Home Ingredients L-Norvaline

L-Norvaline

Evidence Level
Preliminary
7 Clinical Trials
4 Documented Benefits
1/5 Evidence Score

L-norvaline is a non-proteinogenic amino acid, meaning the body does not use it to build proteins. It is sold mainly in pre-workout products on the idea that it blocks arginase, an enzyme that breaks down arginine, leaving more arginine available for making nitric oxide, which relaxes blood vessels. That idea rests on cell and animal research only: no published trial has tested L-norvaline taken by mouth in people, for exercise or for anything else, and its safety in humans has not been studied. A cell study found it damaged cells and their mitochondria at higher concentrations, while other researchers argued those concentrations are far above what a supplement dose would produce, and an animal oral toxicity study of the DL form (a blend of L and D) reported no observable harm. Two of three rat blood pressure studies injected it; one gave it by mouth. Treat it as experimental.

Studied Dose No human dose has been tested in a published trial. A commentary states athletes typically use 200 to 300 mg/day. Rat and mouse studies used about 30 to 50 mg/kg/day, by stomach tube, in drinking water or by injection.
Active Compound L-norvaline, a non-proteinogenic amino acid closely related in structure to the protein amino acid valine.

Benefits

Arginase activity and nitric oxide in rat studies

In rats with fructose-induced or drug-induced metabolic problems, 6 weeks of daily norvaline (50 mg/kg by stomach tube in the fructose study) lowered raised arginase activity, restored nitric oxide release and relaxation in aorta tissue, and reduced rises in blood pressure. These are animal results; no study has measured arginase or nitric oxide in people after taking L-norvaline.

Supported by Trial 3

Blood pressure in rat models

In rats bred for stress-induced high blood pressure, L-norvaline injected for 7 days lowered blood pressure and increased urine output. One study saw no change in normal-pressure rats, while a later one from the same lab described lower pressure in both strains. The doses were given by injection, not by mouth, and blood pressure has not been tested in humans.

Supported by Trial 4, Trial 3

Memory and brain markers in a mouse model

In mice bred to develop Alzheimer's-like brain changes, L-norvaline in drinking water for 2 months improved spatial learning and reduced brain inflammation and toxic amyloid forms; later work from the same group reported higher brain glucose uptake. This is mouse research only, and no study has tested memory in people.

Supported by Trial 5

Inflammation signals in cell and mouse studies

In human blood vessel cells grown in the lab, L-norvaline reduced inflammation-related adhesion molecules, apparently through an enzyme called S6K1 rather than arginase. In high-fat-diet mice, DL-norvaline, a blend of the L and D forms, lowered inflammatory markers. Neither finding has been tested in people.

Supported by Trial 2, Trial 7

Mechanism of action

1

Arginase inhibition, the proposed route to nitric oxide

Arginase and nitric oxide synthase both use arginine. Blocking arginase is proposed to leave more arginine for making nitric oxide, and rat studies found lower arginase activity with norvaline. But in isolated rat arteries norvaline did not act like other arginase inhibitors, and the authors cautioned against assuming such compounds act only on arginase.

2

S6K1 signaling, separate from arginase

In human endothelial cells, L-norvaline's anti-inflammatory effect was not reproduced by blocking arginase in other ways and was not reversed by a nitric oxide synthase blocker; it was partly explained by inhibition of the S6K1 enzyme. The concentrations used (1 to 40 mmol/L) were laboratory levels, not ones shown to occur after a supplement dose.

3

Mimicry of protein amino acids in cells

Because it resembles protein amino acids, L-norvaline may be mistaken for them by cells. In a cell study its toxicity fell when similar protein amino acids were added, which the authors took as a sign of this mimicry. Whether this happens in the body at supplement doses is unknown.

Clinical trials

1
Cell Study: L-Norvaline Toxicity and Mitochondrial Changes (no animals or people)
PubMed

In vitro study of L-norvaline's effects on the viability, death pathway and mitochondria of mammalian cells in culture. (Samardzic et al. 2019, Toxicol In Vitro)

Mammalian cells in culture; a later commentary identifies the line as SH-SY5Y human neuroblastoma cells. No animals or human participants.

L-norvaline reduced cell viability at concentrations as low as 125 micromolar, caused necrotic cell death and altered mitochondrial shape and function. Toxicity was lower when structurally similar protein amino acids were present. A 2019 commentary disputed the interpretation, arguing that many amino acids harm cultured cells at similar levels and that supplement doses likely give much lower tissue levels; neither paper measured anything in people.

