Citrulline, also known as L-citrulline, is a non-essential amino acid that plays a vital role in various bodily functions. Your body makes it on its own, specifically in the liver and intestines. It also exists in some foods, including watermelon. The name “citrulline” comes from the Latin “Citrullus,” which translates to watermelon. It is considered non-essential because the body can produce it. Unlike other amino acids, citrulline doesn’t build proteins. Instead, it plays an important role in the urea cycle, helping your body to get rid of harmful substances, particularly ammonia. It also plays an important role in widening your blood vessels (vasodilation) and may play a part in muscle building.
While the human body makes citrulline, some people increase their numbers by eating foods with the nutrient in them. Some people may also take citrulline supplements to improve athletic performance. Supplements go by a couple of different names: L-citrulline and citrulline malate. Citrulline malate is a mix of citrulline and DL-malate, a compound that may help turn food into energy.
How Citrulline Works
Citrulline is involved in your urea cycle, which gets rid of waste products by excreting them in urine (pee). It’s converted into arginine, an amino acid that produces nitric oxide, a substance that relaxes blood vessels and improves blood flow. The main mechanism by which citrulline could be beneficial for muscle is by increasing nitric oxide, leading to increased blood flow.
Types of Citrulline
There are two main forms of citrulline:
- L-citrulline: This is the form naturally found in your body, in some foods, and in supplements. There’s some research-based evidence that L-citrulline may be helpful for athletic performance because it improves blood flow to working muscles. The potential benefit seems to apply more to anaerobic exercise such as strength training, rather than aerobic exercise, like running. Still, future research might offer more clarity. One study of avid cyclers found that the group taking L-citrulline biked faster and felt less tired after cycling 4 kilometers (roughly 2.5 miles). Participants took 2.4 grams of the supplement every day for eight days before the bike ride.
- Citrulline malate: This form is a combination of citrulline with malic acid. Malic acid is found in apples, among other fruits. Citrulline malate is a direct precursor to nitric oxide. It’s thought that this form of citrulline could have bigger effects because it potentially increases ATP - adenosine triphosphate, or the fuel for working muscles - production and availability. There’s some research that citrulline malate may be beneficial for muscular endurance and strength performance. But overall evidence is mixed on its effectiveness, and more research is needed. In the meantime, since there is a good level of evidence for L-citrulline, it is recommended using that form of the supplement until there is more evidence for the use of citrulline malate.
Health Benefits of Citrulline
While citrulline is necessary for the urea cycle, it also has a few other benefits as well. One of the biggest benefits associated with the amino acid is that it promotes vasodilation, the widening of your blood vessels.
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May Improve Athletic Performance
Several studies show that citrulline may help to improve your athletic performance. It may do this by increasing the amount of oxygen in your muscle tissue. While supplements may not help your body use more oxygen, they could help improve the oxygen usage in your muscles, which can then help to improve your endurance. Some studies also show that citrulline may help improve your weight training performance. One study found that men who took a citrulline malate supplement were able to do 53% more repetitions than those who took a placebo. The supplement also appears to have led to reduced muscle soreness two days later. Taking L-citrulline may benefit your workout by boosting your endurance. One study looked at how L-citrulline supplements could affect athletic performance. Researchers found that when participants took 6 grams of L-citrulline for seven days, they could work harder for longer on a severe-intensity exercise test. But a recent overview of existing research on L-citrulline and aerobic exercise came to a different conclusion. According to the review, there isn’t a clear answer to whether taking L-citrulline can help you gain a competitive edge. Some studies suggested a benefit to taking the supplement, while others showed it doesn’t make a difference. The average gym-goer may notice a benefit during their workout, in terms of performance. And for avid athletes who may work out multiple times a day, L-citrulline could increase your performance and help you recover faster.
