What Does Citrulline Do to the Brain?

December 3, 2025 •

4 min read

L-citrulline, a non-essential amino acid found in foods like watermelon, has been reported to prevent neuronal cell death and protect against cerebrovascular injury. This demonstrates its potential to positively influence brain health and function through several key mechanisms.

Quick Summary

Citrulline enhances nitric oxide production, improving cerebral blood flow and oxygen delivery to the brain. This mechanism offers neuroprotective benefits, combats oxidative stress, and may improve cognitive function by supporting vascular health.

Key Points

Enhances Cerebral Blood Flow: By boosting nitric oxide (NO) production, citrulline promotes vasodilation, increasing oxygen and nutrient delivery to the brain.
Offers Neuroprotection: It helps protect neurons and cerebrovascular health from damage caused by ischemia and excitotoxicity.
Combats Oxidative Stress: Citrulline's antioxidant properties help reduce lipid peroxidation and scavenge free radicals, protecting brain cells from damage.
May Improve Cognitive Function: Animal studies suggest that citrulline supplementation can improve spatial memory, particularly in early-stage cognitive decline.
Exhibits Higher Bioavailability: Unlike L-arginine, citrulline bypasses first-pass liver metabolism, leading to more stable and sustained increases in plasma arginine for NO synthesis.
Supports Post-Exercise Recovery: It has been shown to enhance cerebrovascular recovery in athletes following high-intensity training, which can support cognitive clarity.
Crosses the Blood-Brain Barrier: It is transported into the brain primarily via the LAT1 transporter, allowing it to exert its effects directly on brain tissue.

How Citrulline Influences Brain Function

Citrulline, an amino acid widely recognized for its athletic performance benefits, plays a more nuanced role in brain function through its direct impact on the vascular system and cellular processes. The primary pathway involves its conversion into L-arginine, which then serves as a precursor for nitric oxide (NO) synthesis. Because citrulline bypasses typical metabolism in the liver, it can increase and sustain plasma levels of L-arginine more effectively than direct L-arginine supplementation, leading to more robust NO production.

The Citrulline-Nitric Oxide Pathway and Cerebral Effects

Once produced, nitric oxide is a critical signaling molecule that plays several roles in neurovascular health.

Vasodilation and Cerebral Blood Flow: NO is a potent vasodilator, meaning it helps relax and widen blood vessels. This improves blood flow throughout the body, including to the brain. Enhanced cerebral blood flow ensures that the brain receives an optimal supply of oxygen, glucose, and other nutrients needed for peak cognitive performance. Studies on athletes show that citrulline supplementation enhances cerebrovascular function recovery following high-intensity exercise, suggesting improved circulation to the brain.
Neurotransmitter Modulation: Research indicates that L-citrulline can modulate neurotransmitter release. For instance, in studies on motor nerve terminals, L-citrulline inhibited acetylcholine release by increasing adenosine outflow, thereby activating inhibitory A1 receptors. While this research focuses on motor neurons, it demonstrates citrulline's ability to influence neuronal communication. Additionally, animal studies show that citrulline can influence the metabolism of dopamine, a neurotransmitter crucial for focus and motivation.
Neuroprotection: NO itself has neuroprotective properties at physiological concentrations. By supporting NO levels, citrulline can protect against neuronal cell death and damage from brain ischemia (inadequate blood supply). It also helps protect the blood-brain barrier (BBB) from damage caused by excitotoxicity, a process involving the overstimulation of neurons that can lead to cell death.

Combating Oxidative Stress in the Brain

Oxidative stress, an imbalance between free radicals and antioxidants, contributes significantly to cognitive decline and neurodegenerative diseases. The brain is particularly susceptible due to its high oxygen consumption and lipid content. Citrulline exhibits potent antioxidant properties that help protect neuronal integrity.

How citrulline acts as a neuroprotectant:

Reducing Lipid Peroxidation: Citrulline helps reduce lipid peroxidation, a process where free radicals attack and damage lipids in cell membranes, including those in the brain. By mitigating this damage, it preserves the health and function of neurons.
Enhancing Antioxidant Defense: As a scavenger of hydroxyl radicals, citrulline directly neutralizes some of the most destructive free radicals. This helps maintain the delicate balance of redox signaling essential for cellular health.
Preventing Ferroptosis: Some evidence suggests citrulline can help prevent ferroptosis, a type of programmed cell death linked to iron accumulation and oxidative stress. This protective mechanism is particularly relevant in the context of neurodegenerative diseases.

