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

March 27 2014

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. If you have an interest in a potent herbal sexual formula, Passion Rx is the product to seriously consider rather than eating watermelon. Passion Rx 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
LJ100 which is a Tongkat ali extract, tribulus, catuaba, 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 2014, I have not seen any human research regarding the role of citrulline malate supplements and erectile function and not have come across any human studies in regards to sexual enhancement.

Citrulline side effects, safety
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.

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

Hypertension
Email - I read in Science Daily (Oct 2010) 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.

Questions
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.

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.
    We are not impressed by citrulline as a supplement for erection enhancement or sexual desire improvement. Its use is not likely to significantly influence penis erection.

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.