2
Animal Study: Oral Safety, Absorption and Inflammation Markers of DL-Norvaline
PubMed

Animal toxicology, pharmacokinetic and efficacy study of DL-norvaline in mice, with macrophage cell experiments. (Li et al. 2026, Eur J Pharmacol)

Animals in acute and subchronic oral toxicity tests (species not stated in the abstract), high-fat-diet obese mice, and mice challenged with bacterial endotoxin; plus RAW264.7 macrophage cells. Doses are not given in the abstract.

Oral toxicity testing found no deaths or observable adverse effects. DL-norvaline was rapidly absorbed, distributed mainly to the liver, intestine, fat and kidney, and about 20% was excreted. In high-fat-diet mice it lowered endotoxin and inflammatory markers and liver injury markers. This used the DL form (a blend of L and D), not the pure L form named on most supplement labels, and included no human data.

3
Rat Study: Arginase Inhibitors in Fructose-Fed Rats
PubMed

Controlled rat study comparing three arginase inhibitors (citrulline, norvaline, ornithine) given daily by stomach tube (norvaline 50 mg/kg) for the last 6 weeks of a 12-week fructose diet. (El-Bassossy et al. 2013, Br J Pharmacol)

Rats with metabolic syndrome induced by 10% fructose in drinking water for 12 weeks.

Arginase activity rose with the fructose diet and was significantly inhibited by each treatment. Each treatment, norvaline included, reduced the rise in systolic and diastolic blood pressure, prevented impaired aorta relaxation and nitric oxide generation, and lowered high insulin and triglycerides, but did not change raised uric acid or cholesterol. Animal data only.

4
Rat Study: Injected L-Norvaline and Blood Pressure in Hypertensive and Normal Rats
PubMed

Controlled rat study of L-norvaline (30 mg/kg/day injected into the abdomen for 7 days) versus vehicle. (Gilinsky et al. 2020, Biomed Res Int)

Adult rats with inherited stress-induced arterial hypertension (ISIAH) and normotensive Wistar controls.

Blood pressure fell and urine output rose in the hypertensive rats; blood pressure did not change in the normal rats. Kidney filtration and daily creatinine and urea excretion were unchanged. Nitric oxide metabolites rose in normal but not hypertensive rats. The compound was injected, so the results do not show what an oral supplement does.

5
Mouse Study: L-Norvaline in Drinking Water in an Alzheimer's Model
PubMed

Controlled study of L-norvaline (250 mg/L in drinking water, about 40 to 50 mg/kg/day) for 2 months in transgenic and wild-type mice. (Polis et al. 2018, Neurotherapeutics)

Triple-transgenic (3xTg) Alzheimer's model mice and wild-type mice, treated from 4 months of age (14 transgenic mice per group in the water maze test).

Treated transgenic mice learned a spatial memory task better and showed less microglial activation, more dendritic spines and lower levels of toxic amyloid oligomer and fibril species in the hippocampus. Overall amyloid deposition fell in the cortex but did not differ significantly in the hippocampus. Mouse data only; no human memory study exists.

6
Isolated Rat Arteries: Norvaline Compared With Other Arginase Inhibitors
PubMed

Laboratory study of several arginase inhibitors applied to isolated rings of rat aorta and mesenteric arteries. (Huynh et al. 2009, Br J Pharmacol)

Isolated aorta and mesenteric artery rings from rats; no live animals treated and no people.

Norvaline did not reverse the reduced response to repeated acetylcholine and did not relax the vessels, while the inhibitors BEC and L-NOHA did. The authors concluded that compounds used as arginase inhibitors should not be assumed to act specifically on arginase in blood vessels. A null result for norvaline in this model.

7
Cell Study: L-Norvaline and Inflammation in Human Endothelial Cells
PubMed

In vitro study of L-norvaline on TNF-alpha-stimulated human umbilical vein endothelial cells. (Ming et al. 2009, BMC Cardiovasc Disord)

Human umbilical vein endothelial cells in culture; no animals or human participants.

L-norvaline (1 to 40 mmol/L) reduced the TNF-alpha-induced rise in VCAM-1, ICAM-1 and E-selectin in a concentration-dependent way. Another arginase inhibitor and arginase-II silencing did not reproduce this, and a nitric oxide synthase blocker did not reverse it; the effect was partly explained by S6K1 inhibition. Lab concentrations only.

