What is histidine

Histidine is a semi-essential amino acid that is required in humans for growth and tissue repair and for the synthesis of histamine. Histidine biologically active isomer is L-histidine. Histidine is the only amino acid whose side-chain can switch from an unprotonated to a protonated state under neutral pH conditions due to the pK_a value of 6.0 of its side-chain ¹. This characteristic enables histidine residues to act as both, a proton acceptor or a proton donor, in many cellular enzymatic reactions ². For infants four to six months old, histidine is an essential amino acid that is required from food at 33 mg/kg body weight per day ³. However, it is not clear how adults make small amounts of histidine and dietary sources probably account for most of the histidine in the body. Histidine is abundant in red meat and fish ⁴. It has been reported that lower plasma concentration of histidine is associated with protein-energy wasting, inflammation and oxidative stress in chronic kidney disease patients ⁵. Histidine is important for maintenance of myelin sheaths that protect nerve cells and is metabolized to the neurotransmitter histamine. Histamines play many roles in immunity, gastric secretion, and sexual functions. Histidine is also required for blood cell manufacture and protects tissues against damage caused by radiation and heavy metals. Histidine is a precursor for histamine and carnosine biosynthesis. Inborn errors of histidine metabolism, including histidinemia, maple syrup urine disease, propionic acidemia, and tyrosinemia I, exist and are marked by increased histidine levels in the blood. Elevated blood histidine is accompanied by a wide range of symptoms, from mental and physical retardation to poor intellectual functioning, emotional instability, tremor, ataxia and psychosis.

Histidine and other imidazole compounds have anti-oxidant, anti-inflammatory and anti-secretory properties ⁶. The efficacy of L-histidine in protecting inflamed tissue is attributed to the capacity of the imidazole ring to scavenge reactive oxygen species (ROS) generated by cells during acute inflammatory response ⁶. Histidine, when administered in therapeutic quantities is able to inhibit cytokines and growth factors involved in cell and tissue damage.

Histidine in medical therapies has its most promising trials in rheumatoid arthritis where up to 4. 5 g daily have been used effectively in severely affected patients. Arthritis patients have been found to have low serum histidine levels, apparently because of very rapid removal of histidine from their blood ⁷. Other patients besides arthritis patients that have been found to be low in serum histidine are those with chronic renal failure ⁸. Low plasma concentrations of histidine are associated with protein-energy wasting, inflammation, oxidative stress, and greater mortality in chronic kidney disease patients ⁹. Bergström et al. ¹⁰ reported that the addition of histidine (included in an essential amino acid supplement) to uremia patients improved nitrogen balance and promoted net protein synthesis without any increase of the blood urea concentration. On the basis of this study ⁹ and the results of a study by Kopple and Swendseid ¹¹, histidine has been considered to be an essential amino acid in uremia patients. Moreover, it was shown by Kult ¹² that a daily oral supplementation of 1.5 g histidine, with no other amino acid, for 12 weeks resulted in higher concentrations of total protein, albumin, prealbumin, and the complement components C1q, C3c, C3, C1s inactivator, and C3 activator in 42 chronic kidney disease patients with a glomerular filtration rate <10 mL/min. Currently, oral and intravenous supplementation of amino acids to uremia patients and the use of amino acid-based peritoneal dialysis solutions in general includes histidine because of its status as a conditional essential amino acid in uremia and its associated beneficial effect on the nitrogen metabolism and nutritional status ⁹. The mechanism or mechanisms behind the deranged metabolism of amino acids and the causes of low extracellular and intracellular histidine concentrations in uremia are unclear.

There are conflicting reports on histidine levels and roles in inflammation. Asthma patients exhibit increased serum levels of histidine over normal controls ¹³. In a study by Watanabe and colleagues ⁹, histidine is low in patients with inflammation and was inversely correlated with several inflammation markers. In another study, urinary levels of histidine are reduced in pediatric patients with pneumonia. In contrast, it has been reported that histidine may have an influence on the inflammatory cascade, and histidine has been reported to have potent anti-inflammatory and antisecretory properties ¹⁴. Son et al. ¹⁵ reported that histidine in a dose-dependent manner inhibits oxidative stress and TNF-α–induced IL-8 secretion at the transcriptional level and also abolishes the NF-κB–dependent activation of IL-8 promoter induced by TNF-α. In addition, histidine supplementation could effectively down-regulate IL-6 and TNF-α in a diabetic mice model. In rheumatoid arthritis patients, oral administration of histidine was reported to improve grip strength and walking speed and to reduce the rate of erythrocyte sedimentation ¹⁶. It has been suggested that the absence of histidine led to γ-globulin aggregation and inflammation and, furthermore, that exogenous histidine would then prevent the aggregation of gamma globulin and the consequent inflammatory reaction ¹⁶. Thus, the present findings and those of previous studies suggest that histidine may have anti-inflammatory effects and that the plasma concentration of histidine may be associated with the inflammation state and is not regulated only by nutritional status in chronic kidney disease patients. This possibility is supported by observation that supplementation of amino acids, including histidine, was associated with low C-reactive protein (CRP) ⁹.

Serum histidine levels are lower and are negatively associated with inflammation and oxidative stress in obese women ¹⁷. Histidine supplementation has been shown to reduce insulin resistance, reduce BMI and fat mass and suppress inflammation and oxidative stress in obese women with metabolic syndrome ¹⁷. Recently, plasma histidine levels were reported to show a significant inverse association with fasting and 2 hour blood glucose levels during glucose tolerance tests in individuals without diabetes or newly diagnosed male patients with type 2 diabetes ¹⁸. Histidine was also shown to improve the hyperglycemia induced by the central administration of 2-deoxyglucose in rodents ¹⁹; however, the mechanism by which histidine lowers blood glucose levels is not clear ²⁰. In this study ²⁰, the intraperitoneal administration of histidine induced the phosphorylation of hepatic signal transducer and activator of transcription-3 (STAT3) and reduced blood glucose levels associated with glucose loading. Previous study ²¹ revealed that hepatic signal transducer and activator of transcription-3 (STAT3) decreases the expression of hepatic gluconeogenic enzymes and suppresses hepatic glucose production. Consistent with a previous study showing that histidine is not involved in the secretion of insulin ²², histidine did not significantly affect plasma insulin levels in this study ²⁰. This study ²⁰ demonstrates that the activation of hepatic IL-6/STAT3 signaling pathways and down regulation of hepatic gluconeogenic gene expression by histidine are mediated by central histamine action involving the histamine H₁ receptor (H1R). Central histidine action, which has a central nervous system mechanism that is independent of insulin, augments the insulin-dependent suppression of glucose production in the liver. This study indicates that the central mechanism by which histidine regulates hepatic glucose metabolism and activates hepatic STAT3 is a potential target for the treatment of type 2 diabetic patients with elevated gluconeogenesis ²⁰.

Histidine appears to suppress pro-inflammatory cytokine expression, possibly via the NF-κB pathway, in adipocytes ¹⁷. Histidine may have many other possible functions because it is the precursor of the ubiquitous neurohormone-neurotransmitter histamine. Histidine increases histamine in the blood and probably in the brain. Low blood histamine with low serum histidine occurs in rheumatoid arthritis patients. Low blood histamine also occurs in some manic, schizophrenic, high copper and hyperactive groups of psychiatric patients. Histidine maybe a useful therapy in all patients with low histamine levels.

Histidine foods

Table 1. Foods high in histidine (ordered from highest to low)

