L-CITRULLINE

BACKGROUND

Ingredient Type: Amino Acid

Also Known As: Citrulline, 2-amino-5-(carbamoylamino) pentanoic acid, L-Citrulina, Citrulline Malate, L-Citrulline-Alpha Ketoglutaric Acid, L-Citrulline AKG, Malate de Citrulline, L-Citrulline Malate

A naturally occurring, non-essential amino acid, L-Citrulline, is made in the body, where the body converts it into L-arginine, another amino acid which is known to enhance the production of nitric oxide. The name itself is derived from the Latin term Citrullus vulgaris, specifically used for watermelon. L-Citrulline, which is commonly found in watermelon, as was first isolated in 1914 by Yotaro Koga and Ryo Odake. It however had been named and described by gastroenterologists since around the 19^th century. This particular amino acid is known as a key intermediate in the urea cycle, which allows for mammals to remove toxic ammonia through the conversion into urea, which is then excreted through the urine.

TRADITIONAL USES

Traditionally, people utilized L-citrulline for health benefits such as sickle cell disease, athletic performance, and erectile dysfunction (ED). It was also evident that heart diseases and high blood pressure were also positively supported through the use of L-citrulline supplementation. People in ancient times for instance used L-Citrulline for diseases, including short bowel syndrome, celiac disease, and radiation that caused small bowel damage. It can be consumed in a prescribed dosage in supplementation form (14).

 

Science-Backed Evidence

 

L-citrulline and Erectile Dysfunction (ED)

Erectile dysfunction (ED) has become one of the more significant complications concerning men, even as young adults. ED may lead to poor sexual desire as well as trouble keeping an erection. The causes of ED may include physical issues such as high cholesterol, heart disease, diabetes, smoking, high blood pressure, and obesity. On the other hand, erectile dysfunction can also be caused by stress, anxiety, relationship complications, depression, and other mental health issues that interfere with self-esteem. L-citrulline is a prominent amino acid that has been used for the treatment of erectile dysfunction for ages due to its ability to increase nitric oxide levels.

In one study, oral L-citrulline supplementation was investigated to analyze the safety and efficacy of the improvement of erectile dysfunction (ED) in patients. A single-blind study was performed in which men were included who presented with mild erectile hardness. They received L-citrulline, 1.5 g/d, for one month and a placebo for one month. During this whole time, a number of intercourses per month, erection hardness score, adverse events, and treatment satisfaction were observed and recorded. 24 patients concluded the study with no adverse events. It was observed that L-citrulline supplementation improved the erection hardness score from a 3 to a 4. A score of 3 is considered a mild erection and a 4 is considered normal erectile function, which was achieved after L-citrulline supplementation. It was concluded that L-citrulline supplementation indicated safe outcomes and was well-accepted psychologically. As a result of this research, it was safely concluded that L-citrulline can be used as a treatment for erectile dysfunction (1).

Another study observed the significance of oral L-citrulline supplementation for the treatment of erectile functions in rats. 8-week-old Wistar rats were used who were, of whom were divided into 3 different groups, a control group, a ligation group, and citrulline group which were supplemented with an oral 2% l‐citrulline water supplement. For 3 weeks, citrulline water was provided to rats with arteriogenic erectile dysfunction. Cavernous nerve stimulation was used to measure maximum intracavernous pressure/mean arterial pressure (ICP/MAP) ratios for the evaluation of erectile functioning at 4 weeks. Penises were then resected, followed by a Masson’s trichrome stain. High‐performance liquid chromatography was performed to check serum nitrogen oxide (NOx) levels as well. Statistical analysis was observed through Bonferroni’s multiple t-tests. The results showed that ICP/MAP and SM/collagen ratios had improved with oral l‐citrulline supplementation. It was concluded that l‐citrulline can be used as a therapeutic treatment for acute arteriogenic ED (2).

According to an article, the efficacy of oral l-citrulline for penile structure disruption and erectile dysfunction in a rat model was similarly observed. 15-week-old male Wistar rats were used in the study and divided into several groups, including a control group, a castrated group, and castrated + l-citrulline treated with 2% l-citrulline water. Masson’s trichrome staining was used to evaluate the penile structure. Moreover, l-arginine, NG, NG-dimethylarginine, serum bioavailable testosterone, l-citrulline, and nitrogen oxide levels were assessed. Based on intracavernous pressure changes, erectile function was evaluated, and observed by electrostimulation of cavernous nerves. Reduction of bioavailable testosterone concentrations were indicated in the castrated + l-citrulline group when compared to the control group. Also, l-arginine-to-NG, NG-dimethylarginine ratios, serum l-citrulline, NG, NG-dimethylarginine levels, and l-arginine were significantly enhanced in the castrated + l-citrulline group. It was observed that erectile response in rats was improved by oral l-citrulline (3). 

