40]. Today, the only non-prescription dietary option is L-arginine supplementation for those in need.
Will L-arginine supplementation benefit you?
If you are insulin resistant (have elevated levels of insulin and/or blood glucose), have high blood pressure, elevated blood cholesterol (or more precisely dyslipidemia, i.e. lipid abnormalities), high homocysteine levels , diabetes or cardiovascular disease, and/or have passed middle-age, L-arginine supplementation may work for you in restoring subpar NO production.
In contrast, if you are below middle-age and don’t have any risk factors and, save your money. For you, nitrate or nitrite supplementation, which produces NO via the nitrate–nitrite–NO pathway, is a more promising option. Accumulating research suggests that boosting NO production via the nitrate–nitrite–NO pathway may provide significant health and performance enhancing effects for both those affected by risk factors, as well as healthy people and athlete. For more info on this, see my previous article “Nitrate supplementation – ramp up the less well-known NO synthesizing pathway to boost performance and health“.
1. Bloomer RJ. Nitric oxide supplements for sports. Strength and Conditioning Journal. 2010;32(2):14-20.
2. Bloomer RJ, Farney TM, Trepanowski JF, et al. Comparison of pre-workout nitric oxide stimulating dietary supplements on skeletal muscle oxygen saturation, blood nitrate/nitrite, lipid peroxidation, and upper body exercise performance in resistance trained men. Journal of the International Society of Sports Nutrition. 2010;7:16.
3. Bode-Boger SM, Boger RH, Creutzig A, et al. L-arginine infusion decreases peripheral arterial resistance and inhibits platelet aggregation in healthy subjects. Clin Sci (Lond). 1994;87(3):303-310.
4. Giugliano D, Marfella R, Verrazzo G, et al. The vascular effects of L-Arginine in humans. The role of endogenous insulin. The Journal of clinical investigation. 1997;99(3):433-438.
5. Alvares TS, Meirelles CM, Bhambhani YN, et al. L-Arginine as a potential ergogenic aid in healthy subjects. Sports Med. 2011;41(3):233-248.
6. Wax B, Kavazis AN, Webb HE, et al. Acute L-arginine alpha ketoglutarate supplementation fails to improve muscular performance in resistance trained and untrained men. Journal of the International Society of Sports Nutrition. 2012;9(1):17.
7. Bode-Boger SM, Boger RH, Galland A, et al. L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. British journal of clinical pharmacology. 1998;46(5):489-497.
8. Schwedhelm E, Maas R, Freese R, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. British journal of clinical pharmacology. 2008;65(1):51-59.
9. Robinson TM, Sewell DA, Greenhaff PL. L-arginine ingestion after rest and exercise: effects on glucose disposal. Medicine and science in sports and exercise. 2003;35(8):1309-1315.
10. Vallance P, Chan N. Endothelial function and nitric oxide: clinical relevance. Heart. 2001;85(3):342-350.
11. Boger RH, Bode-Boger SM. The clinical pharmacology of L-arginine. Annual review of pharmacology and toxicology. 2001;41:79-99.
12. Pollock JS, Forstermann U, Mitchell JA, et al. Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proceedings of the National Academy of Sciences of the United States of America. 1991;88(23):10480-10484.
13. Gokce N. L-arginine and hypertension. The Journal of nutrition. 2004;134(10 Suppl):2807S-2811S; discussion 2818S-2819S.
14. Higashi Y, Oshima T, Ozono R, et al. Aging and severity of hypertension attenuate endothelium-dependent renal vascular relaxation in humans. Hypertension. 1997;30(2 Pt 1):252-258.
15. Clarkson P, Adams MR, Powe AJ, et al. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. The Journal of clinical investigation. 1996;97(8):1989-1994.
16. Kawano H, Motoyama T, Hirai N, et al. Endothelial dysfunction in hypercholesterolemia is improved by L-arginine administration: possible role of oxidative stress. Atherosclerosis. 2002;161(2):375-380.
17. Adams MR, McCredie R, Jessup W, et al. Oral L-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery disease. Atherosclerosis. 1997;129(2):261-269.
18. Sydow K, Mondon CE, Cooke JP. Insulin resistance: potential role of the endogenous nitric oxide synthase inhibitor ADMA. Vasc Med. 2005;10 Suppl 1:S35-43.
