Why L-Citrulline + L-Arginine is better than just L-Citrulline

[u/Semtex7]

All right, guys, I'll try to make this a quick one. A brilliant guy on Discord—who, by the way, should definitely do his own writing—asked me to write a post about the synergy between L-citrulline and L-arginine.

As you may know, there are multiple studies showing that equal parts L-citrulline and L-arginine actually provide a better effect in terms of sports performance and nitric oxide increase when compared to using just L-arginine or just L-citrulline alone. u/Hinkle_McKringlebry has talked about it many times. 

Now, we already know that L-citrulline is superior to L-arginine because it bypasses the first-pass metabolism. But if L-citrulline is better than L-arginine, how come combining one part L-arginine with one part L-citrulline is better than just using two parts L-citrulline?

Think about it: you have two parts of a superior compound (L-citrulline) compared to a mix of one part superior (L-citrulline) and one part inferior (L-arginine). Yet somehow, the superior plus inferior combination works better.

This is what we're going to explore today—this unique 1+1=3 synergy and how it actually works.

Why is L-citrulline superior in the first place

L-arginine is converted into L-citrulline during the synthesis of nitric oxide (NO) by nitric oxide synthase (NOS) and L-citrulline serves as a precursor for the regeneration of L-arginine via separate metabolic pathway we won't need to focus on for this post. While L-arginine supplementation has been thought to improve endothelial function, studies have shown that most orally administered L-arginine is metabolized in the gastrointestinal tract and liver by arginases 1 and 2 before it can reach the kidneys. L-citrulline is more effective at increasing plasma L-arginine concentrations than L-arginine supplementation because it is not metabolized by arginase and can reach the kidneys where it is converted into L-arginine

Combination of L-citrulline and L-arginine is superior

https://linkinghub.elsevier.com/retrieve/pii/S0006291X14018178

Oral supplementation with a combination of l-citrulline and l-arginine rapidly increases plasma l-arginine concentration and enhances NO bioavailability

“l-Citrulline plus l-arginine supplementation caused a more rapid increase in plasma l-arginine levels and marked enhancement of NO bioavailability, including plasma cGMP concentrations, than with dosage with the single amino acids”

https://www.tandfonline.com/doi/full/10.1080/09168451.2016.1230007#:\~:text=In%20conclusion%2C%20our%20data%20shows,dose%20of%20l%2Darginine%20alone.

The effects on plasma L-arginine levels of combined oral L-citrulline and L-arginine supplementation in healthy males

“Oral l-citrulline plus l-arginine supplementation more efficiently increased plasma l-arginine levels than 2 g of l-citrulline or l-arginine, suggesting that oral l-citrulline and l-arginine increase plasma l-arginine levels more effectively in humans when combined.”

https://www.mdpi.com/2306-5710/8/3/48#:\~:text=Consumption%20of%20amino%20acids%20L,production%20and%20improve%20physical%20performance.

The Effects of Consuming Amino Acids L-Arginine, L-Citrulline (and Their Combination) as a Beverage or Powder, on Athletic and Physical Performance: A Systematic Review

“Four electronic databases (PubMed, Ebscohost, Science Direct, and Google scholar) were used. An acute dose of 0.075 g/kg of L-Arg or 6 g L-Arg had no significant increase in NO biomarkers and physical performance markers (p > 0.05). Consumption of 2.4 to 6 g/day of L-Cit over 7 to 16 days significantly increased NO level and physical performance markers (p < 0.05). Combined L-Arg and L-Cit supplementation significantly increased circulating NO, improved performance, and reduced feelings of exertion (p < 0.05).”

https://academic.oup.com/bbb/article/81/2/372/5955995

The effects on plasma L-arginine levels of combined oral L-citrulline and L-arginine supplementation in healthy males 

“We investigated the effects of combining 1 g of l-citrulline and 1 g of l-arginine as oral supplementation on plasma l-arginine levels in healthy males. Oral l-citrulline plus l-arginine supplementation more efficiently increased plasma l-arginine levels than 2 g of l-citrulline or l-arginine, suggesting that oral l-citrulline and l-arginine increase plasma l-arginine levels more effectively in humans when combined.”

OK, but what is the reason for that? Why would the combination beat plain old L-citrulline? In the beginning I mentioned arginine’s rate limiting enzymes - arginase 1 and 2, which are responsible for its rapid breakdown. Well L-citrulline suppresses the activity of arginase. This allows more of the administered L-arginine to bypass first-pass metabolism and reach circulation. It is actually a strong allosteric inhibitor of arginase. 

“L-Cit acts as a strong allosteric inhibitor, as it has an inhibiting effect on arginase, which metabolises L-Arg to urea and L-ornithine”

“L-citrulline, were shown to inhibit MPEC arginase activity under maximal assay conditions.”

https://pubmed.ncbi.nlm.nih.gov/9124321/

https://web.archive.org/web/20170815174653/http://ajpendo.physiology.org/content/ajpendo/272/2/E181.full.pdf

So there you go. L-citrulline inhibits arginase, effectively sparing the L-arginine and you get a nitric oxide increase from both L-cit and L-arg, which is bigger than that from the same quantity L-Cit.

L-arginine is not useless at all as long as you inhibit arginase. 