 

 

L-Citrulline and the Kidneys

Kidneys are an important organ as they aid in the removal of extra fluid and waste from the body. The cells of the body produce an acid which is a byproduct of its metabolic functions. It is the kidneys responsibility to neutralize that acid and excrete it through the urine. The kidney ultimately balances salt, minerals (calcium, potassium, sodium, phosphorus), and water in the blood, helping to support its homeostatic environment. L-citrulline is considered a non-essential amino acid that can be changed into L-arginine by the kidneys, which can be used as a therapeutic agent to treat kidney-related complications.

In a study, streptozotocin (STZ)-induced type 1 diabetic mice and rats were used to study the efficiency of l-citrulline for the reduction of diabetic neuropathy (DN). In this study, l-citrulline was given to STZ-C57BL6 mice in drinking water. To evaluate the efficacy, l-cit-treated STZ-rats and diabetic ArgII knock-out mice were used. The protective effects of l-citrulline were indicated in the kidneys of streptozotocin-treated rats. It was also observed that kidney hypertrophy and urinary albumin excretion were reduced. Hypertrophy, greater levels of blood urea nitrogen, and dilated tubules were indicated in diabetic ArgII knock-out mice. The results analyzed were found to restore nitric oxide/reactive oxygen species balance by l-citrulline supplementation. Moreover, the anti-inflammatory profile was observed in the rats treated with l-citrulline. It was concluded that supplementation of l-citrulline in diabetic rats showed a positive response and is highly protective of nephron function. Therefore, it can be concluded that the use of L-citrulline has the potential to be used as a treatment for kidney function (4).

According to one article, the effects of l-citrulline were analyzed on glycerol-induced ARF and kidney function. The subjects that were used for the experiment were divided into 6 groups, including a control group, a glycerol group, a glycerol plus dexamethasone group, and the remaining groups with glycerol plus L-citrulline (300, 600, and 900 mg/kg, respectively). Additionally, kidney tissues were harvested for pathology analysis for future studies. Within the kidney tissues, the content of glutathione, malondialdehyde, nitric oxide, levels of urea nitrogen and creatinine, and activity of superoxide dismutase and nitric oxide were analyzed. Results showed improved kidney function and an enhanced effect of l-citrulline on impaired intrarenal oxygenation compared to the glycerol group. It was also observed that l-citrulline prevented morphological renal deterioration and renal oxidative stress-related damage. It was concluded that l-citrulline has the tendency to impact kidney function and can potentially be used as a therapeutic agent to support overall renal function (5).

 

Alzheimer’s Disease (AD) and L-Citrulline

There are an estimated 6 million individuals at the age of 65 and older that have Alzheimer’s disease, or one newly diagnosed patient every 60 seconds. Alzheimer’s or a closely associated form of dementia is a leading cause of death amongst the elderly. Medically, dementia is considered the decline of mental stability which results in both behavioral, as well as mental changes. Both affect communication abilities, but Alzheimer’s is considered a more severe and deleterious disease as it progresses over time. Alzheimer’s sometimes becomes the reason for complete memory loss as it mainly results in memory impairment and a decline in cognitive function. It specifically interferes with routine life and can affect an individual at any age. It does not only affect memory but also thought processes and language, as it is a degenerative brain disease that leads an overall decline in health and wellbeing.

Research has shown that alterations in the production of neuronal nitric oxide (NO) play a vital role in the pathophysiology of Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple system atrophy (MSA). In the investigation, the levels of amino acids, including l-citrulline, were measured in cerebrospinal fluid (CSF). For this purpose, 12 patients with Alzheimer’s disease, 108 patients with Parkinson’s disease, and 15 patients with MSA were observed. 21 healthy subjects were also included in the study. While CSF L-glutamate was discovered to be significantly decreased in patients with Alzheimer’s disease, CSF L-citrulline was shown to be slightly but statistically elevated in MSA patients. No appreciable shifts in L-arginine levels were detected. The results imply that Alzheimer’s disease is related to a reduction in NO synthesis, even if the relationship between the CSF levels of these amino acids and neuronal NO production is currently unclear (6).

In a study, l-citrulline was given to the 3 × Tg mice with Alzheimer’s disease in order to evaluate its effect on cognitive decline in AD. Brain tissue and cerebrospinal fluid were collected. L-arginine determinations were performed through the use of ultra-performance liquid chromatography. Nitric oxide was evaluated by the Griess method. In the Morris water maze task, 9-month-old male AD mice supplemented with l-citrulline showed improved results. There were no significant changes observed in brain tissue. However, the arginine levels were enhanced in the cerebrospinal fluid. It was concluded that the oral administration of l-citrulline has the potential to improve memory function in those with early stages of Alzheimer’s disease (7).