Side effects and drug interactions

Common Potential side effects

No human safety data: no published study has given L-norvaline to people and tracked side effects, so its short-term and long-term safety in humans is unknown.
In a cell study, L-norvaline reduced cell survival at 125 micromolar and above and disrupted mitochondria. Other researchers argued that many amino acids harm cultured cells at similar levels and that supplement doses likely produce much lower tissue levels. Without human data the question is unresolved.
In animals, oral toxicity testing of the DL form (a blend of L and D) found no deaths or observable adverse effects. In rats given L-norvaline by injection, researchers reported increased urine output and changes in adrenal catecholamines (stress hormones), and noted that it causes various side effects.
It is promoted to raise nitric oxide, and injected norvaline lowered blood pressure in rats, so people with low blood pressure should be cautious.
There is no safety information for pregnancy, breastfeeding or children; avoid use in these groups.
Label accuracy may vary: in a lab analysis that tested two supplements labeled as containing L-norvaline, one matched its label and the other had none detectable.

Important Drug interactions

Blood pressure medicines: no interaction studies exist, but because L-norvaline is intended to raise nitric oxide, effects could add up in theory. Ask a doctor first.
Nitrates (nitroglycerin, isosorbide) and erectile dysfunction drugs (sildenafil, tadalafil, vardenafil) act on the nitric oxide pathway; combining them with nitric oxide boosters is a theoretical concern, so avoid this without medical advice.
Other nitric oxide boosters such as L-arginine and L-citrulline are often combined with norvaline in pre-workout products; the combination has not been studied in people.

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Frequently asked questions about L-Norvaline

Has L-norvaline been tested in people?

No published clinical trial has given L-norvaline to people and measured exercise, blood flow or any other outcome, and ClinicalTrials.gov lists no registered trials of it. Everything known about its effects comes from cells, isolated tissues, rats and mice, and two of the three rat blood pressure studies injected it instead of giving it by mouth.

What did the 2019 cell study on L-norvaline find, and why is it disputed?

Researchers reported that L-norvaline reduced the survival of cultured cells at 125 micromolar and above and damaged their mitochondria, and suggested it acts by mimicking protein amino acids. A commentary replied that many amino acids harm cultured cells at similar levels, that the mitochondrial effect needed very high concentrations combined with another chemical, and that supplement doses likely give much lower tissue levels. Neither side tested people.

How does L-norvaline differ from L-arginine and L-citrulline?

L-arginine is the raw material the body uses to make nitric oxide, and L-citrulline can be turned into arginine. L-norvaline does neither; it is proposed to slow arginase, an enzyme that breaks arginine down. Arginine and citrulline have been studied in human trials, while norvaline has not. See our L-arginine and L-citrulline pages.

Do L-norvaline products contain what the label says?

Testing is limited. In one lab analysis that tested just two L-norvaline products, one matched its label and the other had no detectable L-norvaline. Products with independent third-party testing give more assurance about contents.

What is L-Norvaline?

L-norvaline is a non-proteinogenic amino acid, meaning the body does not use it to build proteins. It is sold mainly in pre-workout products on the idea that it blocks arginase, an enzyme that breaks down arginine, leaving more arginine available for making nitric oxide, which relaxes blood vessels.

What is L-Norvaline used for?

NutraSmarts does not list L-Norvaline under a health category. What the research covers: In rats with fructose-induced or drug-induced metabolic problems, 6 weeks of daily norvaline (50 mg/kg by stomach tube in the fructose study) lowered raised arginase activity, restored nitric oxide release and relaxation in aorta tissue, an…

What is the recommended dosage of L-Norvaline?

No human dose has been tested in a published trial. A commentary states athletes typically use 200 to 300 mg/day. Rat and mouse studies used about 30 to 50 mg/kg/day, by stomach tube, in drinking water or by injection. Always follow the product label and check with a healthcare provider for personal advice.

Is L-Norvaline safe, and does it have side effects?

Side effects and cautions reported for L-Norvaline include: No human safety data: no published study has given L-norvaline to people and tracked side effects, so its short-term and long-term safety in humans is unknown. In a cell study, L-norvaline reduced cell survival at 125 micromolar and above and disrupted mitochondria. It may also interact with some medications. L-Norvaline is not right for everyone, so check with a healthcare provider first if you are pregnant or breastfeeding, have a medical condition, or take prescription medication.

