L-Citrulline

• Vascular health
• Exercise performance
• Blood flow enhancement

• Ammonia clearance
• Muscle recovery
• Immune function
• Erectile function
• Blood pressure regulation

L-Citrulline functions primarily through its role in the nitric oxide (NO) pathway and the urea cycle, with several key mechanisms of action: 1) Nitric Oxide Production: L-Citrulline is converted to L-arginine in the kidneys, which then serves as the direct precursor for nitric oxide synthesis via the enzyme nitric oxide synthase (NOS). This pathway is crucial because L-citrulline supplementation can increase arginine levels more effectively than direct arginine supplementation, as L-citrulline bypasses hepatic first-pass metabolism and is not subject to the same intestinal degradation as arginine. The resulting increase in nitric oxide causes vasodilation, improving blood flow throughout the body. 2) Urea Cycle Function: As a key intermediate in the urea cycle, L-citrulline plays a vital role in ammonia detoxification.

During intense exercise, ammonia accumulates in muscles and can contribute to fatigue. L-Citrulline helps convert ammonia to urea, which is then excreted by the kidneys, potentially delaying fatigue during exercise. 3) Exercise Performance Enhancement: In the form of citrulline malate (L-citrulline bound to malic acid), it may provide additional benefits through malate’s role in the tricarboxylic acid (TCA) cycle. Malate can enhance aerobic energy production by increasing the efficiency of the TCA cycle, potentially providing synergistic effects with citrulline’s NO-boosting properties.

4) Muscle Protein Synthesis: L-Citrulline may indirectly support muscle protein synthesis through improved blood flow, delivering more nutrients and oxygen to muscle tissue. Some research suggests it may also have direct effects on protein synthesis signaling pathways, though this mechanism is less well-established. 5) Antioxidant Effects: L-Citrulline exhibits antioxidant properties, potentially scavenging free radicals and reducing oxidative stress. This may contribute to its beneficial effects on vascular health and exercise recovery.

6) Immune Function Support: L-Citrulline is utilized by immune cells and may support immune function, particularly during periods of physical stress or illness. It serves as a substrate for immune cell proliferation and function. 7) Erectile Function: The NO-mediated vasodilation effects of L-citrulline can improve blood flow to the genital region, potentially enhancing erectile function in men with mild erectile dysfunction. 8) Blood Pressure Regulation: Through its enhancement of nitric oxide production and subsequent vasodilation, L-citrulline may help reduce blood pressure, particularly in individuals with hypertension or pre-hypertension.

9) Endothelial Function: L-Citrulline may improve endothelial function by increasing NO bioavailability, which helps maintain the integrity and function of the vascular endothelium. 10) ATP Production: When consumed as citrulline malate, the malate component may enhance ATP production by serving as an intermediate in the TCA cycle, potentially improving energy availability during exercise.

The effective dosage range for L-Citrulline is typically 3-10 grams per day, with most research supporting efficacy within this range. For citrulline malate, dosages are typically higher (6-10 grams) to account for the malate component, which makes up approximately one-third to one-half of the compound’s weight depending on the ratio (2:1 or 1:1 citrulline to malate).

L-Citrulline has excellent oral bioavailability compared to other amino acids like L-arginine. When consumed orally, L-citrulline is efficiently absorbed in the intestines via both passive diffusion and active transport mechanisms. Unlike L-arginine, L-citrulline largely bypasses hepatic first-pass metabolism, allowing more of the compound to reach systemic circulation. After absorption, L-citrulline is primarily converted to L-arginine in the kidneys, leading to a more sustained increase in plasma arginine levels compared to direct arginine supplementation.

Peak plasma concentrations of citrulline typically occur 1-2 hours after ingestion, while the resulting increase in arginine levels peaks around 2-3 hours post-ingestion and can remain elevated for several hours.

Citrulline Malate formulation: The combination of L-citrulline with malic acid may enhance overall effects, particularly for exercise performance, though this may be due to the additional benefits of malate rather than improved citrulline absorption per se., Taking on an empty stomach: Some evidence suggests that taking L-citrulline on an empty stomach may improve absorption by reducing competition with other amino acids for intestinal transporters., Micronized formulations: Smaller particle size may improve dissolution rate and absorption efficiency., Consistent daily supplementation: Regular intake may lead to more stable plasma levels and enhanced long-term effects compared to single doses., Combining with vitamin C: Some evidence suggests that vitamin C may enhance nitric oxide production when combined with L-citrulline, though this doesn’t directly affect citrulline absorption.