Boosts Heart Health
Some research has shown that the blood vessel-widening properties of citrulline may be beneficial for your heart health. The amino acid may help to lower blood pressure in individuals with hypertension, a risk factor for heart disease. Other research suggests that citrulline doesn’t offer any benefit to those with high blood pressure, so more studies are needed. If you have high blood pressure, taking a citrulline supplement could help. An analysis of research on citrulline’s effect on blood pressure found positive outcomes in most studies. Study participants took from 3 to 8 grams of L-citrulline a day. Researchers analyzed results anywhere from one to 16 weeks after use. According to the analysis, citrulline seemed like it could significantly lower blood pressure. But researchers recommended larger clinical trials to not only confirm promising findings, but also to determine ideal dose amounts and if there were any side effects.
Improves Erectile Dysfunction
L-citrulline may help to boost L-arginine, which helps to boost nitric oxide production. Nitric oxide aids in blood vessel relaxation, which allows more blood to flow through your body. Some research shows that this may help individuals with erectile dysfunction. One small study showed that half of the men who took an L-citrulline supplement had an 8.3% improvement in erectile dysfunction scores over men who took a placebo. Some people believe citrulline is useful for ED. They theorize that because limited blood flow is one of the causes of ED - and because citrulline improves circulation - it could help. In one small but promising study, 50% of the participants had positive effects. They took 1.5 grams of L-citrulline a day for a month. Twelve out of 24 people went from having mild ED to typical erectile function. Scientists recommended further research and studies in this area.
May Provide Antidepressant Effects
Some studies have discovered a link between low levels of arginine and citrulline and a greater risk of depression. One study found a link between bipolar disorder and reduced levels of nitric oxide. The research seems to suggest that increasing citrulline and arginine may help to reduce depressive symptoms.
May Help Those with Sickle Cell Disease
Research indicates that citrulline may help to improve pain in people with sickle cell disease. Supplementation may help to improve blood health as well as overall well-being. There aren’t many studies available, however, so more research is needed to confirm the effectiveness of such a treatment.
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Citrulline and Childhood Obesity
Children with obesity are at higher risk for developing cardiometabolic diseases that once were considered health conditions of adults. Obesity is commonly associated with cardiometabolic risk factors such as dyslipidemia, hyperglycemia, hyperinsulinemia and hypertension that contribute to the development of endothelial dysfunction. Endothelial dysfunction, characterized by reduced nitric oxide (NO) production, precedes vascular abnormalities including atherosclerosis and arterial stiffness. Thus, early detection and treatment of cardiometabolic risk factors are necessary to prevent deleterious vascular consequences of obesity at an early age. Non-pharmacological interventions including L-Citrulline (L-Cit) supplementation and aerobic training stimulate endothelial NO mediated vasodilation, leading to improvements in organ perfusion, blood pressure, arterial stiffness, atherosclerosis and metabolic health (glucose control and lipid profile). Few studies suggest that the combination of L-Cit supplementation and exercise training can be an effective strategy to counteract the adverse effects of obesity on vascular function in older adults.
Obesity and Cardiometabolic Risk Factors
Overweight and obesity are defined as abnormal or excessive fat accumulation. In adults, the World Health Organization (WHO) defines obesity as a Body Mass Index (BMI) greater than or equal to 30 kg/m2, and for children aged between 5-19 years, obesity is considered two standard deviations above the WHO Growth Reference median. Approximately 340 million children and adolescents worldwide were classified as overweight or obese in 2016 and the prevalence is dramatically increasing. The prevalence of hypertension is greater than 70% and increases with progression of obesity grade in adults. In obese children, the prevalence of hypertension is 15.27%, which is substantially higher than 1.9% in those with normal weight. In some cases, individuals are classified as obese based on BMI alone but considered “metabolically healthy obese” (MHO) since they display a normal cardiometabolic profile such as optimal insulin sensitivity, blood pressure, lipid and inflammatory profiles. Obesity is a condition strongly associated with metabolic syndrome (MetS), defined as a constellation of physiological, biochemical, clinical and metabolic factors that are associated with an increased risk of atherosclerosis, T2D and all-cause mortality. MetS can be diagnosed in children (10 to 16 years old) with abdominal obesity and at least two clinical features such as elevated triglycerides, low levels of high-density lipoprotein (HDL) cholesterol, high blood pressure (hypertension) and high fasting blood glucose (hyperglycemia). Childhood obesity and hypertension predict MetS later in life. In children, hypertension is a prevalent cardiovascular risk factor associated with reduced endothelial function, increased vascular thickness and arterial stiffness.