Description	Histidine (g) Value Per 100 grams
Whale, beluga, meat, dried (Alaska Native)	3
Soy protein isolate	2.3
Soy protein isolate, potassium type	2.3
Egg, white, dried, stabilized, glucose reduced	2.05
Egg, white, dried, powder, stabilized, glucose reduced	1.87
Fish, cod, Atlantic, dried and salted	1.85
Egg, white, dried	1.83
Egg, white, dried, flakes, stabilized, glucose reduced	1.75
Cheese, parmesan, shredded	1.61
Pork, cured, bacon, cooked, microwaved	1.59
Soy protein concentrate, produced by alcohol extraction	1.58
Soy protein concentrate, produced by acid wash	1.58
Seeds, cottonseed flour, low fat (glandless)	1.57
Seeds, cottonseed meal, partially defatted (glandless)	1.55
Beverages, Protein powder soy based	1.51
Game meat, deer, cooked, roasted	1.49
Seeds, sesame flour, low-fat	1.48
Game meat, boar, wild, cooked, roasted	1.44
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	1.41
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	1.4
Game meat, antelope, cooked, roasted	1.4
Tofu, dried-frozen (koyadofu)	1.39
Tofu, dried-frozen (koyadofu), prepared with calcium sulfate	1.39
Pork, cured, bacon, cooked, broiled, pan-fried or roasted, reduced sodium	1.39
Pork, cured, bacon, pre-sliced, cooked, pan-fried	1.39
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	1.39
Cheese, parmesan, hard	1.38
Beef, plate steak, boneless, inside skirt, separable lean only, trimmed to 0″ fat, select, cooked, grilled	1.38
Game meat, beaver, cooked, roasted	1.37
Beef, top loin filet, boneless, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	1.35
Pork, cured, bacon, cooked, baked	1.34
Beef, loin, top loin steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	1.34
Beef, loin, top loin steak, boneless, lip off, separable lean only, trimmed to 0″ fat, select, cooked, grilled	1.34
Seeds, sunflower seed flour, partially defatted	1.33
Beef, round, eye of round steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	1.33
Veal, leg (top round), separable lean only, cooked, braised	1.33
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	1.33
Beef, loin, top sirloin petite roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	1.32
Beef, rib, back ribs, bone-in, separable lean only, trimmed to 0″ fat, select, cooked, braised	1.32
Peanut flour, defatted	1.32
Veal, leg (top round), separable lean and fat, cooked, braised	1.31
Beef, rib eye steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	1.31
Beef, rib eye steak, boneless, lip off, separable lean only, trimmed to 0″ fat, select, cooked, grilled	1.31
Pork, fresh, loin, center loin (chops), boneless, separable lean only, cooked, pan-broiled	1.3
Veal, shoulder, arm, separable lean only, cooked, braised	1.3
Beef, rib eye roast, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, roasted	1.3
Beef, plate steak, boneless, outside skirt, separable lean only, trimmed to 0″ fat, select, cooked, grilled	1.29
Seeds, cottonseed flour, partially defatted (glandless)	1.29
Beef, top loin petite roast, boneless, separable lean only, trimmed to 1/8″ fat, select, cooked, roasted	1.29
Beef, ribeye petite roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	1.28
Beef, loin, top sirloin cap steak, boneless, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	1.28
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, grilled	1.27
Beef, round, top round steak, boneless, separable lean and fat, trimmed to 0″ fat, select, cooked, grilled	1.27
Soy flour, defatted	1.27
Veal, cubed for stew (leg and shoulder), separable lean only, cooked, braised	1.27
Pork, fresh, loin, top loin (chops), boneless, separable lean only, with added solution, cooked, pan-broiled	1.27
Beef, loin, tenderloin steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	1.27
Pork, Leg sirloin tip roast, boneless, separable lean and fat, cooked, braised	1.26
Beef, rib eye steak, bone-in, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	1.26
Pork, fresh, loin, sirloin (chops), bone-in, separable lean only, cooked, braised	1.26
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	1.26
Pork, ground, 96% lean / 4% fat, cooked, pan-broiled	1.25
Veal, rib, separable lean only, cooked, braised	1.25
Beef, ribeye filet, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	1.25
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	1.25
Beef, loin, tenderloin roast, separable lean only, boneless, trimmed to 0″ fat, select, cooked, roasted	1.24
Beef, New Zealand, imported, brisket point end, separable lean only, cooked, braised	1.24
Pork, fresh, loin, top loin (chops), boneless, separable lean only, cooked, braised	1.24
Pork, fresh, loin, top loin (chops), boneless, separable lean and fat, with added solution, cooked, pan-broiled	1.24
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	1.24
Pork, fresh, loin, top loin (chops), boneless, separable lean only, cooked, pan-fried	1.24
Game meat, bison, chuck, shoulder clod, separable lean only, cooked, braised	1.24
Beef, round, top round, separable lean only, trimmed to 0″ fat, choice, cooked, braised	1.24
Beef, round, top round, separable lean only, trimmed to 0″ fat, select, cooked, braised	1.24
Pork, fresh, loin, sirloin (roasts), boneless, separable lean only, cooked, roasted	1.24
Beef, short loin, t-bone steak, bone-in, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	1.24
Veal, sirloin, separable lean only, cooked, braised	1.23
Cheese, romano	1.23
Pork, fresh, loin, center loin (chops), bone-in, separable lean only, cooked, braised	1.23
Beef, short loin, porterhouse steak, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	1.23
Beef, round, top round steak, boneless, separable lean and fat, trimmed to 0″ fat, all grades, cooked, grilled	1.22
Veal, shoulder, whole (arm and blade), separable lean only, cooked, braised	1.22
Veal, shoulder, arm, separable lean and fat, cooked, braised	1.22
Beef, rib eye roast, bone-in, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, roasted	1.22
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, choice, cooked, braised	1.22
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, select, cooked, braised	1.22
CRACKER BARREL, grilled sirloin steak	1.22
Veal, loin, separable lean only, cooked, braised	1.22
Beef, plate steak, boneless, inside skirt, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	1.22
Pork, fresh, loin, tenderloin, separable lean only, cooked, broiled	1.22
Soy meal, defatted, raw	1.21
Beef, round, top round roast, boneless, separable lean and fat, trimmed to 0″ fat, select, cooked, roasted	1.21
Beef, round, eye of round steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	1.21
Beef, round, top round steak, boneless, separable lean and fat, trimmed to 0″ fat, choice, cooked, grilled	1.21
Pork, cured, ham with natural juices, slice, bone-in, separable lean only, heated, pan-broil	1.21
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	1.21
Beef, New Zealand, imported, bolar blade, separable lean only, cooked, fast roasted	1.21
Pork, ground, 96% lean / 4% fat, cooked, crumbles	1.21
Pork, fresh, loin, sirloin (roasts), boneless, separable lean and fat, cooked, roasted	1.21
Veal, leg (top round), separable lean only, cooked, pan-fried, not breaded	1.2

[Source ²³] References

1. Nelson DL, Cox MM. Lehninger Biochemie. Berlin, Germany: Springer; 2009.
2. The catalytic triad of serine peptidases. Polgár L. Cell Mol Life Sci. 2005 Oct; 62(19-20):2161-72.
3. Visek WJ. An update of concepts of essential amino acids. Annu Rev Nutr 1984;4:137–55.
4. Li Y-C, Li C-L, Qi J-Y, et al. Relationships of Dietary Histidine and Obesity in Northern Chinese Adults, an Internet-Based Cross-Sectional Study. Nutrients. 2016;8(7):420. doi:10.3390/nu8070420. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963896/
5. Consequences of low plasma histidine in chronic kidney disease patients: associations with inflammation, oxidative stress, and mortality. Watanabe M, Suliman ME, Qureshi AR, Garcia-Lopez E, Bárány P, Heimbürger O, Stenvinkel P, Lindholm B. Am J Clin Nutr. 2008 Jun; 87(6):1860-6.
6. Anti-inflammatory and antisecretory potential of histidine in Salmonella-challenged mouse small intestine. Lab Invest. 1998 May;78(5):523-34. https://www.ncbi.nlm.nih.gov/pubmed/9605177
7. Gerber DA. Low free serum histidine concentration in rheumatoid arthritis. A measure of disease activity. Journal of Clinical Investigation. 1975;55(6):1164-1173. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC301869/pdf/jcinvest00170-0038.pdf
8. Watanabe M, Suliman ME, Qureshi AR et al (2008) Consequences of low plasma histidine in chronic kidney disease patients: associations with inflammation, oxidative stress, and mortality. Am J Clin Nutr 87:1860–1866
9. Makoto Watanabe, Mohamed E Suliman, Abdul Rashid Qureshi, Elvia Garcia-Lopez, Peter Bárány, Olof Heimbürger, Peter Stenvinkel, Bengt Lindholm; Consequences of low plasma histidine in chronic kidney disease patients: associations with inflammation, oxidative stress, and mortality, The American Journal of Clinical Nutrition, Volume 87, Issue 6, 1 June 2008, Pages 1860–1866, https://doi.org/10.1093/ajcn/87.6.1860
10. Bergström J, Furst P, Josephson B, Noree LO. Improvement of nitrogen balance in a uremic patient by the addition of histidine to essential amino acid solutions given intravenously. Life Sci II 1970;9:787–94.
11. Kopple JD, Swendseid ME. Evidence that histidine is an essential amino acid in normal and chronically uremic man. J Clin Invest 1975;55:881–91.
12. Kult J. The action of histidine supplementation on plasma protein metabolism in uremia. In: Kluthe R, Katz NR. eds. Histidine: metabolism, clinical aspects and therapeutic use. First International workshop. Freiburg, Germany: Georg Thieme Publishers Stuttgart, 1978.
13. Serum metabolomics reveals pathways and biomarkers associated with asthma pathogenesis. Clin Exp Allergy. 2013 Apr;43(4):425-33. doi: 10.1111/cea.12089. https://doi.org/10.1111/cea.12089
14. Tanaka S. [Physiological function mediated by histamine synthesis]. Yakugaku Zasshi 2003;123:547–59
15. Son DO, Satsu H, Shimizu M. Histidine inhibits oxidative stress- and TNF-alpha-induced interleukin-8 secretion in intestinal epithelial cells. FEBS Lett 2005;579:4671–7.
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17. Histidine supplementation improves insulin resistance through suppressed inflammation in obese women with the metabolic syndrome: a randomised controlled trial. Feng, R.N., Niu, Y.C., Sun, X.W. et al. Diabetologia (2013) 56: 985. https://doi.org/10.1007/s00125-013-2839-7
18. Hyperglycemia and a common variant of GCKR are associated with the levels of eight amino acids in 9,369 Finnish men. Stancáková A, Civelek M, Saleem NK, Soininen P, Kangas AJ, Cederberg H, Paananen J, Pihlajamäki J, Bonnycastle LL, Morken MA, Boehnke M, Pajukanta P, Lusis AJ, Collins FS, Kuusisto J, Ala-Korpela M, Laakso M. Diabetes. 2012 Jul; 61(7):1895-902
19. Possible role of L-carnosine in the regulation of blood glucose through controlling autonomic nerves. Nagai K, Niijima A, Yamano T, Otani H, Okumra N, Tsuruoka N, Nakai M, Kiso Y. Exp Biol Med (Maywood). 2003 Nov; 228(10):1138-45.
20. Kimura K, Nakamura Y, Inaba Y, et al. Histidine Augments the Suppression of Hepatic Glucose Production by Central Insulin Action. Diabetes. 2013;62(7):2266-2277. doi:10.2337/db12-1701. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712067/
21. Role of hepatic STAT3 in brain-insulin action on hepatic glucose production. Inoue H, Ogawa W, Asakawa A, Okamoto Y, Nishizawa A, Matsumoto M, Teshigawara K, Matsuki Y, Watanabe E, Hiramatsu R, Notohara K, Katayose K, Okamura H, Kahn CR, Noda T, Takeda K, Akira S, Inui A, Kasuga M. Cell Metab. 2006 Apr; 3(4):267-75.
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What is serine

Serine is a nonessential amino acid since it is synthesized in your body from other metabolites, including glycine. Serine can also be derived from your diet and the degradation of protein and/or phospholipids ¹. Serine was first obtained from silk protein, a particularly rich source. Its name is derived from the Latin for silk, sericum. Only the L-stereoisomer (L-serine) appears naturally in proteins. L-serine is required to synthesize membrane lipids such as phosphatidylserine and sphingolipids ². Serine is highly concentrated in all cell membranes. Unlike other amino acids, L-serine is used directly for the synthesis of phosphatidylserine and ceramide, the hydrophobic moiety of sphingolipids. The latter sphingolipids act as important mediators of the signaling cascades involved in various cellular functions, such as apoptosis, proliferation, and the stress response ³. The first step of sphingolipid synthesis is the condensation of L-serine and palmitoyl-CoA catalyzed by serine palmitoyltransferase, which is a rate-limiting enzyme in the sphingolipid synthetic pathway (Figure 2A) ⁴. Like all the amino acid building blocks of protein and peptides, serine can become essential under certain conditions, and is thus important in maintaining health and preventing disease. Low-average concentration of serine compared to other amino acids is found in muscle. L-Serine may be derived from four possible sources: dietary intake; biosynthesis from the glycolytic intermediate 3-phosphoglycerate; from glycine ; and by protein and phospholipid degradation ⁵. Little data is available on the relative contributions of each of these four sources of L-serine to serine homoeostasis. It is very likely that the predominant source of L-serine will be very different in different tissues and during different stages of human development.

