L-Norvaline

• Cardiovascular health
• Endothelial function
• Blood pressure regulation

• Exercise performance
• Cognitive function
• Immune modulation

L-Norvaline is a non-proteinogenic amino acid that functions primarily as an arginase inhibitor. Arginase is an enzyme that converts L-arginine to L-ornithine and urea, effectively reducing the bioavailability of L-arginine for other metabolic pathways. The primary mechanism of action of L-Norvaline centers on its ability to competitively inhibit arginase activity, which indirectly enhances nitric oxide (NO) production through the following pathway: By inhibiting arginase, L-Norvaline prevents the breakdown of L-arginine, thereby increasing L-arginine bioavailability for nitric oxide synthase (NOS). NOS uses L-arginine as a substrate to produce nitric oxide, a potent vasodilator that plays crucial roles in vascular function, blood pressure regulation, immune response, and neurotransmission.

This mechanism is particularly significant in conditions where arginase activity is elevated, such as endothelial dysfunction, hypertension, atherosclerosis, and aging. In these conditions, increased arginase activity can lead to reduced NO production, contributing to vascular dysfunction. L-Norvaline’s inhibition of arginase helps restore the balance between arginase and NOS pathways, potentially improving endothelial function and cardiovascular health. Beyond its effects on the arginase-NO pathway, L-Norvaline has been identified as an inhibitor of the mammalian target of rapamycin (mTOR) pathway, specifically through inhibition of S6 kinase 1 (S6K1).

This mechanism may contribute to its potential anti-inflammatory effects and could play a role in cellular metabolism regulation. Additionally, L-Norvaline may have neuroprotective properties through multiple mechanisms: by enhancing NO production, which can improve cerebral blood flow; by reducing oxidative stress through the restoration of NO-dependent antioxidant mechanisms; and potentially through direct effects on neuronal metabolism. It’s important to note that while L-Norvaline is not incorporated into proteins during normal protein synthesis, under certain conditions it can be misincorporated in place of leucine, which has raised some concerns about potential toxicity with long-term use. However, this misincorporation typically occurs only under specific experimental conditions or at very high concentrations.

The effective dosage range for L-Norvaline is typically 100-600 mg per day, with most research and commercial supplements using doses within

this range. Due to limited human clinical trials

specifically examining L-Norvaline dosing,

these recommendations are based on a combination of preliminary research, animal studies, and common practices in the supplement industry. For most applications, a starting dose of 100-200 mg per day is recommended, which can be increased gradually based on individual response and tolerance. L-Norvaline is often taken in divided doses throughout the day to maintain more consistent blood levels, though single daily dosing is also common in pre-workout formulations.

L-Norvaline is absorbed from the gastrointestinal tract through amino acid transporters, similar to other amino acids. While specific pharmacokinetic data for L-Norvaline in humans is limited, it is believed to have relatively good oral bioavailability based on its chemical structure and the observed biological effects following oral administration. As a small, water-soluble amino acid, L-Norvaline likely reaches peak plasma concentrations within 1-2 hours after ingestion. The compound can cross the blood-brain barrier to some extent, which may contribute to its potential neurological effects.

L-Norvaline is primarily metabolized in the liver, with some metabolism also occurring in the kidneys. The exact half-life in humans has not been well-established in published literature, but based on similar amino acids, it is estimated to be approximately 3-5 hours. Elimination occurs primarily through renal excretion, with some metabolites also being eliminated through bile.

Taking on an empty stomach: Some evidence suggests that taking L-Norvaline on an empty stomach may improve absorption by reducing competition with other amino acids for intestinal transporters., Combining with vitamin C: Theoretical potential for enhanced effects due to vitamin C’s role in supporting nitric oxide stability, though specific research on this combination is limited., Combining with other nitric oxide precursors: L-Arginine, L-Citrulline, or beetroot extract may complement L-Norvaline’s mechanism of action, potentially leading to enhanced overall effects on nitric oxide production., Avoiding high-protein meals when supplementing: Large amounts of dietary amino acids may compete with L-Norvaline for absorption, potentially reducing its bioavailability when taken with high-protein meals.

For cardiovascular health and general nitric oxide support, L-Norvaline can be taken once or twice daily, with consistent timing each day to maintain stable blood levels. When used specifically for exercise performance, L-Norvaline is typically taken approximately 30-60 minutes before exercise to allow for absorption and onset of effects by the time of physical activity. This timing aligns with the estimated peak plasma concentration at 1-2 hours post-ingestion. For potential cognitive benefits, morning dosing is often recommended, though this is based more on practical considerations than on specific chronopharmacological data.

