We had a patient months ago who was supplementing with L-Citrulline (L-CIT). He was convinced that it made him feel better and more energized. Overall, his research showed that it was making significant positive changes to his health, significantly improving erectile dysfunction.
As with many supplements, we like to verify that the information our patients get about supplements is reliable and that those supplements are safe and valuable. So, with that in mind, let’s talk about Citrulline.
What is L-Citrulline?
L- Citrulline is a non-essential amino acid; for those who need clarification, an amino acid is the basic building block of proteins. Amino acids have essential roles in cell structure and multiple metabolic processes. A non-essential amino acid is one that our body can produce under normal conditions.
This non-essential amino acid is usually produced by the liver and intestines; it is a component of the urea cycle, a little rabbit hole. The urea cycle is a metabolic pathway the liver uses to convert toxic ammonia into urea, which can be eliminated in the urine. L-CIT can also be found in multiple food sources, including watermelons (“Citrullus” in Latin), cucumbers, pumpkins, muskmelons, bitter melons, squashes, and gourds.
L-CIT can be derived from Arginine (ARG) in the intestines. Still, in the kidneys, cells can transform L-CIT into Arginine and Nitric Oxide (NO).
As you might know, it has been proven that NO creates vasodilation, improves blood flow and oxygen delivery to the body cells, increase in NO can improve skeletal muscle and heart function and mitochondrial respiration (meaning the process in which the mitochondria uses oxygen to create energy) as described in this study from 2021.
What are the Benefits of L-Citrulline?
Many benefits have been attributed to Citrulline, a lot of them have to do with Arginine. However, supplementation with L-CIT has been described to improve multiple problems; let’s recap the more relevant ones.
Erectile Dysfunction
A small study from Italy showed that 1 month of 1.5 g/d of L-Citrulline improved erections at least in the short term, it was found to be safe and accepted by patients, but the effect was not as strong as with PDE-5 Inhibitors (Cialis, Viagra).
Similar results were found in another study (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302103/) that assessed a combination of L-CIT and Transresveratrol. Resveratrol is a polyphenol found in grapes and wine, there is some evidence that supports the idea that it can increase NO, therefore the use for Erectile Dysfunction.
The results show that the active treatment increased the quality of erections compared to placebo, although this was a really small study.
Research has found that L-CIT can improve response to other therapies, such as electric stimulation, independently of testosterone levels, in surgically castrated mice; the L-Citrulline group had a better penile mean arterial pressure after electric stimulation.
As you can see, research is still developing on this issue; given that sexual performance is one of the main reasons people use Citrulline, it is fair to say that there is some weak evidence that suggest it could help, but we are nowhere close to recommend it like a really good supplement for this purpose, although it seems to be harmless.
Cardiovascular Health
As we mentioned, L-Citrulline has been associated with Nitric Oxide production, which is associated with vessel vasodilation. Research from Texas Tech University has found that 10 grams of L-CIT for 4 weeks can decrease brachial artery flow-mediated dilation (FMD), resting aortic blood pressure and mean arterial blood pressure; in other words, it can cause enough arterial dilation that traduces in lower blood pressure.
Another study reported that supplementing with 3 grams a day of Citrulline Malate was associated with improved heart function and decreased pulmonary artery pressure in people with heart failure. In patients with heart failure, their heart is unable to pump blood adequately due to lack of muscle strength, this can be the result of a heart attack, therefore, decreasing aortic and pulmonary artery pressure is very important to avoid muscle heart exhaustion, and symptoms.
This study showed that it can help decrease blood pressure and maintain heart function in this group of people, unfortunately, it is also a small study that included only 129 participants, and the only one available so far.
It has also been found that L-CIT reduces blood pressure and heart attack damage in mice with reduced oxygenation, as seen in Sleep Apnea Syndrome]; according to a 2022 study.
Another paper suggests that L-CIT can decrease blood pressure by around 4 and 7 points of systolic and diastolic blood pressure, respectively.
L-CIT might also reduce asymmetric dimethylarginine (ADMA) and oxidized LDL, improving endothelial (inner artery layers) function and decreasing lipoprotein oxidation.
Unfortunately, there is insufficient evidence, and the available evidence is still based on small populations.
Cholesterol
A recent study showed that L-CIT supplementation in mice fed a high-fat diet resulted in decreased triglycerides, LDL, and remnant cholesterol with a slight increase in HDL.
We did not find more information that supports the idea that L-CIT can improve lipid metabolism.