In liver tissue, the serine biosynthetic pathway is regulated in response to dietary and hormonal changes. Of the three synthetic enzymes, the properties of 3-phosphoglycerate dehydrogenase (3- PGDH) and phosphoserine phosphatase are the best documented. Hormonal factors such as glucagon and corticosteroids also influence 3-phosphoglycerate dehydrogenase (3- PGDH) and phosphoserine phosphatase activities in interactions dependent upon the diet. L-serine plays a central role in cellular proliferation. L-Serine is the predominant source of one-carbon groups for the de novo synthesis of purine nucleotides and deoxythymidine monophosphate. It has long been recognized that, in cell cultures, L-serine is a conditional essential amino acid, because it cannot be synthesized in sufficient quantities to meet the cellular demands for its utilization. In recent years, L-serine and the products of its metabolism have been recognized not only to be essential for cell proliferation, but also to be necessary for specific functions in the central nervous system. The findings of altered levels of serine and glycine in patients with psychiatric disorders and the severe neurological abnormalities in patients with defects of L-serine synthesis underscore the importance of L-serine in brain development and function ⁵.

Figure 1. Serine biosynthesis

[Source ⁶]

Figure 2. Sphingolipid biosynthetic pathway

Footnotes:

(A) L-Serine and palmitoyl-CoA are condensed by  serine palmitoyltransferase (SPT) to form 3-keto-sphinganine, which is reduced to sphinganine (SA). Then, sphinganine (SA) is N-acylated to form dihydroceramide (DHCer) and desaturated to form ceramide (Cer). In addition, ceramide (Cer) is converted to sphingosine (SO) and subsequently phosphorylated to generate sphingosine 1-phosphate (S1P) by the degradative pathway.

(B) Sphingoid bases generated by serine palmitoyltransferase (SPT), which uses not only L-Serine but also L-Alanine or Glycine as a substrate and synthesizes atypical 1-deoxysphingolipids (doxSLs). Because of the lack of the C1 hydroxyl group, 1-deoxysphingolipids (doxSLs) can neither be converted to complex sphingolipids nor degraded by the degradative pathway.

These results indicate that 1-deoxysphingolipids (doxSLs) are generated under conditions of imbalance between L-Alanine and L-Serine in nonmalignant cells and tissues, suggesting a possible role of 1-deoxysphingolipids (doxSLs) in the pathobiology of L-Serine deficiency disorders and other diseases involving an increased ratio of L-Alanine to L-Serine in serum and/or tissues.

Thus, understanding of molecular interactions between 1-deoxysphingolipids (doxSLs) and cellular components, and their consequences, is expected to facilitate the development of therapeutic strategies against the cellular damage evoked by L-Serine deficiency and other metabolic disorders.

[Source ²]

L-Serine is synthesized de novo from a glycolytic intermediate, 3-phosphoglycerate, through three catalytic steps known as the phosphorylated pathway ⁷. The first step in this pathway is catalyzed by 3-phosphoglycerate dehydrogenase (3- PGDH) ⁸. Phosphohydroxypyruvate is metabolized to phosphoserine by phosphohydroxypyruvate aminotransferase and, finally, phosphoserine is converted into L-serine by phosphoserine phosphatase. Humans with mutated 3-phosphoglycerate dehydrogenase (3- PGDH) have lower levels of free L-Serine in the plasma and in cerebrospinal fluid. These L-Serine-deficient patients exhibit severe neurological symptoms, including congenital microcephaly, psychomotor retardation, and intractable seizures ⁹. In addition to these data from humans with 3-phosphoglycerate dehydrogenase (3- PGDH) deficiency, animal study demonstrated that conventional d-3-phosphoglycerate dehydrogenase knock-out mice display severe consequences of embryonic development, such as brain malformation with overall growth retardation, and die after embryonic day 13.5 ¹⁰. These human and mouse studies highlighted the absolute necessity of L-Serine, synthesized de novo via the phosphorylated pathway, for embryonic viability and nervous system development. In addition, recent functional genomic studies showed that de novo biosynthesis of L-Serine plays a crucial role in invasiveness, malignant transformation, and proliferation of certain types of cancer ¹¹. Many cancer cells consume serine in preference to glycine ¹². Cancer cells selectively consumed exogenous serine, which was converted to intracellular glycine and one-carbon units for building nucleotides ¹³. Restriction of exogenous glycine or depletion of the glycine cleavage system did not impede proliferation. In the absence of serine, uptake of exogenous glycine was unable to support nucleotide synthesis. Indeed, higher concentrations of glycine inhibited proliferation. Under these conditions, glycine was converted to serine, a reaction that would deplete the one-carbon pool. Providing one-carbon units by adding formate rescued nucleotide synthesis and growth of glycine-fed cells. L-Serine also acts on pyruvate kinase M2 as an allosteric effector and supports aerobic glycolysis, which is a metabolic hallmark of cancer cells ¹¹. These reports provide unexpected evidence that enhanced L-Serine availability in the body is involved in intrinsic metabolic reprogramming of cancer cells ² and that nucleotide synthesis and cancer cell proliferation are supported by serine—rather than glycine—consumption ¹³.

Malignant development is accompanied by genetic changes in cancer cells that drive abnormal proliferation, growth, survival, and invasion. Each of these phenotypes is supported by changes in cellular metabolism, and several metabolic enzymes have been identified as oncogenes or tumor suppressors ¹⁴. Although alterations in glucose and glutamine metabolism are central to metabolic transformation ¹⁵, recent studies have focused on the role of the nonessential amino acids serine and glycine in supporting tumor growth ¹⁶. In addition to their role in protein synthesis, serine and glycine contribute to anabolic pathways important for the generation of glutathione, nucleotides, phospholipids, and other metabolites ¹⁶ (see Figure 3). The requirement for intracellular serine and glycine for the support of cell growth and division is therefore clear. However, how cancer cells obtain these nutrients (uptake versus biosynthesis) and how they metabolize them remains to be fully elucidated. Mechanistic insight into this question will significantly enhance our ability to target serine/glycine metabolism for therapeutic gain.

Figure 3. Intracellular serine and glycine metabolism

Footnotes: 1‐C; one carbon unit transferred to and from the tetrahydrofolate (THF) cycle.

Abbreviations: R‐5‐P = ribose 5‐phosphate; PPP = Pentose Phosphate Pathway; SSP = Serine synthesis pathway.

[Source ¹³]

Figure 4. Nucleotide synthesis and cancer cell proliferation are supported by serine rather than glycine

[Source ¹³]

Amplification of 3-phosphoglycerate dehydrogenase (3- PGDH), the first enzyme of the de novo serine synthesis pathway, has been found in breast cancers and melanomas ¹⁷. Many tumor cells, however, remain highly dependent on uptake of exogenous serine ¹⁸, suggesting that in these cells, de novo serine synthesis alone cannot support the requirements for proliferation. A recent study showed that glycine uptake is correlated with rapid proliferation ¹⁹; this contrasts with other studies showing that excess dietary glycine has an inhibitory effect on tumorigenesis in multiple in vivo models ²⁰. Another study suggests that cancer cells fail to consume glycine when serine is plentiful ¹⁸.

The present lack of clarity is due, at least in part, to the complexity of serine and glycine metabolism, which can be carried out by mitochondrial and cytoplasmic pathways ²¹, both of which are upregulated in cancer ¹⁹. Serine can be converted to glycine by serine hydroxymethyl transferase (cytoplasmic, SHMT1; mitochondrial, SHMT2), a reaction that yields one-carbon units, which enter the tetrahydrofolate (THF) cycle and are critical for nucleotide synthesis. Glycine can also be cleaved by the mitochondrial glycine cleavage system to yield one-carbon units that are transferred to the THF cycle ²¹ (see Figure 3). Amplification of GLDC (a component of the glycine cleavage system) in cancers ²² suggests that this pathway is an important source of one-carbon units. In addition to cleavage, glycine can also be converted into serine by SHMT1 and SHMT2. Taken together, these reactions allow serine and glycine to be metabolized into the same set of metabolic precursors, suggesting that serine and glycine may be used interchangeably and may be equally effective in supporting proliferation (Figure 3).

In this study ¹³ the authors demonstrated that exogenous glycine cannot substitute for serine for the support of cancer cell proliferation. Tracking the intracellular fate of exogenous serine and glycine showed that in the absence of exogenous serine, glycine does not enter the one-carbon cycle, but is converted into serine, a process that consumes rather than produces one-carbon units and prevents nucleotide synthesis (see Figure 4). Consistent with this, the authors show that the inability of cells to grow in glycine could be rescued by addition of formate, which directly supplements the one-carbon pool for nucleotide synthesis.

Serine deficiency

Serine deficiency disorders are caused by a defect in one of the three synthesizing enzymes of the L-serine biosynthesis pathway ²³. Serine deficiency disorders give rise to a neurological phenotype with psychomotor retardation, microcephaly and seizures in newborns and children or progressive polyneuropathy in adult patients. There are three defects that cause serine deficiency of which 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency, the defect affecting the first step in the pathway, has been reported most frequently. The other two disorders in L-serine biosynthesis phosphoserine aminotransferase deficiency and phosphoserine phosphatase deficiency have been reported only in a limited number of patients ²³. The biochemical hallmarks of all three disorders are low concentrations of serine in cerebrospinal fluid and plasma. Prompt recognition of affected patients is important, since serine deficiency disorders are treatable causes of neurometabolic disorders. The use of age-related reference values for serine in CSF and plasma can be of great help in establishing a correct diagnosis of serine deficiency, in particular in newborns and young children.

Foods high in serine

Table 1. Serine foods (ordered from highest to low)