Endothelial Dysfunction and Obesity
A hallmark risk factor of MetS is insulin resistance (IR), which is an impairment of insulin function to promote glucose uptake in insulin-sensitive target tissues, such as skeletal muscle and adipose tissue, resulting in abnormal glucose homeostasis. Obesity is also associated with elevated levels of proinflammatory adipokines released by visceral adipose tissue that contribute to the development of IR and impaired endothelial function. Endothelial dysfunction is the result of prolonged hyperglycemia, damaging vascular function and structure that eventually leads to CVD development. Proinflammatory adipokines increase the production of reactive oxygen species (ROS) which triggers the release of inflammatory cytokines, adhesion molecules and growth factors that promote cellular oxidative stress.
Cardiometabolic risk factors contribute to endothelial dysfunction, characterized by a reduced NO bioavailability, which promotes atherosclerosis and arterial stiffness and development of CVD. For these reasons, it is important to evaluate interventions to improve vascular and metabolic function in obese individuals. There are non-pharmacological treatments that can improve the cardiometabolic profile. L-Citrulline (L-Cit) is a non-essential amino acid not used for protein synthesis, but with a key regulatory role of nitrogen homeostasis. Studies in humans have demonstrated the effect of L-Cit supplementation on improving nitrogen homeostasis and its ability to increase the L-Arginine-NO pathway. In middle-aged adults, oral L-Cit supplementation has shown to improve endothelial function, blood pressure and arterial stiffness through stimulation of the L-Arginine-NO pathway which consequently leads to vasodilation. The development of childhood obesity is associated with sedentary behavior, and increased physical activity is recommended to improve overall health in children with excess adiposity. In children and adolescents, aerobic training helps to improve blood pressure, endothelial function, arterial stiffness atherosclerosis, lipid profile and body composition. The use of L-Cit plus exercise, in middle-aged and older adults with obesity-related diseases or risks factors, has yielded improvements in systolic blood pressure (SBP), pressure wave reflection and aortic stiffness. These lifestyle and dietary interventions were implemented in middle-aged and older adults and have elicited no harmful effects.
The Role of the Endothelium and Nitric Oxide
The endothelium is a layer of cells between the vessel lumen and the vascular smooth muscle cells (VSMC). The most important vasodilator produced by the endothelium is NO, generated from L-Arginine (L-Arg) by endothelial-NO synthase (eNOS). NO diffuses into the VSMC where it stimulates soluble guanylyl cyclase and subsequently activates cyclic guanosine monophosphate, leading to a decrease in intracellular calcium concentrations, and therefore, to relaxation and vasodilation. NO is considered an anti-atherogenic agent and prevents platelet aggregation, smooth cell proliferation and adhesion of leukocytes to the endothelium. Endothelial dysfunction is a reversible pathological complication derived from reduced NO bioavailability and impaired vasodilation. Inflammation, oxidative stress, hypertension, dyslipidemia and IR are the main contributing factors in obesity-related endothelial dysfunction through the unbalance between increased ROS and reduced antioxidant capacity. ROS reduces levels of tetrahydrobiopterin (BH4), an essential cofactor for eNOS, by inducing BH4 oxidation (BH4 to BH2) which leads to eNOS uncoupling. In obesity, a main mechanism for endothelial dysfunction is eNOS uncoupling due to reduced L-Arg bioavailability and BH4 oxidation, leading to less NO bioavailability and increased ROS (superoxide anion and peroxynitrite) generation.