Impact on Cognitive Function and Mood

Several studies explore citrulline's potential to enhance cognitive function and improve mood, though more human research is needed. One animal study on an Alzheimer's disease model showed that early-stage citrulline supplementation significantly improved spatial memory. This effect was linked to increased arginine levels in the cerebrospinal fluid and supported NO-mediated synaptic plasticity. Human trials also show promise, with one study noting a significant reduction in depressive mood states among participants taking citrulline, although the effect was not significant when compared directly to the placebo group. By improving cerebral circulation and reducing oxidative stress, citrulline creates a healthier brain environment conducive to better mental performance.

Citrulline vs. L-Arginine for Brain Health


Feature	L-Citrulline	L-Arginine
Nitric Oxide (NO) Synthesis	Provides a slow and sustained increase in NO production via conversion to L-arginine.	Rapidly converted to NO, but much is degraded during first-pass metabolism, leading to a less sustained effect.
Bioavailability	Superior bioavailability. It is not degraded by intestinal or hepatic enzymes, resulting in higher and more stable plasma levels.	Poor bioavailability due to extensive breakdown in the liver and gut.
Brain Transport	Primarily transported across the blood-brain barrier (BBB) via the large neutral amino acid transporter 1 (LAT1).	Also crosses the BBB, but citrulline offers a more stable and efficient delivery mechanism for increasing NO precursors in the body.
Neuroprotective Potential	Indirectly neuroprotective by enhancing NO production and reducing oxidative stress.	Also supports neuroprotection, primarily through NO, but is less efficient systemically.

How Citrulline Reaches the Brain

For any substance to affect the brain, it must first cross the blood-brain barrier (BBB), a selective membrane that protects the brain from harmful substances. Research using rat brain capillary endothelial cells (an in vitro model of the BBB) suggests that L-citrulline is primarily transported across this barrier via the large neutral amino acid transporter 1 (LAT1). This transport mechanism is crucial for supplying citrulline to brain tissue, where it can then be metabolized into arginine to produce NO. This understanding of how citrulline is delivered to the brain opens avenues for its potential as a therapeutic agent for cerebrovascular diseases. A study published in the Journal of Biomedical Science details this transport mechanism.(https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-017-0336-x)

Conclusion

Citrulline's primary brain-related benefits stem from its role in promoting nitric oxide production, which enhances cerebral circulation and provides vital neuroprotective effects. By improving oxygen and nutrient delivery to brain tissues and actively combatting oxidative stress, citrulline helps support cognitive function, memory, and overall neurological health. While many promising findings originate from animal and foundational studies, the evidence points toward citrulline as a valuable supplement for enhancing neurovascular health and mitigating age-related cognitive decline. Further targeted research, especially human clinical trials focused specifically on brain health outcomes, is warranted to fully confirm its therapeutic potential for a broader population, particularly in managing neurodegenerative conditions. For now, its established effects on circulation and cell protection make it a compound of significant interest for maintaining long-term brain health.

Frequently Asked Questions

While not a traditional nootropic, citrulline's ability to enhance cerebral blood flow and provide neuroprotective benefits can support cognitive functions like memory and mental performance, putting it in the category of supplements that indirectly support brain health.

Citrulline is converted into L-arginine in the kidneys, which is then used by enzymes in the brain to produce nitric oxide. Citrulline is a more efficient precursor because it avoids extensive breakdown by the liver, leading to higher arginine availability.

Emerging evidence suggests citrulline's potential in mitigating cognitive decline associated with aging, largely due to its support for vascular health and reduction of oxidative stress, both of which are major factors in age-related neurodegeneration.

L-citrulline is the amino acid itself, while L-citrulline malate is L-citrulline combined with malic acid. Malic acid is believed to enhance energy production, potentially offering an additional benefit for combating exercise-induced fatigue, though the core brain effects come from the L-citrulline component.

The timeline for noticing cognitive effects is not well-established and can vary. While some benefits like improved blood flow might be more immediate, effects on memory and long-term neuroprotection require consistent, long-term supplementation.

Citrulline is generally well-tolerated with minimal side effects. However, it's always best to consult a healthcare professional before starting any new supplement, as optimal dosages have not been established for brain-specific conditions.

Foods like watermelon are rich in citrulline. While dietary intake is beneficial, supplementation often provides higher, more concentrated doses used in clinical studies. Combining dietary sources with supplementation can maximize potential benefits.