Description	Serine (g) Value Per 100 grams
Egg, white, dried, stabilized, glucose reduced	6.16
Egg, white, dried, powder, stabilized, glucose reduced	6.08
Egg, white, dried, flakes, stabilized, glucose reduced	5.67
Egg, white, dried	5.59
Soy protein isolate	4.59
Soy protein isolate, potassium type	4.59
Egg, whole, dried	3.77
Egg, whole, dried, stabilized, glucose reduced	3.66
Soy protein concentrate, produced by alcohol extraction	3.37
Soy protein concentrate, produced by acid wash	3.37
Seaweed, spirulina, dried	3
Beverages, Protein powder soy based	2.96
Egg, yolk, dried	2.81
Seeds, sesame flour, low-fat	2.73
Soy flour, defatted	2.73
Soy meal, defatted, raw	2.6
Gelatins, dry powder, unsweetened	2.6
Snacks, pork skins, plain	2.6
Peanut flour, defatted	2.57
Fish, cod, Atlantic, dried and salted	2.56
Seeds, cottonseed flour, low fat (glandless)	2.49
Snacks, pork skins, barbecue-flavor	2.48
Seeds, cottonseed meal, partially defatted (glandless)	2.46
Whale, beluga, meat, dried (Alaska Native)	2.42
Cheese, parmesan, shredded	2.4
Soybeans, mature seeds, raw	2.36
Soybeans, mature seeds, dry roasted	2.29
Seeds, sunflower seed flour, partially defatted	2.27
Tofu, dried-frozen (koyadofu)	2.26
Tofu, dried-frozen (koyadofu), prepared with calcium sulfate	2.26
Meat extender	2.23
Mollusks, whelk, unspecified, cooked, moist heat	2.22
Seeds, sesame flour, partially defatted	2.2
Cheese, parmesan, hard	2.07
Seeds, cottonseed flour, partially defatted (glandless)	2.05
Soybeans, mature seeds, roasted, salted	2.04
Soybeans, mature seeds, roasted, no salt added	2.04
Soy flour, full-fat, roasted	2.02
Soy flour, full-fat, raw	2
Leavening agents, yeast, baker’s, active dry	1.98
Milk, dry, nonfat, regular, without added vitamin A and vitamin D	1.97
Milk, dry, nonfat, regular, with added vitamin A and vitamin D	1.97
Milk, dry, nonfat, calcium reduced	1.93
Milk, dry, nonfat, instant, with added vitamin A and vitamin D	1.91
Milk, dry, nonfat, instant, without added vitamin A and vitamin D	1.91
Fish, caviar, black and red, granular	1.9
Gelatin desserts, dry mix, reduced calorie, with aspartame, added phosphorus, potassium, sodium, vitamin C	1.88
Gelatin desserts, dry mix, reduced calorie, with aspartame, no added sodium	1.88
Lupins, mature seeds, raw	1.87
Milk, buttermilk, dried	1.87
Cheese, romano	1.84
Seeds, safflower seed meal, partially defatted	1.79
Cheese, roquefort	1.77
Cheese, gruyere	1.72
Seeds, hemp seed, hulled	1.71
Cheese, parmesan, grated	1.69
Seeds, sesame flour, high-fat	1.68
Seeds, pumpkin and squash seed kernels, dried	1.67
Peanut flour, low fat	1.67
Seeds, pumpkin and squash seed kernels, roasted, without salt	1.65
Seeds, pumpkin and squash seed kernels, roasted, with salt added	1.65
Cheese, swiss	1.64
Nuts, butternuts, dried	1.64
Pork, cured, bacon, cooked, microwaved	1.63
Seeds, cottonseed kernels, roasted (glandless)	1.63
Nuts, mixed nuts, oil roasted, without peanuts, without salt added	1.62
Nuts, mixed nuts, oil roasted, without peanuts, with salt added	1.62
Cheese, parmesan, dry grated, reduced fat	1.61
Cheese, edam	1.55
Cheese, gouda	1.54
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	1.52
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	1.51
Seeds, watermelon seed kernels, dried	1.51
Snacks, soy chips or crisps, salted	1.5
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	1.5

[Source ²⁴] References

1. Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease. Nature Communications volume 5, Article number: 3083,2014. https://www.nature.com/articles/ncomms4083.pdf
2. Esaki K, Sayano T, Sonoda C, et al. l-Serine Deficiency Elicits Intracellular Accumulation of Cytotoxic Deoxysphingolipids and Lipid Body Formation. The Journal of Biological Chemistry. 2015;290(23):14595-14609. doi:10.1074/jbc.M114.603860. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505526/
3. Hannun Y. A., Obeid L. M. (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat. Rev. Mol. Cell Biol. 9, 139–150
4. Lowther J., Naismith J. H., Dunn T. M., Campopiano D. J. (2012) Structural, mechanistic and regulatory studies of serine palmitoyltransferase. Biochem. Soc. Trans. 40, 547–554
5. De Koning TJ, Snell K, Duran M, Berger R, Poll-The B-T, Surtees R. L-serine in disease and development. Biochemical Journal. 2003;371(Pt 3):653-661. doi:10.1042/BJ20021785. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1223326/pdf/12534373.pdf
6. Serine. https://en.wikipedia.org/wiki/Serine
7. Ichihara A., Greenberg D. M. (1955) Pathway of serine formation from carbohydrate in rat liver. Proc. Natl. Acad. Sci. U.S.A. 41, 605–609
8. Snell K. (1984) Enzymes of serine metabolism in normal, developing and neoplastic rat tissues. Adv. Enzyme Regul. 22, 325–400
9. de Koning T. J., Klomp L. W., van Oppen A. C., Beemer F. A., Dorland L., van den Berg I., Berger R. (2004) Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency. Lancet 364, 2221–2222
10. Kawakami Y., Yoshida K., Yang J. H., Suzuki T., Azuma N., Sakai K., Hashikawa T., Watanabe M., Yasuda K., Kuhara S., Hirabayashi Y., Furuya S. (2009) Impaired neurogenesis in embryonic spinal cord of Phgdh knockout mice, a serine deficiency disorder model. Neurosci. Res. 63, 184–193
11. Chaneton B., Hillmann P., Zheng L., Martin A. C., Maddocks O. D., Chokkathukalam A., Coyle J. E., Jankevics A., Holding F. P., Vousden K. H., Frezza C., O’Reilly M., Gottlieb E. (2012) Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491, 458–462
12. Serine, but Not Glycine, Supports One-Carbon Metabolism and Proliferation of Cancer Cells. Cell Reports Volume 7, ISSUE 4, P1248-1258, May 22, 2014. https://doi.org/10.1016/j.celrep.2014.04.045
13. Serine, but Not Glycine, Supports One-Carbon Metabolism and Proliferation of Cancer Cells. Cell Reports Volume 7, Issue 4, P1248-1258, May 22, 2014. https://doi.org/10.1016/j.celrep.2014.04.045
14. Shaw, R.J.Cantley, L.C. Decoding key nodes in the metabolism of cancer cells: sugar & spice and all things nice. F1000 Biol. Rep. 2012; 4: 2
15. Jones, N.P.Schulze, A. Targeting cancer metabolism—aiming at a tumour’s sweet-spot. Drug Discov. Today. 2012; 17: 232-241
16. Locasale, J.W. Serine, glycine and one-carbon units: cancer metabolism in full circle.Nat. Rev. Cancer. 2013; 13: 572-583
17. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis.Nat. Genet. 2011; 43: 869-874
18. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells.Nature. 2013; 493: 542-546
19. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation.Science. 2012; 336: 1040-1044
20. Dietary glycine inhibits the growth of B16 melanoma tumors in mice.Carcinogenesis. 1999; 20: 793-798
21. Compartmentalization of Mammalian folate-mediated one-carbon metabolism.Annu. Rev. Nutr. 2010; 30: 57-81
22. Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis.Cell. 2012; 148: 259-272
23. An update on serine deficiency disorders. J Inherit Metab Dis. 2013 Jul;36(4):613-9. DOI:10.1007/s10545-013-9592-4
24. United States Department of Agriculture Agricultural Research Service. USDA Food Composition Databases. https://ndb.nal.usda.gov/ndb/search/list

What is methionine

Methionine (C5-H11-N-O2-S) is one of nine essential amino acids in humans that needs to be provided by food. Methionine is often the most limiting amino acid in the diets of the developing world’s population because of its low concentration in cereal grains ¹. Methionine is required for normal growth, tissue repair and development of humans ². A sulphur-containing amino acid, methionine improves the tone and pliability of skin, hair, and strengthens nails. Burn patients may have an increased demand for methionine to maintain nitrogen balance ³. Methionine is involved in many detoxifying processes, sulphur provided by methionine protects cells from pollutants, slows cells aging, and is essential for absorption and bio-availability of selenium and zinc. Methionine chelates heavy metals, such as lead and mercury, aiding their excretion. Methionine is also acts as a lipotropic agent and prevents excess fat buildup in the liver.

There is a general consensus concerning normal sulfur amino acid requirements. From the classical experiments of Rose ⁴ in healthy men, it was calculated that the minimal intake of methionine required to maintain nitrogen balance is 1.10 g/day, which comes down to ∼13 mg/kg body weight per day. The World Health Organization (WHO) recommendations amount to 13 mg/kg per 24 hour in healthy adults. This amount is roughly doubled in artificial nutrition regimens. In a recent study it was shown that this intake also is sufficient to maintain glutathione synthesis in healthy volunteers ⁵. In infancy and childhood, the dietary requirement for sulfur amino acid is higher ⁶. Sulfur amino acid requirements in elderly subjects are unknown, but it has been suggested that the altered redox state reported in the elderly ⁷ requires increased ingestion of sulfur amino acid. In contrast, the safe upper limit of chronic sulfur amino acid supplementation may be reached earlier in the elderly because of accumulation of homocysteine, which is considered a risk factor for the development of atherosclerosis ⁸. Hyperhomocysteinemia may, however, be prevented by adequate vitamin B and folate supplementation.

In disease or after trauma, requirements may be altered for methionine, cysteine, and taurine. Although in specific cases of congenital enzyme deficiency, prematurity, or diminished liver function, hypermethioninemia or hyperhomocysteinemia may occur, sulfur amino acid supplementation can be considered safe in amounts exceeding 2-3 times the minimum recommended daily intake. Apart from some very specific indications (e. g. acetaminophen poisoning) the usefulness of sulfur amino acid supplementation is not yet established ⁶.

Methionine is the only essential sulfur amino acid and can provide sulfur for cysteine and taurine synthesis. Animal protein is generally considered to be a better source of sulfur amino acid than vegetable protein ⁶. This is primarily because the biological value of animal protein is higher than that of vegetable protein ⁹. Soy, which is the only vegetable protein used for artificial enteral nutrition, is also low in absolute sulfur amino acid content ⁹.

The sulfur amino acid, methionine, has gained renewed interest in recent years largely because of its relation to homocysteine and glutathione (Figure 1). Methionine breakdown occurs by transmethylation to homocysteine ¹⁰. The first step in this pathway is the conversion of methionine to S-adenosylmethionine, which can donate its methyl group for numerous methylation processes including DNA methylation. Separation of the methyl group yields S-adenosylhomocysteine, which can be converted to homocysteine. Homocysteine can be remethylated to methionine by the folate (vitamin B9) and vitamin B-12-dependent enzyme methionine synthetase or enter the irreversible transsulfuration pathway. Homocysteine is a central product in the metabolic pathway of methionine metabolism, and hyperhomocysteinemia has been identified as an independent risk factor for cardiovascular disease in adults ¹¹, ischemic and hemorrhagic stroke in newborns and children ¹² and Alzheimer’s disease in adults ¹³. A high plasma total homocysteine concentration is a risk factor for cardiovascular disease ¹⁴. However despite the function of methionine as a precursor of homocysteine, and the role of homocysteine in vascular damage and cardiovascular disease, there is no evidence that dietary intake of methionine within reasonable limits will cause cardiovascular damage ¹⁵. But intakes higher than 5 times normal (1.10 g/day or 13 mg/kg body weight per day) resulted in elevated homocysteine levels. These effects of methionine on homocysteine and vascular function are moderated by supplements of vitamins B-6, vitamin B-12, vitamin C, and folic acid ¹⁵.

