L-Citrulline Anti-Depressant Effect

Citrulline is an amino acid that is turned into L-arginine in the kidneys after supplementation, L-Citrulline anti-depressant effects still need clinical validation.

This means that L-citrulline supplementation is a more effective method of increasing L-arginine levels in the body than L-arginine supplementation itself.

L-Citrulline is one of the three dietary amino acids in the urea cycle. Others are L-arginine and L-Ornithine.

L-Citrulline is used as a sports performance and cardiovascular health supplement and can result in reduced fatigue and improved endurance for both aerobic and anaerobic prolonged exercise.

Supplementing with L-citrulline can also increase ornithine and arginine plasma content.

This means that L-citrulline supplementation improves the ammonia recycling process and nitric oxide metabolism.

L-citrulline is also used to alleviate erectile dysfunction caused by high blood pressure and can provide a spike of L-arginine in plasma levels over a longer period of time.

The effects of L-citrulline on depression, mood, and anxiety have not been well-researched, but some research has suggested that the absence of L-arginine could lead to fatigue, lethargy, and depressed moods.

This has led to some medical professionals suggest that L-citrulline can support mood. However, more research is needed to rate efficacy.

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L-Citrulline is taken up to a much greater degree in the gut than its counterpart L-Arginine.

This results in a higher plasma level of L-Arginine through the Arginine/Ornithine/Citrulline cycle.

This means that, relative to arginine, citrulline is better absorbed in the intestines and maybe a better source of bodily arginine than arginine itself.

Oral Citrulline supplementation can increase plasma urea cycle amino acids which include citrulline itself, ornithine, and arginine.

Ornithine and Arginine levels can reach up to a doubling with 5-10g of citrulline supplementation and then seems to be restricted from increasing further, while citrulline simply follows linear dose-response patterns.

The majority of L-citrulline either floats in the blood passively or gets transported to the kidneys for conversion into arginine, making most bioactivities of citrulline to be secondary to arginine ingestion.

Anti-Depressant Effects

In the 1970s, L-citrulline was studied in France for its capacities to improve mental functioning and reduce fatigue in patients suffering from Alzheimer’s disease.

These studies were conducted with substandard methodology and were never followed upon.

Citrulline is produced from L-arginine in the body during NO (nitric oxide) synthesis, which occurs through the actions of an enzyme called nitric oxide synthase.

Nitric oxide is a vital compound in mammals because it induces vasodilation, that helps relax blood vessels and accommodates increased blood delivery to organs and tissues throughout the body.

Common anti-depressant medications attempt to benefit users by inducing slight modifications of brain chemicals called neurotransmitters.

Some school of thoughts has theorized that deficiencies in amino acids (like L-Arginine), could exacerbate depressed moods and low energy levels, while some has suggested that the L-arginine-nitric oxide pathway may be linked to the development of a bipolar affective disorder.

Taking all these factors into consideration, L-citrulline could potentially affect mood and depression.

There is the possibility that L-citrulline could worsen or cause manic or depressive symptoms, but more research is needed before any definitive statements can be made

In one research trial, however, nitric oxide levels were found to be higher in patients with bipolar disorder.


Arginine has a few interactions with memory and learning, and as it is the molecule that citrulline acts through, it can offer more view of citrulline’s action.

Citrulline has been found to be normally expressed at higher concentrations in the hippocampus of trained rats relative to untrained rats in a cognitive test.

As mentioned earlier, some research has suggested that supplementing the diet with citrulline increases L-arginine levels more than supplementing with L-arginine itself.

Besides being important for removing ammonia accumulations, arginine is involved with several processes which may affect mental functioning, and possibly depression.

Arginine helps to balance hormones, support immunity, support wound healing, and facilitate cellular division.

Arginine imbalance is not usually thought of as a reason for depression, but it does affect protein synthesis.

Inadequate amino acid availability can cause fatigue, depressed moods, lethargy, and certain other related symptoms.

If there is insufficient citrulline in the body, then arginine synthesis may be partially compromised, and without adequate arginine in the body, certain compounds and hormones may not be produced in adequate amounts.

This could theoretically affect mood.

Another way that citrulline may be related to depression, is in its roles with ammonia detoxification.

If ammonia was to amass excessively in the system, the liver would eventually not be able to perform its roles, and this will negatively affect the whole system.

Safety and Toxicity

Citrulline appears to be well-tolerated by rats in doses up to 3g/kg body weight, but in humans, 15g citrulline taken acutely does not appear to cause diarrhea or intestinal upset.

This is notably different than both ornithine and arginine that may cause diarrhea at 10g dosages when taken in boluses.

This is due to limited absorption of these amino acids which then proceed to the colon to cause osmotic diarrhea.

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L-Citrulline Anti-Depressant

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