Diabetes & Cardiovascular Inflammation
Another relatively small study reports that L-CIT can decrease fasting insulin, decrease HOMA-IR, and some inflammatory markers (such as hs-CRP) in overweight and obese patients with type 2 diabetes.
One similar Randomized Controlled Trial showed that even though L-CIT reduced fasting glucose and HbA1C, it didn’t seem to impact inflammation markers (such as IL-6, TLl-4,, MCP-1)
As you see, evidence still needs to be improved in this space.
Antioxidation
There is a small study on male professional cyclists supplementing with 6 grams of L-CIT Malate, it was found that those who responded to exercise with a progressive decrease on Reactive Oxygen Species, increased NO and less oxidative damage.
Immune System
One study described that patients with Sepsis(Severe infection) were found to have lower levels of Arg. Citrulline supplementation might play a role in improving outcomes for this group of patients, therefore boosting the immune system.
Needless to say, there is not enough research in this field yet.
Wound Healing
In vitro research seems to indicate that Arg and NO have an essential role in wound healing; human studies found that during recovery, there are higher levels of Arg, NO, and Citrulline.
Both are exciting findings. However, research in these two fields is still in diapers.
Alzheimer’s Disease
There is conflicting evidence regarding the role of L-CIT and Alzheimer’s Disease (AD); on one side, there is one study that suggests that people with higher levels of Citrulline in their cerebrospinal fluid, another study reports that NO can increase neuron damage in AD.
On the other hand, researchers report that citrulline supplementation improved cognitive decline in male mice, monitored by Arg and NO levels in the hippocampus (where the memory is processed in the brain)
Athletic Performance
There is evidence that implies that high-intensity exercise increases ammonia levels in skeletal muscle, leading to exhaustion and fatigue; l-cit has shown to increase ammonia elimination and reduce tiredness .
The same authors found that L-CIT supplementation reduces fatigue, improves aerobic energy production and exercise tolerance. L-CIT also enhances athletic performance by improving muscular contraction efficiency
Another clinical trial tested 8 g of L-CIT supplementation with short rest times and relief from post-exercise muscle soreness; it was found to have a 40% reduction in soreness after 48 hours using L-CIT supplementation.
This is likely one of the most popular benefits of L-CIT and the one with the most substantial evidence, but it isn’t enough; research is still developing.
What are the Side Effects of L-Citrulline?
Citrulline is safe; however, some people have reported bloating, cramping, diarrhea, and sweating.
However, due to the already described effects of NO in the blood vessels, consider consulting with your doctor if you are using medications such as nitrates or PDE-5s Inhibitors like sildenafil (Revatio, Viagra), Tadalafil (Cialis) or Vardenafil (Levitra, Staxyn).
What Other Types of Citrulline Exist?
There are 2 forms of Citrulline, as you already have seen.
L-Citrulline is the natural form found in the body. As we mentioned, it is usually produced in the intestines from L-Arginine. Still, it can also be formed from glutamine and proline, other amino acids traditionally obtained from food.
Citrulline malate is a combination of L-Citrulline with Malic Acid. Malic Acid is an alpha-hydroxy compound usually found in many fruits and vegetables. Citrulline malate is a direct precursor to nitric oxide; some think this is a more effective supplement form.
Which Foods contain L-Citrulline?
You can find L-CIT in beets, fennel, lettuce, parsley, radishes, and spinach. We also mentioned watermelon, legumes, meat, and even nuts.
What is the recommended dose?
There is no definitive standard. The recommendation can go from 3-6 grams daily for L-Citrulline to 8 grams for Citrulline Malate.
It is also true that most studies did not find significant side effects in doses reaching 10 grams or a little more. However, it has also been found that absorption decreases at doses of 15 grams or higher.
Most presentations of L-Citrulline have 750 mg per capsule. Citrulline malate capsules can also be found in 1200 mg capsules and powder presentation. Still, those might require a scale to get to the proper doses.
It is attractive to notice that there is evidence that proposes that after one hour of supplementation with 6 grams of L-Citrulline, NO exhaled levels increase, therefore the recommendation to take L-Citrulline before exercise if it is taken to improve performance.
Bottom Line
There is a lot of hype in regards to Citrulline. It is very common to find that people recommend it to improve your athletic and sexual performance, to decrease blood pressure, and even to improve diabetes, high blood pressure, and heart disease; unfortunately, as you have read in this article, the evidence doesn’t seem to be very strong and conclusive, I’ll tell you what I would do If I’m already doing lifestyle changes, and I want to have a little push in any of those areas, I might try it; however, I don’t see myself supplementing with Citrulline for the rest of my life. But
I’ll let you be the captain of your ship.
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