If taking multiple daily doses, spacing them evenly throughout the day (e.g., morning and evening) may help maintain more consistent blood levels. Taking L-Norvaline on an empty stomach or at least 30 minutes before meals may enhance absorption, though this may not be practical for all users. If gastrointestinal discomfort occurs, taking L-Norvaline with a small amount of food may help mitigate these effects. When used as part of a pre-workout formula, follow the timing recommendations for the complete formula, which typically suggest consumption 20-30 minutes before exercise.

• Gastrointestinal discomfort (nausea, stomach pain)
• Headache
• Dizziness
• Fatigue
• Potential cytotoxicity and mitochondrial dysfunction at high doses or with long-term use (based on in vitro studies)
• Potential protein misincorporation (L-Norvaline can be mistakenly incorporated into proteins in place of leucine under certain conditions)

• Pregnancy and breastfeeding (insufficient safety data)
• Children and adolescents under 18 years (insufficient safety data)
• Individuals with liver or kidney disease (due to the role of these organs in amino acid metabolism)
• Individuals with hypotension (low blood pressure), as L-Norvaline may further lower blood pressure through nitric oxide enhancement
• Individuals scheduled for surgery within two weeks (potential concerns regarding blood pressure regulation during surgery)
• Individuals with neurodegenerative conditions (due to concerns about potential protein misincorporation)
• Individuals with mitochondrial disorders (due to concerns about potential mitochondrial effects)

• Blood pressure medications (potential additive effects leading to hypotension)
• Nitrates and PDE5 inhibitors like sildenafil (potential additive effects on nitric oxide pathways, increasing risk of hypotension)
• Immunosuppressants (theoretical interaction due to L-Norvaline’s potential effects on immune function through nitric oxide modulation)
• Medications metabolized by the liver (theoretical potential for interactions, though specific evidence is limited)
• Other arginase inhibitors (potential additive effects)
• Medications affecting mitochondrial function (potential additive adverse effects on mitochondria)

No established upper limit by major regulatory bodies. Most supplements use doses between 100-600 mg per day. A 2019 in vitro study raised concerns about potential cytotoxicity and mitochondrial dysfunction at higher concentrations, though these findings have been debated and may not directly translate to in vivo effects at typical supplemental doses. A 2019 response paper argued that the reported toxicity may be greatly overstated.

Due to limited long-term human safety data and some concerns about potential protein misincorporation and mitochondrial effects, conservative use is recommended. Short-term use (less than 8 weeks) at recommended doses appears to have a reasonable safety profile based on limited available data, but long-term safety has not been well-established. Cycling L-Norvaline (periods of use followed by breaks) may be prudent until more safety data becomes available.

In the United States, L-Norvaline exists in a regulatory gray area. It is not explicitly approved as a food additive or dietary ingredient by the FDA. Unlike many amino acids that are common components of the diet, L-Norvaline is a non-proteinogenic amino acid not typically found in significant amounts in the human diet. It does not have GRAS (Generally Recognized as Safe) status.

Companies marketing L-Norvaline as a dietary supplement ingredient are technically required to submit a New Dietary Ingredient (NDI) notification to the FDA before marketing, though compliance with this requirement varies in the supplement industry. The FDA has not issued specific warnings or enforcement actions specifically targeting L-Norvaline, but this does not constitute tacit approval. As with many supplement ingredients, the FDA would likely take action if evidence of significant safety concerns emerged. Manufacturers cannot make disease claims for L-Norvaline and are limited to structure/function claims (e.g., ‘supports nitric oxide production’ rather than ‘treats hypertension’).

The European Food Safety Authority (EFSA) has not issued a specific opinion on L-Norvaline as a supplement ingredient. In the European Union, novel food regulations would likely apply to L-Norvaline, requiring authorization before it can be legally marketed as a food or food supplement ingredient. There is no evidence that L-Norvaline has received novel food authorization in the EU. Some products containing L-Norvaline may still be found in the European market, but their regulatory compliance is questionable.

The regulatory status varies somewhat between individual EU member states, with some countries having more stringent enforcement of novel food regulations than others.

Health Canada has not explicitly approved L-Norvaline as a Natural Health Product (NHP) ingredient.

It is not listed in the Natural Health Products Ingredients Database (NHPID) with an approved medicinal role. Products containing L-Norvaline would likely require premarket authorization with supporting safety and efficacy data before

they could be legally sold in Canada with a Natural Product Number (NPN). Some products containing L-Norvaline may be found in the Canadian market, particularly in the sports nutrition category, but their regulatory compliance is uncertain.

The Therapeutic Goods Administration (TGA) of Australia has not

specifically approved L-Norvaline as an ingredient for listed complementary medicines.

It is not included in the TGA’s list of permitted ingredients for listed medicines. Products containing L-Norvaline would likely require registration rather than listing, which involves a more rigorous premarket evaluation process. As with other jurisdictions, some products containing L-Norvaline may be found in the Australian market, particularly in the sports nutrition category, but their regulatory compliance is questionable.

