L Citrulline supplement benefit and side effects, relation to l arginine, is it useful for hypertension or impotence treatment?
June 28 2017 by Ray Sahelian, M.D.

L Citrulline, like arginine, is an important amino acid since it can convert into nitric oxide. This nutrient is found in watermelon rind and less so in watermelon flesh, but I doubt consuming watermelon rind or eating watermelon fruit will have any significant sexual enhancing effect.

Sexual enhancement, better erections
If you are planning to use Citrulline pills as a way to enhance erectile function, consider instead a potent herbal sexual formula. Passion Rx with Yohimbe is much more potent than citrulline or arginine in terms of libido and erectile function.

Mechanism of action, potential uses and benefits
l-citrulline is a naturally occurring non-essential amino acid, an intermediate in urea cycle. It is a hydroxyl radical scavenger and a more effective precursor of arginine and nitric oxide NO than arginine itself. Supplementation is being tested in conditions like erectile dysfunction, sickle cell anemia, short bowel syndrome (to restore nitrogen balance), cancer chemotherapy, and urea cycle disorders.

Better erections with nitric oxide
Although citrulline is touted as a way to improve erections, there are more potent dietary supplements that work for erectile dysfunction including catuaba, yohimbe, muira puama, LJ100 which is a Tongkat ali extract, panax ginseng, tribulus, and horny goat weed. If you really want to enhance libido, sensation and sexual stamina, Passion Rx with Yohimbe is one of your best options. 

Q. I read online about a product called citrulline malate used to increase nitric oxide and wondered if you had any information about its effectiveness. I wondered if taken in the form of citrulline malate the results might be different in terms of sexual enhancement or desire or erectile function.
   A. As of 2016, I have seen one human research regarding the role of citrulline malate supplements that found improved erectile function and sexual enhancement.

How does citrulline supplement affect erections and sexual desire? How does it affect the penis in the flaccid state since there is more nitric oxide in the system.
    Citrulline as a supplement works to increase nitric oxide levels and could be of help for erection enhancement or sexual desire improvement. Its use likely has a minor influence on penis erection and is not as effective as a treatment for ED as prescription medications.

Urology. 2011. Oral L-citrulline supplementation improves erection hardness in men with mild erectile dysfunction. To test the efficacy and safety of oral L-citrulline supplementation in improving erection hardness in patients with mild erectile dysfunction (ED). L-arginine supplementation improves nitric oxide-mediated vasodilation and endothelial function; however, oral administration has been hampered by extensive presystemic metabolism. In contrast, L-citrulline escapes presystemic metabolism and is converted to L-arginine, thus setting the rationale for oral L-citrulline supplementation as a donor for the L-arginine/nitric oxide pathway of penile erection. In the present single-blind study, men with mild ED (erection hardness score of 3) received a placebo for 1 month and L-citrulline, 1.5 g/d, for another month. The erection hardness score, number of intercourses per month, treatment satisfaction, and adverse events were recorded. There was mild improvement in those who took the natural supplement.

Andrology (Los Angeles). 2015. Treatment with a combination of ginger, L-citrulline, muira puama and Paullinia cupana can reverse the progression of corporal smooth muscle loss, fibrosis and veno-occlusive dysfunction in the aging rat. Aging associated erectile dysfunction is characterized within the corpora by a progressive apoptosis of the smooth muscle cells and their replacement by collagen. Nitric oxide from iNOS has been shown to inhibit these histological changes in the corpora while PDE5 inhibitors as well as certain nutraceuticals such as ginger, paullinia cupana, muira puama and L-citrulline are known to enhance the effects of NO. We evaluated whether the daily oral administration for 2 months with a combination of ginger, paullinia cupana, muira puama and L-citrulline (COMP-4) can effectively delay the ongoing corporal fibrosis, smooth muscle cell apoptosis and cavernosal veno-occlusive dysfunction (CVOD) seen in middle aged rats similar to that seen with tadalafil. 10 Month old Fisher 344 rats were treated or not for two months with COMP-4, tadalafil or a combination of tadalafil plus COMP-4. CVOD was determined by dynamic infusion cavernosometry. Penile sections of the corpora cavernosa were subjected to Masson trichrome staining to evaluate fibrosis and immunohistochemistry for desmin as a marker of smooth muscle content and inducible nitric oxide synthase (iNOS) followed by image analysis. Oxidative stress levels were determined by GSH/GSSG ratio in whole blood. A decline in the non-treated rat's erectile function is evident by 10-12 months of age and is accompanied by a decrease in the corporal smooth muscle content determined by desmin expression and an increase in corporal fibrosis. The daily treatment for two months with COMP-4 reverses this process by reducing systemic oxidative stress and increasing desmin and iNOS expression, similar to that seen with tadalafil or the combination of COMP-4 plus tadalafil. An oral combination of ginger, muira puama, Paullinia cupana and L-citrulline seems to be as effective as daily PDE5 inhibitor therapy in either delaying or reversing the onset of the histological and functional characteristics of aging related erectile dysfunction.