 

L-Citrulline and the Immune System

The immune system is a large network of chemicals, white blood cells, organs, and antibodies. It functions to protect a living body from viruses, bacteria, fungi, and parasites. It is significant to use essential supplementation to boost the immune system and protect the body from illnesses and infections.

A study examined the effect of L-citrulline and L-arginine supplementation on male infantile rats’ immune systems. Normal saline, L-citrulline (200 mg/kg per day), and L-arginine (200 mg/kg per day) were provided to the infantile male rats over postnatal days 8 to 14. Later, they were sacrificed and their blood was taken for further analysis. The spleen was indicated to analyze the immune system after stimulation with lipopolysaccharide and concanavalin A. It was observed that the Th1 immune response was enhanced by the supplementation of L-arginine through the increase in the production of IFN-γ. The regulatory T-cell (Treg) immune effects can be modulated by L-citrulline and L-arginine therapy by increasing the level of increasing IL-10. A TGF-β1 increase was observed in the L-citrulline group. Concurrently, SMAD7 expression was decreased by L-citrulline therapy. However, the L-citrulline treatment was found to modulate FOXP3 expression. The study concluded that supplementation with L-citrulline and L-arginine had the tendency to modulate regulatory T-cells functions differently for infantile rats (8).

In this article, the effect of oral supplementation of L-arginine and L-citrulline for the prevention of plasmodium growth was observed through the analysis of malaria-infected mice. In this study, Plasmodium berghei-infected mice were divided into several groups. A few groups were provided with L-citrulline and L-arginine, in which parasitemia was measured. Immunotyping was performed after sacrificing mice 10 days’ post-infection. The results indicated that l-arginine supplementation induced a conducive environment for the growth of Plasmodium. It led the mice to die earlier than the control group. It was observed that supplementation of L-citrulline inhibits the growth of parasites, thus allowing the subjects to live longer. L-arginine supplementation increased TLA-4 in the T cell population, which was further analyzed by flow cytometric analysis. It was identified that L-citrulline showed more positive effects than L-arginine due to lower parasitemia and expression of inhibitory molecules, which improved the survival of the infected mice. It is suggested that L-citrulline is highly essential for the immune system (9).

 

L-Citrulline for Exercise Performance

Many people use L-citrulline to enhance exercise performance due to its ability to increase natural levels of nitric oxide. Especially in athletes or those with debilitating conditions, exercise performance and stamina could always benefit from improvement. The key, however, is to continue the treatment of L-citrulline in order to sustain enhanced performance.

In this article, the effects of L-citrulline were observed on exercise performance in humans. The purpose was to determine the effects of watermelon juice, a pre-exercise dose of l-citrulline, maximal oxygen consumption (VO2max), flow-mediated vasodilation, and anaerobic threshold. In this randomized, double-blind study, 22 male participants were selected, and they were supplemented with either 710 mL of watermelon juice or a 7.5% sucrose drink containing 6 g of l-citrulline or a 7.5% sucrose placebo drink. The administration of supplementation was 1 to 2 hours before exercise. The results showed no significant effects between supplements, VO2max, time to exhaustion, flow-mediated vasodilation, or anaerobic threshold. Moreover, watermelon juice or a single dose of l-citrulline as a pre-exercise supplement shows no effects in improving exercise performance. Hence, according to this study, single doses may not have much of a significant effect on exercise performance. However, the effects of greater doses of l-citrulline on exercise performance have yet to be identified (10).

 

SAFETY

Interactions

• Men’s sexual dysfunction medications (Phosphodiesterase-5 Inhibitors) Major Interaction: Blood pressure may be reduced by l-citrulline. Blood pressure can be lowered by several male sexual dysfunction drugs. If these drugs are combined with L-citrulline for male erection problems, the blood pressure could fall too low. Some medications for male sexual dysfunction include tadalafil (Cialis), sildenafil (Viagra), and vardenafil (Levitra) (11).
• Medications that enhance cardiac blood flow (Nitrates) Major Interaction: L-citrulline may lower blood pressure while boosting blood flow. Combining L-citrulline with other drugs that boost cardiac blood flow makes a person more prone to fainting and dizziness. Isosorbide (Isordil, Imdur) and Nitroglycerin (Nitro-Dur, Nitrostat, Nitro-Bid) are a couple of these drugs that increase blood flow to the heart.
• Medications to lower blood pressure (Antihypertensive drugs) Moderate interaction: Blood pressure may be reduced by l-citrulline. The blood pressure could drop too low if a person takes L-citrulline with blood pressure drugs. Vasotec, Capoten, Cozaar, Cardizem, HydroDIURIL, Lasix, Norvasc, Diovan, and many other drugs are examples of those used to treat high blood pressure (12).