Japan: L-Norvaline is not approved as a Food for Specified Health Uses (FOSHU) ingredient. China: Not included in the approved list of health food ingredients. South Korea: Not explicitly approved for use in functional foods. Brazil: Would likely require registration as a novel ingredient through ANVISA.

Russia and Eastern European countries: Often have less stringent regulation of amino acid supplements, and products containing L-Norvaline may be more readily available. In most jurisdictions globally, L-Norvaline exists in a regulatory gray area rather than having explicit approval or prohibition. The regulatory approach to L-Norvaline varies significantly between countries, with some taking a more permissive approach to novel supplement ingredients while others require substantial premarket safety data.

L-Norvaline is not available as a prescription medication in any major jurisdiction. It is exclusively found in the supplement market or used as a research chemical. No medical conditions have approved L-Norvaline as a standard treatment. Some healthcare providers with interests in integrative or functional medicine may recommend L-Norvaline supplementation for specific conditions, but this represents off-label use rather than standard medical practice.

L-Norvaline supplements typically range from $0.30 to $1.00 per 200 mg dose for standalone products. For a typical monthly supply at a dosage of 200 mg per day, consumers can expect to pay approximately $9-$30. L-Norvaline is more commonly found as an ingredient in multi-component formulations (particularly pre-workout supplements and nitric oxide boosters) rather than as a standalone product. In these formulations, the cost attributable to the L-Norvaline component is difficult to isolate but generally represents a small fraction of the total product cost.

Powder forms, when available, are generally more economical than capsules or tablets. Specialized or branded forms of L-Norvaline are uncommon, unlike some other amino acids that have patented or trademarked delivery systems.

When compared to other nitric oxide-enhancing supplements, L-Norvaline offers a unique mechanism of action (arginase inhibition) that complements rather than duplicates the effects of common alternatives like L-Arginine and L-Citrulline. L-Norvaline is generally more expensive per gram than L-Arginine but less expensive than specialized ingredients like Nitrosigine (inositol-stabilized arginine silicate) or NO3-T (nitrate-enhanced trimethylglycine). For enhancing nitric oxide production, a combination of L-Citrulline (3-6g daily at $0.30-$0.60 per effective dose) and L-Norvaline (200mg daily at $0.30-$1.00 per effective dose) may offer better value than high-dose L-Arginine (6-10g daily at $0.50-$1.00 per effective dose) due to better absorption and complementary mechanisms. Compared to pharmaceutical options for conditions like hypertension or erectile dysfunction, L-Norvaline is significantly less expensive but also has a much more limited evidence base for efficacy.

The value proposition of L-Norvaline is strongest when used as part of a comprehensive approach to nitric oxide enhancement rather than as a standalone solution. The cost-efficiency is enhanced when used strategically to complement other nitric oxide-supporting compounds rather than replace them.

Purchasing L-Norvaline powder in bulk (25g-100g) can significantly reduce costs, often bringing the price down to $0.15-$0.30 per 200 mg dose. This approach is most economical for those committed to long-term use. However, proper measurement tools (such as a milligram scale) are necessary when purchasing bulk powder to ensure accurate dosing. Bulk L-Norvaline is primarily available through specialty supplement retailers rather than mainstream supplement stores.

Some manufacturers offer bulk discounts or subscription services that can reduce costs by 10-20% for regular users.

L-Norvaline supplements are not covered by conventional health insurance plans. Some Health Savings Accounts (HSAs) or Flexible Spending Accounts (FSAs) may cover L-Norvaline supplements with a physician’s recommendation, though policies vary widely and approval is unlikely given its limited clinical evidence base.

For comparison, prescription medications for conditions that L-Norvaline might theoretically address (such as hypertension or erectile dysfunction) are often covered by insurance but typically come with copays of $5-$50 per month depending on the medication and insurance plan, plus the cost of doctor visits.

Pure L-Norvaline powder typically has a shelf life of 2-3 years

when stored properly under recommended conditions. L-Norvaline in capsule or tablet form generally has a shelf life of 1-2 years, depending on the formulation and presence of other ingredients.

When included in multi-ingredient formulations such as pre-workout supplements, the shelf life may be limited by the least stable component in the mixture, typically ranging from 1-2 years. Manufacturers often recommend using opened products within 6-12 months for optimal potency, even if the formal expiration date is further in the future.

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, Avoid exposure to heat sources or temperature fluctuations, Keep away from strong oxidizing agents, Store in the original container or in an airtight container if transferred

Exposure to high humidity (can cause clumping and potential degradation of powder forms), 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), Enzymatic degradation in liquid formulations without preservatives, Repeated freeze-thaw cycles, Chemical interactions with other ingredients in multi-component formulations

L-Norvaline is generally stable in aqueous solution at neutral pH for short periods (up to 1 week) when refrigerated. Stability decreases in strongly acidic or alkaline conditions. For maximum stability in solution, a pH range of 6.0-7.5 is optimal. Solutions should be stored in the refrigerator (2-8°C) in a tightly sealed container to prevent microbial growth.