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Enhanced oxidative stress by ROS upregulates arginase activity/expression competing with eNOS for L-Arg, a common substrate. Cardiometabolic risk factors (obesity, hyperglycemia, hypertension) stimulates arginase to contribute to further ROS production. Arginase converts L-Arg to L-ornithine and urea, decreasing L-Arg availability for eNOS. Evidence has demonstrated that obesity-induced endothelial dysfunction associated with arterial stiffening, hyperglycemia, hypertension, and oxidative stress were prevented with arginase inhibition. Under normal conditions, insulin favors the release of NO by activation of eNOS, and therefore, has vasodilator, anti-inflammatory and anti-atherosclerotic effects. Hyperinsulinemia contributes to increased vasoconstriction through mitogen activated protein kinase signaling by releasing endothelin-1, a powerful vasoconstrictor agent that promotes IR, oxidative stress and reduced NO bioavailability.
In a healthy individual, leptin inhibits insulin production in pancreatic β cells, while insulin stimulates leptin production in adipocytes. In a state of leptin resistance, characterized by hyperleptinemia, leptin ceases the inhibition of insulin production leading to a phase of hyperinsulinemia and IR. Moreover, elevated leptin in obesity contributes to increase blood pressure through increased renal sympathetic activity and oxidative stress in VSMC, reducing vasodilation. Leptin and adiponectin have antagonistic effects on vascular tone regulation, inducing vasoconstriction and vasodilation, respectively. Adiponectin promotes glucose metabolism and fatty acid oxidation, contributes to lower IR, and may protect against hypertension through an endothelial-dependent mechanism. Hypoadiponectinemia in obesity is associated with increased leptin, IR, impaired glucose and fat metabolism, and consequently, hyperglycemia and increased fat accumulation.
Assessing Endothelial Function
Flow-mediated vasodilation (FMD) is a non-invasive technique commonly used to assess macrovascular endothelial function. FMD evaluates the capacity of conduit arteries (e.g., brachial, femoral, popliteal) to increase their diameter relative to the baseline diameter in response to transient ischemia induced by 5 min of arterial occlusion. Brachial artery FMD is considered the gold standard non-invasive measure of endothelial function and is a predictor of CVD. The increase in arterial diameter indicates the vasodilator effect derived from local production of NO induced by increased shear stress after rapid reperfusion. Impaired FMD is associated with atherosclerosis and arterial stiffness and is apparent in children and adolescents with chronic kidney disease, T2D and type 1 diabetes mellitus. It has been shown that children with obesity have a lower FMD than normal-weight counterparts. Middle-aged adults with prediabetes showed endothelial dysfunction and increased oxidative stress. In children and adolescents, endothelial dysfunction assessed as brachial artery FMD was inversely related to age, total and abdominal obesity, blood pressure, fasting insulin and glucose, and homeostatic model assessment-insulin resistance (HOMA-IR). IR impairs endothelial function even in children and adolescents. Hyperglycemia increases the production of ROS and activity of arginase 1, which mediates endothelial dysfunction by decreasing L-Arg bioavailability. To sum up, cardiometabolic risk factors are associated with endothelial dysfunction, and obese children and adolescents may present lower brachial artery FMD compared to lean counterparts; therefore, this is a useful technique to evaluate the cardiovascular risk in the obese pediatric population.