The increase in total homocysteine induced by methionine, the sole dietary precursor of homocysteine, might be modulated by other amino acids present in dietary proteins. A randomized crossover trial was conducted in 24 healthy men. Each subject ingested 4 meals on separate days, which were separated by 1 week. Total homocysteine concentrations were measured in the fasting state and at 2, 4, 6, 8, 10, and 24 hours after meal ingestion. The meals were #1) a low-protein meal fortified with 30 mg methionine/kg body body weight (methionine only); #2) meal 1 additionally fortified with 60.6 mg serine/kg body body weight (Methionine + Serine); #3) meal 1 additionally fortified with 12.3 mg cystine/kg body body weight (Methionine + Cystine) and 4) a protein-rich meal containing 30 mg methionine, 60.6 mg serine, and 12.3 mg cystine per kg body body weight (Methionine + Serine + Cystine). RESULTS: The mean fasting total homocysteine concentration was 37% (Methionine + Serine), 32% (Methionine + Cystine) and 77%  (Methionine + Serine + Cystine) lower. CONCLUSIONS: Dietary methionine increases total homocysteine much less than does free methionine. Serine and cystine reduce the total homocysteine-raising effect of free methionine (i.e. methionine supplement). Thus, dietary proteins with a high content of serine or cystine relative to methionine may lead to lower postprandial total homocysteine responses ¹⁴.

Methionine is also required for synthesis of cysteine. Undisputed functions of cysteine include protein synthesis and the biosynthesis of taurine, sulfate ¹⁶ and glutathione ¹⁷. However, the ability of cysteine to provide a portion of the total sulfur amino acid requirement in humans, thereby providing a sparing effect on the dietary methionine requirement, has been an area of considerable debate.

Methionine is accepted as the metabolic precursor for cysteine ¹⁸. Only the sulfur atom from methionine is transferred to cysteine; the carbon skeleton of cysteine is donated by serine ¹⁸. Cysteine is not a precursor for methionine because of the irreversibility of the cystathionase synthase reaction ¹⁹ (see Figure 1). Consequently, any substitution by cysteine for dietary methionine requirement can only be via inhibition of the sulfur amino acid pathway that leads to synthesis of the transsulfuration metabolites, including cysteine itself.

Glutathione, the most prevalent intracellular thiol ²⁰ and an important endogenous antioxidant and scavenger ²¹, is synthesized de novo within all cells ²², and intracellular availability of cysteine is believed to be the most important rate-limiting factor for glutathione synthesis ¹⁷. More importantly, glutathione concentrations are reduced in several disease states including HIV ²³, liver cirrhosis ²⁴, diabetes ²⁵ and Alzheimer’s disease ²⁶. Glutathione concentration is also found to be reduced in surgical trauma patients ²⁷, septic patients ²⁸, premature infants ²⁹, and in children with severe protein–energy malnutrition ³⁰. Comprehensive understanding of sulfur amino acid requirements and their complex metabolism clearly has many implications for human health.

When present in sufficiently high levels, methionine can act as an atherogen and a metabotoxin. An atherogen is a compound that when present at chronically high levels causes atherosclerosis and cardiovascular disease ¹⁵. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels. Chronically high levels of methionine are associated with at least ten inborn errors of metabolism, including cystathionine beta-synthase deficiency, glycine N-methyltransferase deficiency, homocystinuria, tyrosinemia, galactosemia, homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, methionine adenosyltransferase deficiency, methylenetetrahydrofolate reductase deficiency, and S-adenosylhomocysteine hydrolase deficiency. Chronically elevated levels of methionine in infants can lead to intellectual disability and other neurological problems, delays in motor skills, sluggishness, muscle weakness, and liver problems ¹⁵. Many individuals with these metabolic disorders tend to develop cardiovascular disease later in life. Studies on feeding rodents high levels of methionine have shown that methionine promotes atherosclerotic plaques independently of homocysteine levels ³¹. A similar study in Finnish men showed the same effect where it was found that “long-term, moderately high dietary methionine intake may increase the risk of acute coronary events in middle-aged Finnish men free of prior coronary heart disease”³².

Figure 1. Methionine metabolism in mammalian tissue

Footnotes: Illustration of the pathways of methionine metabolism in mammalian tissue via transmethylation (TM), transsfulfuration (TS), and remethylation (RM). The numbers represent the following enzymes or reaction sequences: 1, L-methionine-S-adenosyl-transferase; 2, transmethylation reaction; 3, adenosylhomocysteinease; 4, cystathionine-β-synthase; 5, cystathionase; 6, multiple reactions leading from methionine to sulfate or taurine, cysteine used for protein or GSH or protein synthesis, or the reversible conversion between cysteine and cystine; 7, betaine-homocysteine methyl transferase; 8, methyltetrahydrofolate homocysteine methyltransferase; 9, choline dehydrogenase and betaine aldehyde dehydrogenase; 10, serine hydroxymethylase; 11, methylene tetrehydrofolate reductase.

[Source ¹]

In addition to being a substrate for protein synthesis, mehionine is an intermediate in transmethylation reactions, serving as the major methyl group donor in vivo, including the methyl groups for DNA and RNA intermediates. Methionine is a methyl acceptor for 5-methyltetrahydrofolate-homocysteine methyltransferase (methionine synthase), the only reaction that allows for the recycling of this form of folate, and is also a methyl acceptor for the catabolism of betaine. Methionine is the metabolic precursor for cysteine. Only the sulfur atom from methionine is transferred to cysteine; the carbon skeleton of cysteine is donated by serine ¹.

Methionine is known to exacerbate psychopathological symptoms in schizophrenic patients, but there is no evidence of similar effects in healthy subjects. The role of methionine as a precursor of homocysteine is the most notable cause for concern. Acute doses of methionine can lead to acute increases in plasma homocysteine, which can be used as an index of the susceptibility to cardiovascular disease. Sufficiently high doses of methionine can actually result in death. Longer-term studies in adults have indicated no adverse consequences of moderate fluctuations in dietary methionine intake, but intakes higher than 5 times the normal amount resulted in elevated homocysteine levels. These effects of methionine on homocysteine and vascular function are moderated by supplements of vitamins B-6, B-12, C, and folic acid ¹⁵.

Methionine rich foods

Table 1. Foods high in methionine (ordered from highest to low)

Description	Methionine (g) Value Per 100 gram
Egg, white, dried, powder, stabilized, glucose reduced	3.2
Egg, white, dried, flakes, stabilized, glucose reduced	2.99
Egg, white, dried, stabilized, glucose reduced	2.99
Egg, white, dried	2.79
Fish, cod, Atlantic, dried and salted	1.86
Seeds, sesame flour, low-fat	1.66
Egg, whole, dried, stabilized, glucose reduced	1.56
Egg, whole, dried	1.5
Whale, beluga, meat, dried (Alaska Native)	1.35
Seeds, sesame flour, partially defatted	1.33
Mollusks, whelk, unspecified, cooked, moist heat	1.21
Seaweed, spirulina, dried	1.15
Beef, New Zealand, imported, brisket point end, separable lean only, cooked, braised	1.14
Soy protein isolate	1.13
Soy protein isolate, potassium type	1.13
Nuts, brazilnuts, dried, unblanched	1.12
Cheese, parmesan, shredded	1.11
Beef, New Zealand, imported, bolar blade, separable lean only, cooked, fast roasted	1.1
Beef, New Zealand, imported, flat, separable lean only, cooked, braised	1.09
Lamb, New Zealand, imported, fore-shank, separable lean only, cooked, braised	1.09
Pork, cured, bacon, cooked, microwaved	1.07
Lamb, New Zealand, imported, hind-shank, separable lean only, cooked, braised	1.06
Beef, New Zealand, imported, chuck eye roll, separable lean only, raw	1.05
Beef, New Zealand, imported, chuck eye roll, separable lean only, cooked, braised	1.05
Beef, New Zealand, imported, brisket point end, separable lean and fat, cooked, braised	1.05
Beef, New Zealand, imported, flat, separable lean and fat, cooked, braised	1.05
Seeds, sunflower seed flour, partially defatted	1.04
Beef, New Zealand, imported, variety meats and by-products, heart, cooked, boiled	1.03
Beef, New Zealand, imported, bolar blade, separable lean and fat, cooked, fast roasted	1.03
Beef, New Zealand, imported, hind shin, separable lean only, cooked, braised	1.03
Lamb, New Zealand, imported, neck chops, separable lean only, cooked, braised	1.02
Seeds, sesame flour, high-fat	1.02
Lamb, New Zealand, imported, square-cut shoulder chops, separable lean only, cooked, braised	1.01
Beef, New Zealand, imported, flank, separable lean only, cooked, braised	1.01
Beef, New Zealand, imported, rump centre, separable lean only, cooked, fast fried	0.99
Beef, New Zealand, imported, flank, separable lean and fat, cooked, braised	0.99
Lamb, New Zealand, imported, fore-shank, separable lean and fat, cooked, braised	0.99
Beef, New Zealand, imported, cube roll, separable lean only, cooked, fast roasted	0.99
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	0.99
Beef, New Zealand, imported, rump centre, separable lean and fat, cooked, fast fried	0.99
Beef, New Zealand, imported, chuck eye roll, separable lean and fat, raw	0.98
Beef, New Zealand, imported, chuck eye roll, separable lean and fat, cooked, braised	0.98
Beef, New Zealand, imported, oyster blade, separable lean only, cooked, braised	0.98
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	0.98
Beef, New Zealand, imported, hind shin, separable lean and fat, cooked, braised	0.98
Beef, New Zealand, imported, oyster blade, separable lean and fat, cooked, braised	0.98
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, braised	0.98
Beef, New Zealand, imported, eye round, separable lean only, cooked, slow roasted	0.98
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	0.97
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, braised	0.97

[Source ³³]

Methionine supplement side effects

When present in sufficiently high levels, methionine can act as an atherogen and a metabotoxin. An atherogen is a compound that when present at chronically high levels causes atherosclerosis and cardiovascular disease ¹⁵. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels. Chronically high levels of methionine are associated with at least ten inborn errors of metabolism, including cystathionine beta-synthase deficiency, glycine N-methyltransferase deficiency, homocystinuria, tyrosinemia, galactosemia, homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, methionine adenosyltransferase deficiency, methylenetetrahydrofolate reductase deficiency, and S-adenosylhomocysteine hydrolase deficiency. Chronically elevated levels of methionine in infants can lead to intellectual disability and other neurological problems, delays in motor skills, sluggishness, muscle weakness, and liver problems ¹⁵. Many individuals with these metabolic disorders tend to develop cardiovascular disease later in life. Studies on feeding rodents high levels of methionine have shown that methionine promotes atherosclerotic plaques independently of homocysteine levels ³¹. A similar study in Finnish men showed the same effect where it was found that “long-term, moderately high dietary methionine intake may increase the risk of acute coronary events in middle-aged Finnish men free of prior coronary heart disease”³².