For exercise performance, L-citrulline or citrulline malate is most effective when taken approximately 60-90 minutes before exercise to allow for optimal absorption and conversion to arginine. This timing aligns with peak plasma arginine levels occurring 2-3 hours after citrulline ingestion. For blood pressure management and cardiovascular health, consistent daily supplementation is more important than specific timing, though dividing larger doses (>5g) into 2-3 smaller doses throughout the day may help maintain more stable plasma levels. For erectile function, taking L-citrulline approximately 1-2 hours before sexual activity may be beneficial, though regular daily supplementation appears to provide better cumulative effects.

When using citrulline malate specifically for exercise performance, some individuals report gastrointestinal discomfort when taken too close to exercise, so adjusting timing based on individual tolerance is recommended. For general health purposes, L-citrulline can be taken with or without food, though taking it with meals may help reduce potential gastrointestinal discomfort that some individuals experience with higher doses.

• Gastrointestinal discomfort (mild stomach pain, nausea, or diarrhea), particularly at higher doses
• Heartburn or acid reflux (more common with citrulline malate due to the acidic nature of malic acid)
• Mild headaches (uncommon)
• Changes in urination patterns (uncommon)
• Mild allergic reactions in rare cases

• Individuals taking medications that affect nitric oxide pathways, such as phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil) due to potential additive effects on blood pressure
• Individuals with low blood pressure (hypotension) should use caution due to L-citrulline’s vasodilatory effects
• Individuals with renal dysfunction or kidney disease should consult healthcare providers before use, as citrulline metabolism primarily occurs in the kidneys
• Pregnant or breastfeeding women (insufficient safety data)
• Individuals with Herpes simplex infections (theoretical concern that increased arginine levels might promote viral replication)
• Individuals scheduled for surgery within two weeks (potential concerns regarding blood pressure regulation during surgery)

• Erectile dysfunction medications (sildenafil, tadalafil, vardenafil): Potential additive effects on blood pressure reduction, which could lead to hypotension
• Antihypertensive medications: May enhance blood pressure-lowering effects
• Nitrates (e.g., nitroglycerin): Potential for additive effects on blood pressure reduction
• Medications metabolized by nitric oxide pathways: Theoretical interactions due to L-citrulline’s role in nitric oxide production
• Immunosuppressants: Theoretical interaction due to L-citrulline’s potential effects on immune function

No established upper limit by major regulatory bodies. Clinical studies have used doses up to 15 grams per day with minimal adverse effects. Most side effects are mild and dose-dependent, with gastrointestinal discomfort being the most common at higher doses. For most individuals, staying within the 3-10 gram per day range minimizes the risk of side effects while providing potential benefits.

Long-term safety studies beyond several months are limited, though L-citrulline is an endogenous compound naturally produced in the body, suggesting good long-term safety profile.

In the United States, L-Citrulline is classified as a dietary supplement ingredient under the Dietary Supplement Health and Education Act (DSHEA) of 1994. It is generally recognized as safe (GRAS) when used as directed. As a supplement, manufacturers cannot make specific disease claims without FDA approval, but can make general structure/function claims related to exercise performance, blood flow, and cardiovascular health. The FDA has not established a recommended daily allowance (RDA) or tolerable upper intake level (UL) for L-citrulline.

L-citrulline is not approved as a drug for any specific indication, though it has been studied for various medical conditions.

The European Food Safety Authority (EFSA) has evaluated several health claims for L-citrulline but has not approved any specific health claims due to insufficient evidence. L-citrulline is regulated as a food supplement under Directive 2002/46/EC. In some European countries, citrulline malate has been used as a pharmaceutical product for the treatment of asthenia and fatigue, particularly in France where it was marketed under the brand name Stimol®.