Inflammation and Obesity
Obesity fosters a pro-inflammatory milieu primarily due to abnormally high visceral adipose tissue leading to low-grade chronic inflammation, oxidative stress, IR, and impaired endothelial function. Adipocyte hypertrophy alters the balance of adipokines, leading to monocyte infiltration in the vascular wall where they are differentiated into pro-inflammatory M1-macrophages. Under these conditions, adipose tissue releases free fatty acids, proinflammatory adipokines (leptin, resistin, tumor necrosis factor alpha (TNFα), and interleukin-6 (IL-6) into circulation, while secretion of adiponectin is reduced. The unbalance between pro- and anti-inflammatory adipokines results in the generation of ROS, which increases vascular tone by inhibiting the synthesis and action of NO leading to vasoconstriction. Increased visceral abdominal fat is related to hypertension, the major cardiovascular risk factor associated with obesity. Overweight and obese children and adolescents who remain obese with age are at increased risk of developing cardiometabolic diseases, such as T2D, hypertension, dyslipidemia, and carotid artery atherosclerosis. There is a linear relationship between hypertension and obesity in White, Black, Hispanic and Asian individuals. Sustained elevations in blood pressure in obese adolescents increases the risk of developing CVD when entering adulthood. Individuals with obesity, hyperglycemia, vascular oxidative stress and inflammation are at higher risk of hypertension. Hypertension in individuals with obesity seems to be the consequence of several hemodynamic, renal and neurohormonal changes caused by excess adipose tissue, particularly the abdominal visceral fat. In addition, excessive sodium reabsorption in the kidneys lead to increased extracellular fluid volume and elevated blood pressure, that may injure blood vessels and organs.
Atherosclerosis and Obesity
Atherosclerosis is the main cause of coronary artery disease, peripheral artery disease, and ischemic stroke. It is defined as a chronic inflammatory process affecting the intima and media layers decreasing the arterial lumen, and in turn, causing reduced blood flow and ischemia. In the earliest stages, atherosclerosis begins as fatty streaks where the accumulation of fat-filled macrophages, termed foam cells, begin aggregating within the intima layer. The progressive accumulation of foam cells, fibrous tissue and inflammatory proteins within the intima forms an atherosclerotic plaque called atheroma. This increase in blockage adversely affects the great arteries, mainly the aorta, coronary, carotid, iliac, femoral and popliteal. The link between atherosclerosis and obesity is via adipokine induced inflammation, IR, and endothelial dysfunction. Carotid ultrasonography is a commonly used measure of subclinical atherosclerosis.
Dosage and Side Effects
In general, citrulline supplements are considered safe, even at higher doses. Even so, there are some instances in which taking it can pose a potential risk. If you want to try a L-citrulline supplement, see a healthcare provider first. Plus, some supplements can interact badly with other medicines you might be taking. If you’re cleared to take L-citrulline, a safe dosage is 3 to 6 grams a day. Start with the lowest amount. You can always increase the dosage to see if it affects your results if you don’t experience any side effects.
To supplement L-citrulline for circulatory health or to alleviate erectile dysfunction, take 2,000 mg of citrulline, three times a day with meals, for a total daily dose of 6,000 mg. To supplement L-citrulline to enhance sports performance, take 6,000 - 8,000 mg of citrulline malate about an hour before exercise. On days that you don't exercise, it can be broken up into smaller doses.
Amino acids like citrulline can cause gastrointestinal upset. That’s why it’s important to start at the smallest dose to see how your body reacts. Side effects may include:
- Bloating
- Cramping
- Diarrhea
- Sweating
Pregnancy Concerns
There is not enough research showing the effects of citrulline during pregnancy or while breastfeeding. As such, women who are pregnant or nursing should consult with their doctor before taking a supplement or avoid taking it.
Medication Interactions
Citrulline may interact with certain medications. If you take phosphodiesterase-5 inhibitors for erectile dysfunction, taking citrulline may cause your blood pressure to drop too low, leading to hypotension. Similar effects may occur if you take medications for high blood pressure or nitrate medications for heart conditions. Talk to your doctor first before adding any supplement, including citrulline, to your regimen.
Food Sources of Citrulline
Your body makes citrulline itself. You can increase your levels by consuming certain foods, such as:
- Watermelon
- Squash
- Chickpeas
- Pumpkin
- Cucumbers
- Nuts
- Bitter Gourds
You can also find powdered citrulline supplements, which you mix with water or blend into a smoothie.
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