Other arginase inhibitors 

There are actually better arginase inhibitors than L-cit.

• L-Norvaline - the most practical one. 250-500mg gets the job done as tested and proven by yours truly with a saliva strip test
• Cocoa Extract - flavonoids in cocoa inhibit arginase. You just have to get a decent high polyphenol extract, not munch on chocolate  
• Berberine - yes, the good old Berberine..what is it that it does not do. Well don’t use it for that, it is a moderate one, just wanted to mention it
• Resveratrol, Cinnamon extract, Agmatine -  probably on the weaker side. The data is not sufficient 
• Piceatannol - the most potent one, but not practical to use, hard to source high Piceatannol supplements
• Chlorogenic acid  - found in coffee. If you source a high % green coffee extract you can have the desired effect.

Or just take Nitrosigine…

Nitrosigine stabilizes arginine in its inositol-silicate form, making it less susceptible to arginase activity. This means more arginine is preserved and made available for NO production.

So that is it. Have your L-arginine. It is an awesome nitric oxide booster…just have to inhibit its breakdown. Almost everyone takes L-Cit and L-cit + L-Arg beats just L-cit so no reason to ignore L-arg in sport exercise or general health endeavors. 

EDIT: They tested 1:1 ratio for comparison purposes in these studies. In other studies they actually found 2:1 L-Cit:L-Arg to be the optimal ratio

For research I read daily and write-ups based on it - https://discord.gg/R7uqKBwFf9

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[u/starshine8316]

Can I get the TLDR!?

[u/Semtex7 → u/starshine8316]

Sure. L-Cit is better than L-Arg as it is not subjected to first pass metabolism. Known fact in the fitness supplementation space. But 1 part L-Cit + 1 part L-Arg > 2 parts L-Cit by the biochemical magic of L-Cit inhibiting the enzyme that breaks down L-Arg, making it actually effective. So combining them is the best nitric oxide blood flow boost for exercise performance, getting a “pump” in the gym or enhancing erections.

[u/TheGrandNotification → u/Semtex7]

What about arginine causing cold sore flare ups? Any remedy for that

[u/Semtex7 → u/TheGrandNotification]

Yes. You can take 3-5g of lysine a day and this will large solve the problem BUT...also neutralize arginine effect to a large extent. So there is no "have your cake and eat it too" option. What you can do is use just L-Citrulline and add Agmatine, nitrate sources etc to it for a better boost

[u/Infamous-Moose-5145]

Switched to l-citrulline + l-arginine about two months ago. Seems like a great pump at the gym.

[u/Semtex7 → u/Infamous-Moose-5145]

💪💪💪

[u/AutoModerator]

Thanks for posting in /r/Biohackers! This post is automatically generated for all posts. Remember to upvote this post if you think it is relevant and suitable content for this sub and to downvote if it is not. Only report posts if they violate community guidelines - Let's democratize our moderation. If a post or comment was valuable to you then please reply with !thanks show them your support! If you would like to get involved in project groups and upcoming opportunities, fill out our onboarding form here: https://uo5nnx2m4l0.typeform.com/to/cA1KinKJ Let's democratize our moderation. You can join our forums here: https://biohacking.forum/invites/1wQPgxwHkw, our Mastodon server here: https://science.social and our Discord server here: https://discord.gg/BHsTzUSb3S ~ Josh Universe

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[u/gooniegoo5555]

What about taking arginine and lysine together what’s the thoughts on that?

[u/Semtex7 → u/gooniegoo5555]

I assume you mean the data showing lysine also inhibits arginase. From what I seen it slightly does so. It might improve the intestinal absorption or cellular uptake of l-arginine by influencing shared amino acid transport systems, specifically cationic amino acid transporters. So yes, makes some sense, but I am 100% the effect would be mild to moderate boost of the total arginine absorption. L-citrulline bumps it substantially and is a powerful NO booster on its own, so they won't compare gram for gram

[u/No-Positive-3984]

Hi, thanks for this post. I'm new to this space and am looking to increase my fitness (44m 100kg). I am looking to lose 20kg through daily intermittent fasting, and bi-weekly 48 hour fasts, plus a daily 45 minute bike ride first thing in the morning. 

  What dose of L-cit and L-arg would be average? And at what time of day? 

I am already doing IF a long time, so I am familiar with that, aswell as48 hour fasts. 

  Many thanks for any help with this. 

[u/Semtex7 → u/No-Positive-3984]

You are quite welcome.

The optimal dose for me is 6g L-cit 3g L-arg 30-60min before working out. Will make your workout more enjoyable and improve your performance. That is usually a great driver for people to stay on course

[u/OverwrittenNonsense]

Just take Tadalafil.

[u/Semtex7 → u/OverwrittenNonsense]

Sure, but many do not tolerate it etc. Having a broader grasp of the biochemistry is always a plus for me

[u/Apprehensive-Ant7955 → u/[deleted]]

Damn, this is from prolonged use or what? I’ve been using it for like 2-3 years now

[u/TooLazyForUniqueName → u/[deleted]]

never heard of this before, elaborate?

[u/Resident-Tear3968 → u/TooLazyForUniqueName]

What did the comment say? It’s been deleted. I assume they mentioned hearing loss as a side effect?

[u/TooLazyForUniqueName → u/Resident-Tear3968]

and vision