Health Canada permits L-citrulline as a Natural Health Product (NHP) ingredient. It is listed in the Natural Health Products Ingredients Database (NHPID) with both medicinal and non-medicinal roles. Health Canada has approved certain claims related to L-citrulline’s role in amino acid metabolism and as a nitric oxide precursor when specific conditions are met.

The Therapeutic Goods Administration (TGA) of Australia regulates L-citrulline as a listed complementary medicine ingredient. It can be used in listed medicines with appropriate evidence for its safety and quality. Specific therapeutic claims require higher levels of evidence and may require registration rather than listing.

Regulations regarding L-citrulline supplementation vary significantly by country. In Japan, L-citrulline is recognized under the Foods for Specified Health Uses (FOSHU) system for certain applications. In Russia and several Eastern European countries, citrulline malate has been used as a metabolic enhancer in sports medicine. Some countries have established maximum daily doses for supplement use, typically ranging from 3-10 grams per day.

The regulatory status of different forms of L-citrulline (such as citrulline malate) may vary from the base form in some jurisdictions.

In most countries, L-citrulline is available as an over-the-counter supplement without prescription. In France and some other European countries, citrulline malate has been available as a prescription medication for asthenia under the brand name Stimol®, though its status may have changed in recent years. In the United States and most other countries, L-citrulline is not available as a prescription medication for any indication, though

it may be used in clinical settings for certain rare metabolic disorders under medical supervision.

L-Citrulline supplements typically range from $0.15 to $0.50 per gram for pure L-citrulline powder, and $0.20 to $0.60 per gram for citrulline malate. Capsule and tablet forms are generally more expensive, ranging from $0.30 to $0.80 per gram. For a typical monthly supply at a dosage of 6 grams per day, consumers can expect to pay approximately $25-$90, depending on the form and brand. Premium brands, specialized formulations, or products with additional ingredients can cost significantly more.

When compared to other nitric oxide boosters, L-citrulline offers good value, particularly in powder form. It is generally more cost-effective than L-arginine for increasing blood arginine levels and nitric oxide production, as L-citrulline is better absorbed and more efficiently converted to arginine in the body. Compared to prescription medications for erectile dysfunction (e.g., sildenafil, tadalafil), L-citrulline is significantly less expensive but also generally less effective, particularly for moderate to severe cases. For exercise performance, citrulline malate may offer better value than many pre-workout supplements, which often contain proprietary blends with undisclosed amounts of active ingredients.

Natural sources of L-citrulline, such as watermelon, provide relatively poor value in terms of cost per gram of L-citrulline, as the concentration is relatively low (approximately 2.1 mg/g of fresh watermelon).

Purchasing L-citrulline or citrulline malate powder in bulk (250g-1kg) can significantly reduce costs, often bringing the price down to $0.10-$0.20 per gram. This approach is most economical for those requiring higher doses or long-term supplementation. However, proper measurement tools (such as a milligram scale) and storage containers are necessary when purchasing bulk powder. Many manufacturers offer bulk discounts or subscription services that can reduce costs by 10-20% for regular users.

L-Citrulline supplements are typically not covered by conventional health insurance plans. In rare cases where L-citrulline is prescribed for specific metabolic disorders, insurance coverage may be possible with proper medical documentation. Some Health Savings Accounts (HSAs) or Flexible Spending Accounts (FSAs) may cover L-citrulline supplements with a physician’s recommendation, though policies vary widely.

Pure L-Citrulline powder typically has a shelf life of 2-3 years when stored properly. L-Citrulline in capsule or tablet form generally has a shelf life of 2-3 years, depending on the formulation and presence of other ingredients. Citrulline malate may have a slightly shorter shelf life (1.5-2.5 years) due to the potential for the malic acid component to absorb moisture over time.

Store in a cool, dry place away from direct sunlight, Optimal temperature range: 15-25°C (59-77°F), Keep container tightly closed to protect from moisture, Refrigeration is not necessary but may extend shelf life, For powder forms, use the provided scoop or a clean, dry utensil to prevent moisture introduction, Citrulline malate is particularly hygroscopic (attracts moisture) and should be stored with extra care to prevent clumping, Avoid exposure to heat sources or temperature fluctuations

Exposure to high humidity (can cause clumping and degradation, particularly for citrulline malate), Prolonged exposure to high temperatures (>30°C/86°F), Direct sunlight or UV radiation, Oxidation (particularly in solution), Microbial contamination if exposed to moisture, Extreme pH conditions (highly acidic or alkaline environments), For citrulline malate, the acidic nature of malic acid may accelerate degradation under certain conditions

L-Citrulline is generally stable in aqueous solution at neutral pH for short periods (1-2 weeks) when refrigerated. Stability decreases in acidic or alkaline conditions. For maximum stability in solution, a pH range of 6.5-7.5 is optimal. Solutions should be stored in the refrigerator (2-8°C) in a tightly sealed container.