Methionine has gained renewed interest in recent years largely because of their relation to homocysteine and glutathione (see Figure 1). Homocysteine is a central product in the metabolic pathway of methionine metabolism, and hyperhomocysteinemia has been identified as an independent risk factor for cardiovascular disease in adults ¹¹, ischemic and hemorrhagic stroke in newborns and children ¹² and Alzheimer’s disease in adults ¹³. Glutathione, the most prevalent intracellular thiol ²⁰ and an important endogenous antioxidant and scavenger ²¹, is synthesized de novo within all cells ²², and intracellular availability of cysteine is believed to be the most important rate-limiting factor for glutathione synthesis ¹⁷. More importantly, glutathione concentrations are reduced in several disease states including HIV ²³, liver cirrhosis ²⁴, diabetes ²⁵ and Alzheimer’s disease ²⁶. Glutathione concentration is also found to be reduced in surgical trauma patients ²⁷, septic patients ²⁸, premature infants ²⁹, and in children with severe protein–energy malnutrition ³⁰. Comprehensive understanding of sulfur amino acid requirements and their complex metabolism clearly has many implications for human health.

Toxicity of methionine in liver disease was established halfway through the twentieth century by Dame Sheila Sherlock ³⁴, who recognized that high methionine intake (∼10 g per day or 133 mg/kg per day for a 75 kg person) in patients with impaired liver function resulted in hyperammonemia and a deterioration of neurological functions, which could be alleviated with antibiotics. In addition, high levels of methionine may be directly hepatotoxic, and it has been suggested from results of animal studies that high amounts of methionine in feeding formulas are causally related to the onset of cholestasis during tube feeding or parenteral feeding ³⁵. It has been shown that there is no relation between methionine intake and hyperhomocysteinemia, provided that vitamin status is optimal. In most cases hyperhomocysteinemia can be treated by vitamin B-12 (Cobalamin), vitamin B-6 (Pyridoxine), and/or folate (vitamin B-9) supplementation ³⁶. In the old literature it is mentioned that methionine restriction and cysteine supplementation can prevent cognitive retardation in children with inborn errors of sulfur amino acid metabolism ³⁷.

Oral methionine supplements (8.0 g daily for 4 days) were given to five normal volunteers who continued to eat their usual diet ³⁸. This treatment resulted in a significant fall in serum folate (vitamin B-9) concentration. Three days after the end of treatment concentrations had not completely returned to control values. The fall in concentration was prevented by giving oral folic acid supplements. The study authors suggested that folic acid supplements should be given to patients who are receiving intravenous infusions of methionine amino acid mixtures.

As an essential amino acid, methionine is a standard component of artificial feeding formulas. According to the reported methionine amount and dose recommendation of standard tube feeds (Table 2), the daily amount of methionine administered to enterally or parenterally fed patients is ∼26 mg/kg per day, which apparently is twice the minimally required amount. Disease-specific feeds for malnutrition or metabolic stress are even higher in total protein and sulfur amino acid content and provide ∼4 times the recommended daily dose of sulfur amino acid ⁶.

Table 2. Sulfur amino acid content of commercially available feeding solutions

[Source ⁶]

Amino acid concentrations of pediatric protein and hydrolysate-based enteral formulas exceed that of breast milk, leading to a moderate increase of plasma levels of amino acids and urea nitrogen in enterally fed children ³⁹. The consequences of this mild elevation of blood nitrogen concentration are difficult to assess in the light of the other differences between formula feeds and mother milk. However, no clinical data indicating specific amino acid toxicity in formula-fed children without errors in metabolism are known.

Methionine intake in infants at 14–28 days with various formulas may reach up to 120 mg/kg per day ⁴⁰. A methionine-fortified hydrolysate providing up to 260 mg/kg per day to newborn healthy children was shown to induce only moderate elevations in methionine plasma level and no signs of methionine toxicity ⁴¹. In a retrospective case study of 10 children without enzyme deficiencies receiving the same methionine-fortified formula, however, severe hypermethionemia was found, which may have induced brain edema in 2 patients ⁴⁰. A conclusive explanation for the increased sensitivity to high methionine intake was not given, but these findings led the authors to suggest that precaution is especially warranted in premature children, children with a very low birth weight, and children with liver disease.

References

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18. Du Vigneaud V, Kilmer GW, Rachele JR, Cohn M. On the mechanism of the conversion in vivo of methionine to cystine. J Biol Chem. 1944;155:645–51.
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What is leucine

Leucine (C₆H₁₃O₂N) is an essential branched-chain amino acid (BCAA) that is used in the biosynthesis of proteins, many metabolic functions and important for hemoglobin formation. Leucine is one of nine essential amino acids in humans meaning your body cannot synthesize it, leucine must be obtained from food and leucine is also used as a food additive (E641) as a flavor enhancer. Human dietary sources of leucine are foods that contain protein, such as meats, dairy products, soy products, beans and legumes and leucine deficiency is rare. Leucine contributes to regulation of blood-sugar levels; growth and repair of muscle and bone tissue; growth hormone production; and wound healing. Leucine is available to skeletal muscle where it functions as a nutrient signal, is used for protein synthesis, and serves as a metabolic fuel and/or a nitrogen donor for the synthesis of glutamine and alanine ¹. Leucine also prevents breakdown of muscle proteins after trauma or severe stress and may be beneficial for individuals with phenylketonuria. Additionally, similarly to other amino acids, the carbon skeleton of leucine can be used to generate ATP ². Therefore, leucine supplementation has been studied in a variety of conditions such as aging, muscle lesions, protein/energy deprivation, obesity, and diabetes mellitus. Because leucine availability influences signaling pathways involved in the regulation of metabolism and because the incidence of metabolic diseases has reached alarming levels worldwide, investigating nutritional supplements that are potentially beneficial for the treatment and prevention of obesity and diabetes mellitus has become of paramount importance. However, base on the available evidence, oral leucine supplementation produces no or very mild effects on food intake ². Furthermore, despite the well-known stimulatory effects of leucine on protein synthesis, leucine supplementation in aging rats or humans ³, ⁴ apparently did not lead to an increase in lean and protein body mass. Interestingly, several studies found no effects on adiposity ⁵ or even a predisposition to accumulate more body fat ⁶ in animals that began to receive leucine supplementation when they were already obese. A likely explanation for these findings is that mTOR complex 1 (mTORC1) activation may promote fat storage in adipocytes by suppressing lipolysis and stimulating de novo lipogenesis ⁷. Additionally, mice with disrupted mTORC1 complex exhibit less adipose tissue, suggesting that fat deposition may depend on mTORC1 activity ⁸. Branched-chain amino acid (BCAA) supplementation in pregnant rats consuming a protein-restricted diet restored the fat mass of their offspring to levels similar to those of non-restricted animals ⁹. Studies that initiated leucine supplementation in already-obese animals found no beneficial effects of leucine or even found worsening of the degree of adiposity ². Therefore, based on the presented data, leucine supplementation is not likely to be helpful as a dietary supplement for treating obesity ².

The initiation of mRNA translation is the major mechanism by which leucine stimulates protein synthesis. Classical studies have shown that the regulation of mRNA translation by leucine is dependent on the mammalian target of rapamycin (mTOR) because rapamycin, a specific mTOR inhibitor, is able to blunt the effects of leucine ¹⁰. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that is involved in the regulation of multiple cellular processes, including protein synthesis and cell growth, proliferation, and survival. Mammalian target of rapamycin (mTOR) controls protein synthesis through mTOR complex 1 (mTORC1), which comprises mTOR itself and other proteins.

Figure 1. Intracellular mechanisms activated by leucine

Footnotes:

The mammalian target of rapamycin complex 1 (mTORC1) comprises mTOR, Raptor, mLST8, PRAS40, and DEPTOR. mTORC1 is activated by amino acids (especially leucine) as well as by hormones such as leptin, insulin, and IGF-1. mTORC1 can be activated by different pathways. Hormonal activation primarily occurs through the TSC complex. However, amino acid-dependent mTORC1 activation occurs through the Rag complex. The leucyl-tRNA synthetase is responsible for sensing leucine cellular levels and activating the Rag complex. The cellular uptake of L-glutamine and its subsequent rapid efflux in the presence of leucine represent the rate-limiting step of mTOR activation. The protein p70-S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) are key downstream targets of mTORC1. S6K1 also phosphorylates components of the insulin signaling pathway, which may lead to insulin resistance in situations of nutrient abundance such as in obesity. The anorexigenic effects of leptin require both the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mTOR/S6K1 signaling pathways. Because mTOR is a downstream target of PI3K signaling, the acute anorexigenic effects of leptin may depend on the PI3K/mTOR/S6K1 pathway.

[Source ²]

How much leucine per day?

42 mg/kg body weight/day ¹¹

What is L-leucine

L-leucine, also known as 2-amino-4-methylvaleric acid, belongs to leucine and derivatives class of compounds. Those are compounds containing leucine or a derivative thereof resulting from reaction of leucine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom. L-leucine is soluble (in water) and a moderately acidic compound. L-leucine can be found primarily in most biofluids, including blood, cerebrospinal fluid (CSF), feces, and sweat, as well as throughout most human tissues. Within the cell, L-leucine is primarily located in the mitochondria. It can also be found in the extracellular space. L-leucine exists in all living species, ranging from bacteria to humans.

Figure 2. Leucine-responsive tissues

Footnotes:

After protein-rich meals, circulating branched-chain amino acid (BCAA) levels significantly increase, whereas other amino acids are highly metabolized by the gut or liver before reaching the systemic circulation. Branched-chain amino acid transaminase (BCAT) catalyzes the first and reversible transamination step of leucine degradation. This enzyme is not expressed in the liver, which allows the BCAAs to bypass the portal venous system following their intestinal absorption. In the brain, leucine is metabolized by the cytosolic form of BCAT (BCATc), whereas in other tissues (e.g., white adipose tissue, skeletal muscle, and pancreas), the mitochondrial form of BCAT (BCATm) prevails.

[Source ²]

Does leucine work for weight loss?