Side-Effects

L-citrulline is possibly safe and has no adverse effects if taken in a normal dosage and not combined with any other medications. However, excess dosages and/or medication combinations may lead to severe side effects which can exacerbate one’s current condition or potentially even lead to death (1, 13).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

References

1. Cormio, L., De Siati, M., Lorusso, F., Selvaggio, O., Mirabella, L., Sanguedolce, F., & Carrieri, G. (2011). Oral L-citrulline supplementation improves erection hardness in men with mild erectile dysfunction. Urology, 77(1), 119-122.
2. Shiota, A., Hotta, Y., Kataoka, T., Morita, M., Maeda, Y., & Kimura, K. (2013). Oral l‐citrulline supplementation improves erectile function in rats with acute arteriogenic erectile dysfunction. The journal of sexual medicine, 10(10), 2423-2429.
3. Hotta, Y., Shiota, A., Kataoka, T., Motonari, M., Maeda, Y., Morita, M., & Kimura, K. (2014). Oral l‐citrulline supplementation improves erectile function and penile structure in castrated rats. International Journal of Urology, 21(6), 608-612.
4. Romero, M. J., Yao, L., Sridhar, S., Bhatta, A., Dou, H., Ramesh, G., … & Caldwell, R. W. (2013). L-citrulline protects from kidney damage in type 1 diabetic mice. Frontiers in immunology, 4, 480.
5. Liu*, Y., Fu*, X., Gou, L., Li, S., Lan, N., Zheng, Y., & Yin, X. (2013). L-citrulline protects against glycerol-induced acute renal failure in rats. Renal failure, 35(3), 367-373.
6. Kuiper, M. A., Teerlink, T., Visser, J. J., Bergmans, P. L. M., Scheltens, P., & Wolters, E. C. (2000). L-glutamate, L-arginine and L-citrulline levels in cerebrospinal fluid of Parkinson’s disease, multiple system atrophy, and Alzheimer’s disease patients. Journal of neural transmission, 107(2), 183-189.
7. Martínez-González, K., Serrano-Cuevas, L., Almeida-Gutiérrez, E., Flores-Chavez, S., Mejía-Aranguré, J. M., & Garcia-delaTorre, P. (2021). Citrulline supplementation improves spatial memory in a murine model for Alzheimer’s disease. Nutrition, 90, 111248.
8. Lee, Y. C., Su, Y. T., Liu, T. Y., Tsai, C. M., Chang, C. H., & Yu, H. R. (2018). L-arginine and l-citrulline supplementation have different programming effect on regulatory t-cells function of infantile rats. Frontiers in Immunology, 9, 2911.
9. Awasthi, V., Chauhan, R., & Das, J. (2022). Administration of L-citrulline prevents Plasmodium growth by inhibiting/modulating T-regulatory cells during malaria pathogenesis. Journal of Vector Borne Diseases, 59(1), 45.
10. Cutrufello, P. T., Gadomski, S. J., & Zavorsky, G. S. (2015). The effect of l-citrulline and watermelon juice supplementation on anaerobic and aerobic exercise performance. Journal of sports sciences, 33(14), 1459-1466.
11. Oketch-Rabah, H. A., Roe, A. L., Gurley, B. J., Griffiths, J. C., & Giancaspro, G. I. (2016). The importance of quality specifications in safety assessments of amino acids: The cases of L-tryptophan and L-citrulline. The Journal of Nutrition, 146(12), 2643S-2651S.
12. Vors, C., Rancourt-Bouchard, M., Couillard, C., Gigleux, I., Couture, P., & Lamarche, B. (2021). Sex May Modulate the Effects of Combined Polyphenol Extract and L-citrulline Supplementation on Ambulatory Blood Pressure in Adults with Prehypertension: A Randomized Controlled Trial. Nutrients, 13(2), 399.
13. Mahboobi, S., Tsang, C., Rezaei, S., & Jafarnejad, S. (2019). RETRACTED ARTICLE: Effect of l-citrulline supplementation on blood pressure: a systematic review and meta-analysis of randomized controlled trials. Journal of human hypertension, 33(1), 10-21.

Kaore SN, Amane HS, Kaore NM. Citrulline: pharmacological perspectives and its role as an emerging biomarker in future. Fundam Clin Pharmacol. 2013 Feb;27(1):35-50. doi: 10.1111/j.1472-8206.2012.01059.x. Epub 2012 Jul 31. PMID: 23316808.