Does L-Norvaline interact with any medications?

Possible interactions include: Blood pressure medicines: no interaction studies exist, but because L-norvaline is intended to raise nitric oxide, effects could add up in theory. Ask a doctor first. If you take prescription medication, check with a pharmacist or doctor before using it.

How strong is the scientific evidence for L-Norvaline?

NutraSmarts rates the evidence for L-Norvaline as Preliminary (1 out of 5). It is backed by 7 study summaries and 12 cited references summarized on this page. A higher rating reflects more, larger, and better-designed human studies.

References(12 citations)

Evidence ratings on NutraSmarts are based on the totality of human clinical research, with emphasis on randomized controlled trials, meta-analyses, and systematic reviews. The references below directly support claims made throughout this page.

  1. Samardzic K, Rodgers KJ. Cytotoxicity and mitochondrial dysfunction caused by the dietary supplement l-norvaline. Toxicol In Vitro. 2019;56:163-171. doi: 10.1016/j.tiv.2019.01.020.PubMedUsed to support: Cell culture study: L-norvaline reduced the viability of mammalian cells at concentrations as low as 125 micromolar, caused necrotic cell death and changed mitochondrial shape and function. Adding structurally similar protein amino acids reduced the toxicity, suggesting L-norvaline harms cells by mimicking them. No animals or people were studied.
  2. Polis B, Gilinsky MA, Samson AO. Reports of L-Norvaline Toxicity in Humans May Be Greatly Overstated. Brain Sci. 2019;9(12):382. doi: 10.3390/brainsci9120382.PubMedUsed to support: Commentary disputing the 2019 cell toxicity study: argues that many amino acids harm cultured cells at similar concentrations, that the mitochondrial effect was significant only at 2000 micromolar combined with a nitric oxide synthase blocker, that a single cancer-derived cell line without astrocytes is a poor model, and that the 200 to 300 mg/day it says athletes use should give far lower tissue levels. Presents no new data; written by researchers whose group studies norvaline as a treatment candidate.
  3. Li X, Wang X, Lü X. DL-norvaline attenuated HFD-induced metabolic inflammation and dysfunction with integrated pharmacokinetic, biodistribution, and safety evaluation. Eur J Pharmacol. 2026;1026:178943. doi: 10.1016/j.ejphar.2026.178943.PubMedUsed to support: Animal and cell study of DL-norvaline (a mix of the L and D forms): acute and subchronic oral toxicity tests showed no deaths or observable adverse effects; it was rapidly absorbed, spread widely to the liver, intestine, fat and kidney, and about 20% was excreted. In high-fat-diet mice it lowered inflammatory markers and liver injury markers. Animal data only.
  4. Polis B, Srikanth KD, Elliott E, Gil-Henn H, Samson AO. L-Norvaline Reverses Cognitive Decline and Synaptic Loss in a Murine Model of Alzheimer's Disease. Neurotherapeutics. 2018;15(4):1036-1054. doi: 10.1007/s13311-018-0669-5.PubMedUsed to support: Mouse study: triple-transgenic Alzheimer's model mice given L-norvaline in drinking water (250 mg/L, about 40 to 50 mg/kg/day) for 2 months (14 transgenic mice per group in the water maze) showed better spatial memory learning, less microglial activation, more dendritic spines and lower levels of toxic amyloid oligomer and fibril species in the hippocampus than untreated mice. Animal data only.
  5. Polis B, Squillario M, Gurevich V, Srikanth KD, Assa M, Samson AO. Effects of Chronic Arginase Inhibition with Norvaline on Tau Pathology and Brain Glucose Metabolism in Alzheimer's Disease Mice. Neurochem Res. 2022;47(5):1255-1268. doi: 10.1007/s11064-021-03519-3.PubMedUsed to support: Mouse study from the same group: in an Alzheimer's model, long-term norvaline treatment raised brain glucose uptake on PET imaging, raised hippocampal insulin receptor and glucose transporter-3 levels, and lowered tau protein phosphorylation. Animal data only.