J Int Soc Sports Nutr. 2015. Combined L-citrulline and glutathione supplementation increases the concentration of markers indicative of nitric oxide synthesis. Nitric oxide (NO) is endogenously synthesized from L-arginine and L-citrulline. Due to its effects on nitric oxide synthase (NOS), reduced glutathione (GSH) may protect against the oxidative reduction of NO. The present study determined the effectiveness of L-citrulline and/or GSH on markers indicative of NO synthesis in in vivo conditions with rodents and humans and also in an in vitro condition. Combining L-citrulline with GSH augments increases in nitrite and NOx levels during in vitro and in vivo conditions.

Citrulline side effects, safety, is there a danger with use?
I have not seen any reports in the medical literature regarding citrulline side effects and have not had any consumers email with such side effects.

Watermelon content
Watermelon consumption increases plasma arginine concentrations in adults.
Nutrition. 2007. USDA-ARS, South Central Agricultural Research Laboratory, Lane, Oklahoma, USA.
Watermelon is a rich source of citrulline. No detailed studies have been conducted to evaluate plasma arginine response in humans after long-term feeding of citrulline from natural plant sources. This study investigated if watermelon juice consumption increases fasting concentrations of plasma arginine, ornithine, and citrulline in healthy adult humans. Subjects consumed a controlled diet and 0 (control), 780, or 1560 g of watermelon juice per day for 3 weeks in a crossover design. The treatments provided 1 and 2 gram of citrulline per day. Compared with the baseline, fasting plasma arginine concentrations increased 12% after 3 wk of the lower-dose watermelon treatment; arginine and ornithine concentrations increased 22% and 18%, respectively, after 3 wk of the higher-dose watermelon treatment. Fasting citrulline concentrations did not increase relative to the control but remained stable throughout the study. The increased fasting plasma concentrations of arginine and ornithine and stable concentrations of plasma citrulline in response to watermelon juice consumption indicated that the citrulline from this plant origin was effectively converted into arginine.

Does watermelon have effects similar to Viagra?
In 2008 the media made a big story of watermelon having Viagra-like effects since watermelon contains a substance called citrulline which converts into the amino acid arginine. Arginine helps dilate blood vessels. Because of this biochemical connection, Bhimu Patil, a researcher and director of Texas A&M's Fruit and Vegetable Improvement Center was quoted saying, "Arginine boosts nitric oxide, which relaxes blood vessels, the same basic effect that Viagra has, to treat erectile dysfunction and maybe even prevent it." Well, this is all the media needed to hype this story. But, does eating watermelon flesh or rind have any sexual enhancing effects? I love watermelon, it is one of my favorite foods. I actually love the combination of watermelon and feta cheese. I have been known to eat half a large watermelon at one sitting. I have not noticed any Viagra-like effects from eating watermelon or drinking watermelon juice. I have also tried citrulline supplements and arginine supplements and have not noticed much of an effect on erectile function. Even if citrulline and arginine dilate blood vessels, their effects are brief.
   According to Bhimu Patil, more citrulline - about 60 percent - is found in watermelon rind than in the flesh.