Several studies found that central leucine infusion (infusion of leucine into the brain) reduces food intake in rodents ¹². However, the capacity of leucine to modulate food intake is controversial ². Many supplementation approaches have been used to study the effects of leucine on food intake, including leucine supplementation in the drinking water, in the diet and through gavage, as well as by subcutaneous (sc), intraperitoneal (ip), and central injections ². To clarify whether leucine supplementation is able to influence feeding behavior, the studies evaluating the effects of central leucine infusion observed decreased food intake ². These findings demonstrated that leucine could inhibit food intake by directly affecting the CNS (central nervous system) (see Figure 3). This result is interesting because it is well known that the brain is able to sense changing nutrient levels to regulate the energy balance ¹³. However, of 30 studies investigating the effects of leucine supplementation in the diet, two studies found increased food intake in leucine-treated animals ¹⁴, ¹⁵, and only four studies reported decreased food intake in the leucine-supplemented groups ¹⁶, ¹⁷, ¹⁸, ¹². From these studies, two observed increased taste aversion to the leucine-rich diet, which may explain the reduction in food intake ¹⁶, ¹². To avoid possible aversive behavior in relation to the diet, several studies supplemented leucine in the drinking water. Of 13 studies, two observed that leucine supplementation decreased food intake in mice in specific conditions ⁵, ¹⁹. For example, leucine supplementation in the drinking water decreased the food intake of a polygenic model predisposed to type 2 diabetes (RCS10 mice) but did not affect the food intake of a monogenic model predisposed to obesity and severe insulin resistance (yellow agouti mice) ⁵. In another study, leucine supplementation in the drinking water decreased the food intake in males but not in females consuming a regular rodent diet. No effect was observed in mice consuming an high fat diet ¹⁹. Additionally, one study reported increased food intake in animals supplemented with leucine in the drinking water ²⁰. No changes in food intake were observed in mice that received leucine supplementation through gavage, intraperitoneal or subcutaneous injections. Thus, the central anorexigenic effect of leucine is not well repeated when leucine supplementation is provided through an oral form (Figure 3).

The divergent results caused by oral or central leucine supplementation may be explained by the capacity of leucine to cross the blood-brain barrier (BBB) and reach the CNS. Although a previous study demonstrated that a 4% leucine-enriched meal could increase the leucine concentration in the cerebrospinal fluid to 44% ¹³, whether this change is robust enough to reduce food intake or to persist in the long term remains unknown. In this same study, a high-protein diet did not significantly increase the leucine concentration in the cerebrospinal fluid (CSF). Additionally, the changes in leucine levels were approximately seven-fold higher in the plasma than in the cerebrospinal fluid ¹³. Therefore, additional studies are warranted to establish the minimum increase in central leucine levels to significantly affect food intake. The blood-brain barrier (BBB) and glial cells maintain amino acid concentrations in the CNS parenchyma at well-controlled levels. This is important because several ubiquitous neurotransmitters are amino acids (i.e., glutamate and glycine) or molecules derived from amino acids (i.e., GABA, dopamine, noradrenaline, serotonin, and histamine). Earlier studies have suggested that leucine availability affects the synthesis of amino acid neurotransmitters such as glutamate ²¹. Abrupt changes in amino acid levels in the brain can cause cell death and serious neuronal dysfunction. For example, excessive activation of the N-methyl-D-aspartate (NMDA) receptor, which is a glutamate receptor, causes neuronal death ²². Similarly, treatment with monosodium glutamate (MSG) at a young age, when the blood-brain barrier (BBB) is not completely formed, causes lesions in several brain areas ²³. Therefore, the ingestion of specific amino acids does not necessarily lead to pronounced changes in their levels in the brain. Likewise, the direct infusion of amino acids into the brain does not necessarily reproduce the physiological effects caused by oral supplementation and therefore may produce supraphysiological effects. Even brain nuclei that are located near circumventricular organs (CVOs) are not free from the blood-brain barrier (BBB) influence. For example, the arcuate nucleus of the hypothalamus (ARH) is close to the median eminence (ME), and the nucleus of the solitary tract (NTS) is close to the area postrema (AP) (Figure 3). Blood vessels in these areas allow nutrients and hormones to more easily gain access to the CNS. Nonetheless, the BBB and glial cells in these areas remain capable of controlling abrupt changes in the concentration of molecules. Therefore, the available evidence suggests that oral leucine supplementation produces no or very mild effects on food intake (Figure 3). Because previous studies have suggested a role of leucine supplementation in the treatment of obesity ²⁴, the practical implication is that if leucine regulates the energy balance and favors a reduced adiposity, this effect is likely not mediated by changes in food intake.

Furthermore, several studies found leucine supplementation had no effects on adiposity ⁵ or even a predisposition to accumulate more body fat ⁶ in animals that began to receive leucine supplementation when they were already obese. A likely explanation for these findings is that mTOR complex 1 (mTORC1) activation may promote fat storage in adipocytes by suppressing lipolysis and stimulating de novo lipogenesis ⁷. Additionally, mice with disrupted mTORC1 complex exhibit less adipose tissue, suggesting that fat deposition may depend on mTORC1 activity ⁸. Branched-chain amino acid (BCAA) supplementation in pregnant rats consuming a protein-restricted diet restored the fat mass of their offspring to levels similar to those of non-restricted animals ⁹.

Therefore, based on the presented data, leucine supplementation is not likely to be helpful as a dietary supplement for treating obesity ².

Figure 3. Brain effects of leucine on feeding

Footnotes:

Neuronal circuitries required for the central effects of leucine on feeding. Central leucine administration (intracerebroventricular or parenchymal) acutely decreases food intake and body weight. This response is due to the activation of hypothalamic nuclei involved in regulating energy balance, including the paraventricular nucleus of the hypothalamus (PVH) and the arcuate nucleus of the hypothalamus (ARH), as well as extra-hypothalamic sites such as the nucleus of the solitary tract (NTS). Conversely, oral leucine administration does not induce neuronal activation in the PVH, ARH, or NTS but does cause c-Fos expression in the area postrema (AP). Consequently, no robust evidence indicates that oral leucine intake affects food intake. CVO = circumventricular organ; ME = median eminence.

[Source ²]

Leucine supplement side effects

Leucine toxicity, as seen in decompensated maple syrup urine disease, causes delirium and neurologic compromise, and can be life-threatening.

A high intake of leucine may cause or exacerbate symptoms of pellagra in people with low niacin status because it interferes with the conversion of L-tryptophan to niacin ²⁵.

Leucine at a dose exceeding 500 mg/kg/d was observed with hyperammonemia ²⁶. On the basis of plasma and urinary variables, the tolerable upper intake level (UL) for leucine in healthy adult men can be suggested at 500 mg/kg body weight per day or 35 g/day as a cautious estimate under acute dietary conditions ²⁶.