19. Piatti PM, Monti LD, Valsecchi G, et al. Long-term oral L-arginine administration improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients. Diabetes care. 2001;24(5):875-880.
20. Pieper GM, Siebeneich W, Dondlinger LA. Short-term oral administration of L-arginine reverses defective endothelium-dependent relaxation and cGMP generation in diabetes. European journal of pharmacology. 1996;317(2-3):317-320.
21. Bode-Boger SM, Muke J, Surdacki A, et al. Oral L-arginine improves endothelial function in healthy individuals older than 70 years. Vasc Med. 2003;8(2):77-81.
22. Boger RH, Cooke JP, Vallance P. ADMA: an emerging cardiovascular risk factor. Vasc Med. 2005;10 Suppl 1:S1-2.
23. Cooke JP. ADMA: its role in vascular disease. Vasc Med. 2005;10 Suppl 1:S11-17.
24. Boger RH. Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the “L-arginine paradox” and acts as a novel cardiovascular risk factor. The Journal of nutrition. 2004;134(10 Suppl):2842S-2847S; discussion 2853S.
25. Sibal L, Agarwal SC, Home PD, et al. The Role of Asymmetric Dimethylarginine (ADMA) in Endothelial Dysfunction and Cardiovascular Disease. Current cardiology reviews. 2010;6(2):82-90.
26. Cooke JP. Asymmetrical dimethylarginine: the Uber marker? Circulation. 2004;109(15):1813-1818.
27. Tran CT, Leiper JM, Vallance P. The DDAH/ADMA/NOS pathway. Atherosclerosis Supplements. 2003;4(4):33-40.
28. Tsikas D, Sandmann J, Savva A, et al. Assessment of nitric oxide synthase activity in vitro and in vivo by gas chromatography-mass spectrometry. Journal of chromatography B, Biomedical sciences and applications. 2000;742(1):143-153.
29. Boger RH, Vallance P, Cooke JP. Asymmetric dimethylarginine (ADMA): a key regulator of nitric oxide synthase. Atherosclerosis Supplements. 2003;4(4):1-3.
30. Bode-Boger SM, Scalera F, Ignarro LJ. The L-arginine paradox: Importance of the L-arginine/asymmetrical dimethylarginine ratio. Pharmacology & therapeutics. 2007;114(3):295-306.
31. Boger RH, Bode-Boger SM, Thiele W, et al. Restoring vascular nitric oxide formation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. Journal of the American College of Cardiology. 1998;32(5):1336-1344.
32. Sydow K, Schwedhelm E, Arakawa N, et al. ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins. Cardiovascular research. 2003;57(1):244-252.
33. Boger RH, Bode-Boger SM, Szuba A, et al. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation. 1998;98(18):1842-1847.
34. Boger RH, Zoccali C. ADMA: a novel risk factor that explains excess cardiovascular event rate in patients with end-stage renal disease. Atherosclerosis Supplements. 2003;4(4):23-28.
35. Cooke JP, Ghebremariam YT. DDAH says NO to ADMA. Arteriosclerosis, thrombosis, and vascular biology. 2011;31(7):1462-1464.
36. Cooke JP. DDAH: a target for vascular therapy? Vasc Med. 2010;15(3):235-238.
37. Asagami T, Abbasi F, Stuelinger M, et al. Metformin treatment lowers asymmetric dimethylarginine concentrations in patients with type 2 diabetes. Metabolism: clinical and experimental. 2002;51(7):843-846.
38. Stuhlinger MC, Abbasi F, Chu JW, et al. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA : the journal of the American Medical Association. 2002;287(11):1420-1426.
39. Ito A, Egashira K, Narishige T, et al. Renin-angiotensin system is involved in the mechanism of increased serum asymmetric dimethylarginine in essential hypertension. Japanese circulation journal. 2001;65(9):775-778.
40. Delles C, Schneider MP, John S, et al. Angiotensin converting enzyme inhibition and angiotensin II AT1-receptor blockade reduce the levels of asymmetrical N(G), N(G)-dimethylarginine in human essential hypertension. American journal of hypertension. 2002;15(7 Pt 1):590-593.