  6. Ming XF, Rajapakse AG, Carvas JM, Ruffieux J, Yang Z. Inhibition of S6K1 accounts partially for the anti-inflammatory effects of the arginase inhibitor L-norvaline. BMC Cardiovasc Disord. 2009;9:12. doi: 10.1186/1471-2261-9-12.PubMedUsed to support: Cell study in human umbilical vein endothelial cells: L-norvaline (1 to 40 mmol/L) reduced TNF-alpha-induced adhesion molecules (VCAM-1, ICAM-1, E-selectin). The effect did not depend on arginase or nitric oxide synthase, since another arginase inhibitor and arginase-II silencing did not reproduce it; it was partly explained by inhibition of the S6K1 enzyme.
  7. El-Bassossy HM, El-Fawal R, Fahmy A, Watson ML. Arginase inhibition alleviates hypertension in the metabolic syndrome. Br J Pharmacol. 2013;169(3):693-703. doi: 10.1111/bph.12144.PubMedUsed to support: Rat study: in rats given fructose water for 12 weeks, daily citrulline, norvaline (50 mg/kg by stomach tube) or ornithine (separate groups) in the last 6 weeks lowered raised arginase activity, reduced the rise in systolic and diastolic blood pressure, prevented impaired aorta relaxation and nitric oxide generation, and lowered high insulin and triglycerides. Animal data only.
  8. El-Bassossy HM, El-Fawal R, Fahmy A. Arginase inhibition alleviates hypertension associated with diabetes: effect on endothelial dependent relaxation and NO production. Vascul Pharmacol. 2012;57(5-6):194-200. doi: 10.1016/j.vph.2012.01.001.PubMedUsed to support: Rat study: in streptozotocin-diabetic rats, daily citrulline, norvaline or ornithine for the last 6 weeks inhibited raised arginase activity, reduced the rise in diastolic blood pressure, prevented impaired aorta relaxation, and restored nitric oxide and reactive oxygen species generation in the aorta. Animal data only.
  9. Gilinsky MA, Polityko YK, Markel AL, Latysheva TV, Samson AO, Polis B, Naumenko SE. Norvaline Reduces Blood Pressure and Induces Diuresis in Rats with Inherited Stress-Induced Arterial Hypertension. Biomed Res Int. 2020;2020:4935386. doi: 10.1155/2020/4935386.PubMedUsed to support: Rat study: L-norvaline injected into the abdomen (30 mg/kg/day for 7 days) lowered blood pressure and increased urine output in rats bred for stress-induced high blood pressure, but did not change blood pressure in normal Wistar rats. Nitric oxide metabolites rose in the normal rats but not the hypertensive ones. Injection, not oral use.
  10. Gilinsky MA, Polityko YK, Markel AL, Aftanas LI. Hypotensive Effects of Arginase Inhibition by L-Norvaline in Genetic Models of Normotensive and Hypertensive Rats. Bull Exp Biol Med. 2023;174(5):674-677. doi: 10.1007/s10517-023-05767-5.PubMedUsed to support: Rat study: injected L-norvaline (30 mg/kg for 7 days) is described as lowering blood pressure; in hypertensive rats this came with more urine output and higher adrenal catecholamine content, while in normal-pressure rats urine output changed little and catecholamines fell. The authors note that norvaline causes various side effects in these animals. Injection, not oral use.
  11. Huynh NN, Harris EE, Chin-Dusting JF, Andrews KL. The vascular effects of different arginase inhibitors in rat isolated aorta and mesenteric arteries. Br J Pharmacol. 2009;156(1):84-93. doi: 10.1111/j.1476-5381.2008.00036.x.PubMedUsed to support: Isolated rat artery study comparing arginase inhibitors: norvaline neither reversed tolerance to acetylcholine nor relaxed the vessels, unlike BEC and L-NOHA. The authors caution against treating such compounds as specific arginase inhibitors in blood vessels without checking by other methods.
  12. Xu D, Sánchez-López E, Wang Q, Jiang Z, Marina ML. Determination of l-norvaline and l-tryptophan in dietary supplements by nano-LC using an O-[2-(methacryloyloxy)-ethylcarbamoyl]-10,11-dihydroquinidine-silica hybrid monolithic column. J Pharm Anal. 2020;10(1):70-77. doi: 10.1016/j.jpha.2019.10.001.PubMedUsed to support: Analytical chemistry methods paper that applied its test to dietary supplements, including two products labeled as containing L-norvaline: one matched its labeled amount, the other showed no detectable L-norvaline even after concentrating the sample, and no D-norvaline was found in any sample.