Blood flow, dilation of blood vessels
Research on this topic is no always consistent 

Appl Physiol Nutr Metab. 2017. Effect of acute nitrate and citrulline supplementation on muscle microvascular response to ischemia-reperfusion in healthy humans.Nitric oxide (NO) is implicated in vasomotor control mechanisms altering the diameter of the vessels under various physiological and pathological conditions. There are two main NO production pathways, one NO synthase (NOS) independent (nitrate-nitrite-NO) and the other is NOS dependent (citrulline-arginine-NO). The objective of the study was to evaluate the effect of acute nitrate and citrulline supplementation on post ischemic vascular response in healthy subjects. Fourteen subjects performed two leg vascular occlusion tests, 3 days apart. They were randomly assigned to consume a drink containing 1200 mg of nitrate and 6 g of citrulline (N+C) or a placebo (Pl). Changes in total hemoglobin (Hbtot) and oxyhemoglobin (HbO2) concentrations were recorded by near infrared spectroscopy (NIRS) on the thigh and calf muscles. No differences between N+C and Pl were observed during the ischemic period. Hbtot increased to a larger extent during the reperfusion period for the thigh and the calf in the N+C versus Pl condition. Similar results were found regarding HbO2 for the thigh and the calf. The larger post-occlusive Hbtot and HbO2 responses observed after N+C intake suggests a greater post-ischemic vasodilation which may be due to increased NO availability, via the activation of the two main NO production pathways.

This study shows no improvement
Am J Physiol Endocrinol Metab. 2014. Citrulline does not enhance blood flow, microvascular circulation, or myofibrillar protein synthesis in elderly men at rest or following exercise. Aging is associated with anabolic resistance, a reduced sensitivity of myofibrillar protein synthesis (MPS) to postprandial hyperaminoacidemia, particularly with low protein doses. Impairments in postprandial skeletal muscle blood flow and/or microvascular perfusion with hyperaminoacidemia and hyperinsulinemia may contribute to anabolic resistance. We examined whether providing citrulline, a precursor for arginine and nitric oxide synthesis, would increase arterial blood flow, skeletal muscle microvascular perfusion, MPS, and signaling through mTORC1. Twenty-one elderly males (65-80 yr) completed acute unilateral resistance exercise prior to being assigned to ingest a high dose (45 g) of whey protein (WHEY) or a low dose (15 g) of whey protein with 10 g of citrulline (WHEY + CIT) or with 10 g of nonessential amino acids (WHEY + NEAA).

I have no reason to believe that citrulline and arginine would not be safe when used in low dosages by a person with diabetes.

Exercise, physical performance
J Sports Sci. 2014 Dec 17. The effect of l-citrulline and watermelon juice supplementation on anaerobic and aerobic exercise performance. A single dose of l-citrulline or watermelon juice as a pre-exercise supplement appears to be ineffective in improving exercise performance.

Email - I read in Science Daily about citruline from watermelon being good for hypertension. FSU Assistant Professor Arturo Figueroa and Professor Bahram H. Arjmandi found that when six grams of the amino acid L-citrulline / L-arginine from watermelon extract was administered daily for six weeks, there was improved arterial function and consequently lowered aortic blood pressure in all nine of their prehypertensive subjects (four men and five postmenopausal women, ages 51-57).
   Response: It would help to see additional studies to determine whether the results are consistent and what the required dosage would be.

Content in foods
Citrulline is found in high concentrations in watermelon rind and flesh. it is also present in other curcubits, like cucumbers and cantaloupe, at very low levels, and in the milk protein casein. The highest concentrations are found in walnut seedlings.

Information on Arginine, Citrulline, and Ornithine
The kidney plays a major role in arginine amino acid metabolism in 3 principal ways: arginine synthesis, creatine synthesis, and arginine reabsorption. Appreciable quantities of arginine are synthesized in the kidney from citrulline produced by the intestine. The rate of arginine synthesis depends on citrulline delivery and does not appear to be regulated by dietary arginine availability. Renal arginine synthesis in humans produces approximately 2 g /d, which may be compared to an intake, from a Western diet, of approximately 4 to 5 g/d. Spontaneous, nonenzymatic breakdown of creatine and creatine phosphate to creatinine causes the excretion of 1 to 2 g creatinine/d and requires the replacement of an equivalent amount of creatine from the diet and by endogenous synthesis. The first enzyme of creatine biosynthesis, L-arginine:glycine amidinotransferase, occurs in the kidney and produces guanidinoacetate, which is released into the renal vein. The renal output of guanidinoacetate, however, is rather low, and we propose that the entire pathway of creatine synthesis may also occur in the liver. Renal arginine reabsorption salvages approximately 3 g arginine/d. At the apical membrane of proximal tubular cells, arginine shares a transporter with lysine, ornithine, and cystine. Defects in this heteromeric transporter cause cystinuria, which is also characterized by urinary loss of arginine, lysine, and ornithine. Arginine amino acid is transported out of the proximal tubular cells at the basolateral membrane by another heteromeric transporter, which also transports lysine and ornithine. Defects in this transporter cause lysinuric protein intolerance.