When mixed in beverages, L-Norvaline remains stable for several days when refrigerated, though other ingredients may degrade more quickly. L-Norvaline is relatively resistant to thermal degradation in solution at moderate temperatures, making it suitable for inclusion in warm (but not boiling) beverages. Commercial liquid formulations typically include preservatives to maintain potency throughout the product’s shelf life. For research applications requiring long-term storage of L-Norvaline solutions, freezing at -20°C in aliquots to avoid repeated freeze-thaw cycles is recommended.

Solutions should be prepared fresh when possible, especially for critical applications where precise dosing is important.

Natural Sources

Synthetic Production Methods

Quality Indicators

Sustainability Considerations

Unlike many other supplements with long histories of traditional use, L-Norvaline does not have a significant history of traditional medicinal applications. As a non-proteinogenic amino acid that is not abundantly found in common food sources, it was not specifically identified or utilized in traditional medicine systems. While various amino acids have been used therapeutically throughout history in different cultural medical traditions, L-Norvaline specifically was not recognized or intentionally employed for health purposes prior to modern scientific investigation. This contrasts with many other supplements that have histories dating back centuries or millennia in traditional Chinese medicine, Ayurveda, or other traditional healing systems.

The absence of traditional use is primarily due to the fact that L-Norvaline was not readily isolated or identified until modern analytical techniques became available, and its specific biological activities were not understood until relatively recent scientific investigations.

L-Norvaline was first identified and characterized as a distinct amino acid in the early 20th century as part of the broader scientific exploration of amino acid chemistry. However, its potential biological significance remained relatively unexplored for decades. The modern interest in L-Norvaline as a bioactive compound began in the late 1990s, when researchers investigating nitric oxide metabolism discovered its properties as an arginase inhibitor. A key paper published in 1998 by Chang et al.

in the American Journal of Physiology demonstrated that L-Norvaline could inhibit arginase activity in macrophages, thereby increasing nitric oxide production. This finding opened the door to research on L-Norvaline’s potential applications in conditions where arginase activity is elevated and nitric oxide production is compromised. Throughout the 2000s, additional research explored L-Norvaline’s effects in various experimental models, particularly related to vascular function, inflammation, and metabolism. In 2009, researchers published findings on L-Norvaline’s potential benefits for endothelial function in cardiovascular disease models, further expanding interest in its therapeutic potential.

The identification of L-Norvaline as an inhibitor of S6K1 (a component of the mTOR pathway) in the 2010s added another dimension to scientific understanding of its biological activities, suggesting potential applications beyond nitric oxide modulation.

The evolution of L-Norvaline usage has been primarily driven by scientific research rather than traditional practices. In the early 2000s, following the discovery of its arginase-inhibiting properties, L-Norvaline began to attract interest primarily in research settings for studying nitric oxide metabolism and arginase function. By the mid-2000s, some sports nutrition companies began incorporating L-Norvaline into pre-workout and ‘pump’ supplements, marketing it for its potential to enhance blood flow and nutrient delivery to muscles through nitric oxide modulation. This application was based on the theoretical benefits of arginase inhibition for increasing nitric oxide production during exercise.

Around 2010-2015, interest expanded to potential applications in cardiovascular health, with some research exploring L-Norvaline’s effects on endothelial function, blood pressure, and vascular health. During this period, it began appearing in some cardiovascular support formulations, though typically as part of multi-ingredient products rather than as a standalone supplement. More recently, from 2015 onward, some research has investigated L-Norvaline’s potential neuroprotective properties and applications in cognitive health, based on the role of nitric oxide in cerebral blood flow and neuronal function. This has led to its inclusion in some nootropic formulations.

In 2019, a study raising concerns about potential cytotoxicity and mitochondrial effects of L-Norvaline prompted debate about its safety profile, with subsequent publications contesting these findings. This scientific discussion has influenced how L-Norvaline is perceived and utilized in the supplement industry, with some companies becoming more cautious about its inclusion in products while others continue to use it based on the overall body of research. Currently, L-Norvaline remains primarily used in sports nutrition and some cardiovascular support supplements, though typically at moderate doses and often as part of complex formulations rather than as a high-dose standalone product.

Limited information available on ongoing clinical trials specifically focused on L-Norvaline supplementation in humans, Some research groups are investigating arginase inhibitors, including L-Norvaline, for potential applications in cardiovascular health, cognitive function, and metabolic disorders, Preclinical research continues to explore the mechanisms and potential therapeutic applications of L-Norvaline and other arginase inhibitors