Citrulline malate solutions are more acidic due to the malic acid component and may have reduced stability compared to pure L-citrulline solutions. Pre-mixed solutions should ideally be consumed within 24-48 hours for optimal potency. When mixed in protein shakes or sports drinks, L-citrulline remains stable for several hours at room temperature but should be consumed within the same day for best results.

Natural Sources

Synthetic Production Methods

Quality Indicators

Sustainability Considerations

Unlike many other nutritional compounds, L-Citrulline does not have a significant documented history of traditional medicinal use as an isolated compound. However, watermelon, the richest natural source of L-citrulline, has been used in traditional medicine systems across various cultures. In Traditional Chinese Medicine, watermelon was used to clear summer heat, promote urination, and quench thirst. In Ayurvedic medicine, watermelon was valued for its cooling properties and used to support kidney and bladder health.

In various folk medicine traditions across Africa and the Middle East, watermelon was used to treat dehydration and heat-related illnesses. While these traditional uses were not specifically targeting L-citrulline content, they align with some of the modern applications related to improved blood flow and kidney function.

L-Citrulline was first isolated from watermelon in 1914 by Japanese researchers, with its name derived from ‘citrullus,’ the Latin word for watermelon. Its role in the urea cycle was elucidated in the 1930s by Hans Krebs and Kurt Henseleit as part of their groundbreaking work on the urea cycle (also known as the Krebs-Henseleit cycle). For several decades, L-citrulline was primarily of interest to biochemists studying metabolic pathways rather than being recognized for therapeutic potential. In the 1970s and 1980s, research began to explore L-citrulline’s role in various metabolic disorders, particularly those affecting the urea cycle.

The discovery of nitric oxide (NO) as a signaling molecule in the late 1980s, which led to the 1998 Nobel Prize in Physiology or Medicine, dramatically increased interest in L-citrulline due to its role as a precursor to L-arginine and subsequently nitric oxide. By the early 2000s, research began to focus on L-citrulline’s potential benefits for cardiovascular health, exercise performance, and erectile function, primarily through its effects on nitric oxide production.

Initially, L-citrulline was primarily used in clinical settings to diagnose and treat rare urea cycle disorders. In the 1990s, following the discovery of nitric oxide’s importance in vascular function, interest in L-citrulline began to grow in cardiovascular research. By the early 2000s, L-citrulline supplementation was being investigated for potential benefits in conditions characterized by endothelial dysfunction, including hypertension, heart failure, and erectile dysfunction. The mid-2000s saw the emergence of citrulline malate as a sports supplement, particularly in Europe, with claims of reducing muscle fatigue and improving recovery.

This application was based partly on research conducted in the 1980s in France, where citrulline malate was used to treat asthenia (abnormal physical weakness). The late 2000s and 2010s witnessed a significant increase in L-citrulline’s popularity in the fitness and bodybuilding communities, primarily for its purported benefits on ‘muscle pumps’ during resistance training and potential ergogenic effects. More recently, research has expanded to explore L-citrulline’s potential benefits for cognitive function, immune support, and healthy aging. The evolution of L-citrulline usage reflects the growing understanding of nitric oxide’s diverse roles in human physiology and the advantages of L-citrulline supplementation over direct L-arginine supplementation for increasing systemic arginine levels.

Effects of L-citrulline supplementation on vascular function in older adults (ClinicalTrials.gov Identifier: NCT03358264), L-citrulline supplementation for improving exercise tolerance in patients with heart failure (ClinicalTrials.gov Identifier: NCT03629340), Citrulline malate supplementation for enhancing recovery from resistance exercise (ClinicalTrials.gov Identifier: NCT04163120)