Citrulline malate supplement
Citrulline malate promotes aerobic energy production in human exercising muscle.
Br J Sports Med. 2002.
To investigate the effects of citrulline malate supplementation on muscle energetics. Eighteen men complaining of fatigue but with no documented disease were included in the study. A rest-exercise (finger flexions)-recovery protocol was performed twice before, three times during, and once after 15 days of oral supplementation with 6 g/day citrulline malate. Citrulline malate ingestion resulted in a significant reduction in the sensation of fatigue, a 34% increase in the rate of oxidative ATP production during exercise, and a 20% increase in the rate of phosphocreatine recovery after exercise, indicating a larger contribution of oxidative ATP synthesis to energy production. The changes in muscle metabolism produced by citrulline malate treatment indicate that it may promote aerobic energy production.

Combining arginine with citrulline
I am a healthy 71 year old married man experiencing some reduction of erectile function. I have been taking two 750 mg L-Arginine capsules per day, one in the morning and one in the evening, and my perception is that this does provide some improvement. I can usually function sexually several times per month without resorting to Cialis or Viagra, but I'm not as reliable as I used to be most of my life. I tried using your Passion Rx product and used a 30 day supply, following the directions of taking one every other day. Frankly, I couldn't notice any effect at all with this product. I have recently read articles regarding the combination of L-citruline and L-Arginine indicating that this combination seems to have significantly more effect than L-Arginine alone. However, I don't find any guideline for dosages of these amino acid products. Do you have any advice regarding the combination?
   At present we don't have any research on anecdotes on the combination of arginine and citrulline. We have about an 80 % response rate to Passion Rx, we wish it was higher but for some reason some people don't respond while others notice significant benefit with even a third of a capsule. Some people who don't respond to Passion Rx respond to Prostate Power Rx, but this is not consistent either. Studies show Viagra and Cialis have about a 60 to 70 percent response rate.

How is L-citrulline ethyl ester HCl different clinically?
   I have not seen any studies comparing L-Citrulline Ethyl Ester HCl to plain citrulline, so not much can be said at this time.

Does taking them together help them work better in the body? If so which one should I take more of or is arginine effective when taken alone? Which one is better when converting to nitric oxide in the body
    The best way to find out is to try each one alone and together in varying dosages. There's not enough human research to know whether one works better than the other or whether the combination is more effective. I have not seen comparison studies to know which one converts better and longer to nitric oxide.

This is a question to add to the various information and questions and answers on your website concerning these two amino acids. Does Dr. Sahelian have any specific reaction to the substantial comments on this subject by Louis J. Agnarro, PhD, who I understand won the Nobel Prize for Medicine in 1998 for his research into nitric acid. I saw his comments on pages 485-6 of Bottom Line Publication's 2006 expanded edition of "The World's Greatest Treasury of Health Secrets." The comments in summary were that nitric acid helps prevent heart disease and stroke by expanding blood vessels, controlling platelet function, reducing arterial plaque by 50%, and lowering total cholesteral by 10% to 20%. And that it is hard to get sufficient l-arginine from food so supplements are recommended that will increase production of nitric acid in blood vessels. L-arginine is recommended at a dosage of 2000 to 3000 mg taken twice daily for a total of 4000 to 6000 mg, and L-citrulline is recommended at a dosage of 400 to 600 mg daily (the L-citrulline is needed because supplemental arginine doesn't enter cells readily unless combined with it). Dr. Ignarro also recommends a daily multivitamin that includes about 50 IU of vitamin E, and 500 mg of vitamin C, and aerobic exercise and minimized intake of saturated fat and more fiber. Dr. Sahalian's reaction to Dr. Ignarro's specifics would be much appreciated.
    Studies with the use of arginine and citrulline supplements have not shown consistent results in terms of their benefit for cardiovascular disease, therefore, at this time, it is difficult to say for certain whether the regular use of these supplements for prolonged periods will have long lasting health benefits. The use of small amounts of vitamin E complex and a few hundred mg of vitamin C are reasonable.

Now Foods, L-Citrulline, 750 mg, 180 Capsules

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Supplement Facts
Serving Size: 2 Capsules
Servings Per Container: 90
  Amount Per Serving % Daily Value
L-Citrulline 1.5 g (1,500 mg) *
* Daily Value not established.

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