Leucine rich foods

Table 1. Foods high in leucine

Description	Leucine (g) Value Per 100 gram
Egg, white, dried, stabilized, glucose reduced	7.36
Egg, white, dried, powder, stabilized, glucose reduced	7.17
Egg, white, dried	6.84
Soy protein isolate	6.78
Soy protein isolate, potassium type	6.78
Egg, white, dried, flakes, stabilized, glucose reduced	6.7
Whale, beluga, meat, dried (Alaska Native)	5.78
Fish, cod, Atlantic, dried and salted	5.11
Seaweed, spirulina, dried	4.95
Soy protein concentrate, produced by alcohol extraction	4.92
Soy protein concentrate, produced by acid wash	4.92
Beverages, Protein powder soy based	4.6
Egg, whole, dried, stabilized, glucose reduced	4.23
Egg, whole, dried	4.15
Cheese, parmesan, shredded	4.01
Seeds, sesame flour, low-fat	3.84
Soy flour, defatted	3.83
Mollusks, whelk, unspecified, cooked, moist heat	3.81
Soy meal, defatted, raw	3.66
Tofu, dried-frozen (koyadofu)	3.64
Tofu, dried-frozen (koyadofu), prepared with calcium sulfate	3.64
Milk, dry, nonfat, regular, without added vitamin A and vitamin D	3.54
Milk, dry, nonfat, regular, with added vitamin A and vitamin D	3.54
Seeds, sunflower seed flour, partially defatted	3.5
Milk, dry, nonfat, calcium reduced	3.48
Cheese, parmesan, hard	3.45
Milk, dry, nonfat, instant, with added vitamin A and vitamin D	3.44
Milk, dry, nonfat, instant, without added vitamin A and vitamin D	3.44
Seeds, cottonseed flour, low fat (glandless)	3.4
Peanut flour, defatted	3.38
Milk, buttermilk, dried	3.36
Seeds, cottonseed meal, partially defatted (glandless)	3.35
Snacks, pork skins, plain	3.32
Soybeans, mature seeds, raw	3.31
Meat extender	3.26
Soybeans, mature seeds, dry roasted	3.22
Snacks, pork skins, barbecue-flavor	3.22
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	3.22
Pork, cured, bacon, cooked, microwaved	3.21
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	3.19
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	3.17
Beef, plate steak, boneless, inside skirt, separable lean only, trimmed to 0″ fat, select, cooked, grilled	3.15
Cheese, gruyere	3.1
Seeds, sesame flour, partially defatted	3.09
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	3.08
Cheese, romano	3.07
Beef, top loin filet, boneless, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	3.07
Beef, loin, top loin steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	3.05
Beef, loin, top loin steak, boneless, lip off, separable lean only, trimmed to 0″ fat, select, cooked, grilled	3.04
Beef, round, eye of round steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	3.04
Beef, loin, top sirloin petite roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	3.02
Beef, rib, back ribs, bone-in, separable lean only, trimmed to 0″ fat, select, cooked, braised	3.01
Cheese, parmesan, dry grated, reduced fat	2.98
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, grilled	2.98
Beef, rib eye steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	2.98
Beef, rib eye steak, boneless, lip off, separable lean only, trimmed to 0″ fat, select, cooked, grilled	2.98
Cheese, swiss	2.96
Beef, rib eye roast, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, roasted	2.95
Beef, plate steak, boneless, outside skirt, separable lean only, trimmed to 0″ fat, select, cooked, grilled	2.94
Beef, top loin petite roast, boneless, separable lean only, trimmed to 1/8″ fat, select, cooked, roasted	2.93
Veal, leg (top round), separable lean only, cooked, braised	2.92
Leavening agents, yeast, baker’s, active dry	2.92
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	2.92
Beef, ribeye petite roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	2.92
Beef, loin, top sirloin cap steak, boneless, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	2.92
Egg, yolk, dried	2.91
Game meat, bison, chuck, shoulder clod, separable lean only, cooked, braised	2.9
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	2.89
Beef, loin, tenderloin steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	2.89
Pork, cured, bacon, cooked, broiled, pan-fried or roasted, reduced sodium	2.88
Veal, leg (top round), separable lean and fat, cooked, braised	2.88
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	2.88
Beef, rib eye steak, bone-in, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	2.88
Beef, round, top round steak, boneless, separable lean and fat, trimmed to 0″ fat, select, cooked, grilled	2.87
Soybeans, mature seeds, roasted, salted	2.87
Soybeans, mature seeds, roasted, no salt added	2.87
Beef, round, top round, separable lean only, trimmed to 0″ fat, choice, cooked, braised	2.85
Beef, round, top round, separable lean only, trimmed to 0″ fat, select, cooked, braised	2.85
Beef, ribeye filet, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	2.85
Veal, shoulder, arm, separable lean only, cooked, braised	2.84
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, all grades, cooked, braised	2.83
Soy flour, full-fat, roasted	2.83
Beef, loin, tenderloin roast, separable lean only, boneless, trimmed to 0″ fat, select, cooked, roasted	2.83
Beef, plate steak, boneless, inside skirt, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	2.82
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, choice, cooked, braised	2.81
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, select, cooked, braised	2.81
Pork, cured, bacon, pre-sliced, cooked, pan-fried	2.81
Beef, round, top round steak, boneless, separable lean and fat, trimmed to 0″ fat, all grades, cooked, grilled	2.81
Beef, short loin, t-bone steak, bone-in, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	2.81
Soy flour, full-fat, raw	2.81
Beef, round, top round steak, boneless, separable lean and fat, trimmed to 0″ fat, choice, cooked, grilled	2.81
Beef, round, eye of round steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	2.81
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	2.8
Seeds, cottonseed flour, partially defatted (glandless)	2.8
Beef, short loin, porterhouse steak, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	2.8
CRACKER BARREL, grilled sirloin steak	2.79
Spices, parsley, dried	2.79
Pork, cured, bacon, cooked, baked	2.78
Veal, cubed for stew (leg and shoulder), separable lean only, cooked, braised	2.78
Beef, round, bottom round, steak, separable lean only, trimmed to 0″ fat, select, cooked, braised	2.78
Beef, rib eye roast, bone-in, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, roasted	2.78
Beef, loin, top loin steak, boneless, lip off, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	2.78
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, braised	2.78
Lamb, shoulder, arm, separable lean only, trimmed to 1/4″ fat, choice, cooked, braised	2.76
Mutton, cooked, roasted (Navajo)	2.76
Beef, chuck, arm pot roast, separable lean only, trimmed to 1/8″ fat, choice, cooked, braised	2.76
Beef, top loin filet, boneless, separable lean only, trimmed to 1/8″ fat, all grades, cooked, grilled	2.76
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, braised	2.76
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, roasted	2.76
Beef, chuck, arm pot roast, separable lean only, trimmed to 1/8″ fat, all grades, cooked, braised	2.76
Beef, chuck, arm pot roast, separable lean only, trimmed to 1/8″ fat, select, cooked, braised	2.75
Game meat, beaver, cooked, roasted	2.75
Cheese, parmesan, grated	2.75
Beef, round, top round roast, boneless, separable lean and fat, trimmed to 0″ fat, select, cooked, roasted	2.74
Lupins, mature seeds, raw	2.74
Veal, rib, separable lean only, cooked, braised	2.74
Beef, round, bottom round, steak, separable lean only, trimmed to 1/8″ fat, select, cooked, braised	2.74
Beef, loin, top sirloin petite roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	2.74
Beef, round, bottom round, steak, separable lean and fat, trimmed to 0″ fat, select, cooked, braised	2.74
Beef, round, top round, separable lean and fat, trimmed to 1/8″ fat, select, cooked, braised	2.73
Beef, loin, top loin steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, all grades, cooked, grilled	2.73
Beef, round, bottom round, steak, separable lean only, trimmed to 1/8″ fat, all grades, cooked, braised	2.73
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, roasted	2.73
Game meat, deer, shoulder clod, separable lean only, cooked, braised	2.73
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, braised	2.73
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, grilled	2.73
Beef, round, eye of round roast, boneless, separable lean and fat, trimmed to 0″ fat, select, cooked, roasted	2.72
Beef, round, bottom round, steak, separable lean only, trimmed to 1/8″ fat, choice, cooked, braised	2.72
Beef, round, top round, separable lean and fat, trimmed to 1/8″ fat, all grades, cooked, braised	2.71
Beef, composite of trimmed retail cuts, separable lean only, trimmed to 0″ fat, select, cooked	2.71
Beef, ribeye filet, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	2.71
Beef, round, bottom round, steak, separable lean only, trimmed to 0″ fat, all grades, cooked, braised	2.71
Veal, sirloin, separable lean only, cooked, braised	2.7
Beef, round, top round, separable lean only, trimmed to 1/8″ fat, choice, cooked, pan-fried	2.7
Beef, brisket, flat half, separable lean only, trimmed to 0″ fat, select, cooked, braised	2.7
Beef, round, top round, separable lean and fat, trimmed to 1/8″ fat, choice, cooked, braised	2.69
Beef, chuck for stew, separable lean and fat, choice, cooked, braised	2.69
Beef, chuck for stew, separable lean and fat, all grades, cooked, braised	2.68
Beef, loin, tenderloin steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	2.68
Beef, round, eye of round steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, grilled	2.68
Veal, shoulder, whole (arm and blade), separable lean only, cooked, braised	2.68
Veal, shoulder, arm, separable lean and fat, cooked, braised	2.68
Beef, chuck for stew, separable lean and fat, select, cooked, braised	2.67
Beef, brisket, flat half, separable lean and fat, trimmed to 0″ fat, select, cooked, braised	2.67
Veal, loin, separable lean only, cooked, braised	2.67
Beef, variety meats and by-products, liver, cooked, braised	2.67
Beef, round, bottom round, steak, separable lean and fat, trimmed to 0″ fat, all grades, cooked, braised	2.67
Beef, rib, back ribs, bone-in, separable lean only, trimmed to 0″ fat, all grades, cooked, braised	2.67
Beef, top loin petite roast, boneless, separable lean only, trimmed to 1/8″ fat, all grades, cooked, roasted	2.67
Cheese, fontina	2.66

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14. Zeanandin G., Balage M., Schneider S.M., Dupont J., Hebuterne X., Mothe-Satney I., Dardevet D. Differential effect of long-term leucine supplementation on skeletal muscle and adipose tissue in old rats: An insulin signaling pathway approach. Age. 2012;34:371–387. doi: 10.1007/s11357-011-9246-0
15. Li X., Wang X., Liu R., Ma Y., Guo H., Hao L., Yao P., Liu L., Sun X., He K., et al. Chronic leucine supplementation increases body weight and insulin sensitivity in rats on high-fat diet likely by promoting insulin signaling in insulin-target tissues. Mol. Nutr. Food Res. 2013;57:1067–1079. doi: 10.1002/mnfr.201200311
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What is phenylalanine

Phenylalanine (C₉H₁₁NO₂) is an essential amino acid in humans that comes from a person’s diet and is used by your body to make other amino acids and is important in the structure and function of many proteins and enzymes. The L-isomer (L-phenylalanine) is used to biochemically form proteins, coded for by DNA, while the D-form (D-phenylalanine) acts as a painkiller. Phenylalanine is converted to tyrosine, used in the biosynthesis of dopamine, norepinephrine (noradrenaline) neurotransmitters and the skin pigment melanin. Melanin pigment is responsible for skin and hair color. Like tyrosine, phenylalanine is also a precursor for catecholamines including tyramine, dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline). Catecholamines are neurotransmitters that act as adrenaline-like substances. Interestingly, several psychotropic drugs (mescaline, morphine, codeine, and papaverine) also have phenylalanine as a constituent. Phenylalanine is highly concentrated in the human brain and plasma. Normal metabolism of phenylalanine requires biopterin, iron, niacin, vitamin B6, copper, and vitamin C.

As an essential amino acid, phenylalanine is not synthesized in humans, you must eat phenylalanine or phenylalanine-containing proteins. For infants, the source of phenylalanine can be either breast milk ¹ or infant formula (containing DHA/arachidonic acid). An average adult ingests 5 g of phenylalanine per day and may optimally need up to 8 g daily. Phenylalanine is highly concentrated in a number of high protein foods, such as meat, cottage cheese, and wheat germ (see Table 1 below). An additional dietary source of phenylalanine is artificial sweeteners containing aspartame. As a general rule, aspartame should be avoided by phenylketonurics and pregnant women. When present in sufficiently high levels, phenylalanine can act as a neurotoxin and a metabotoxin. A neurotoxin is a compound that disrupts or attacks neural cells and neural tissue. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels. Chronically high levels of phenylalanine are associated with at least five inborn errors of metabolism, including Hartnup disorder, hyperphenylalaninemia due to guanosine triphosphate cyclohydrolase deficiency, phenylketonuria (PKU), tyrosinemia type 2 (or Richner-Hanhart syndrome), and tyrosinemia type III (TYRO3).

Figure 1. Phenylalanine in humans may ultimately be metabolized into a range of different substances

Phenylalanine also has some potential benefits. Phenylalanine can act as an effective pain reliever. Its use in premenstrual syndrome and Parkinson’s may enhance the effects of acupuncture and electric transcutaneous nerve stimulation (TENS). Phenylalanine and tyrosine, like L-DOPA, produce a catecholamine-like effect. Phenylalanine is better absorbed than tyrosine and may cause fewer headaches. Low phenylalanine diets have been prescribed for certain cancers with mixed results. For instance, some tumors use more phenylalanine than others (particularly melatonin-producing tumours called melanomas).

Phenylalanine is also used in the manufacture of food and drink products and sold as a nutritional supplement for its reputed analgesic and antidepressant effects. Phenylalanine is a direct precursor to the neuromodulator phenethylamine, a commonly used dietary supplement.

Phenylalanine is found in all food proteins and in some artificial sweeteners such as aspartame (E 951) (a methyl ester of aspartic acid/phenylalanine) and as a flavoring agent and nutritional supplement. As the breakdown of aspartame in the gut is very rapid and complete, any effect reported to occur in the body following ingestion of aspartame will be caused by one or more of the three constituents: aspartic acid, phenylalanine or methanol. The European Food Safety Authority’s scientific opinion reviews possible risks associated with the three breakdown products and concludes that these do not pose a safety concern at current levels of exposure ². Following a thorough review of evidence provided both by animal and human studies, experts have ruled out a potential risk of aspartame causing damage to genes and inducing cancer ². The European Food Safety Authority’s experts also concluded that aspartame does not harm the brain, the nervous system or affect behavior or cognitive function in children or adults ². Experts of European Food Safety Authority Panel on Food Additives and Nutrient Sources added to Food have considered all available information and, following a detailed analysis, have concluded that the current Acceptable Daily Intake (ADI) of 40mg/kg body weight per day is protective for the general population ². However, phenylalanine is known to be toxic at high intake levels, in particular to the developing fetus in women suffering from the medical condition phenylketonuria (PKU).

What is Phenylketonuria?

Phenylketonuria (PKU) is a rare inherited, which means it is passed down through families. Phenylketonuria (PKU) is inherited in families in an autosomal recessive pattern. That means both parents must pass on a nonworking copy of the gene in order for a baby to have the condition. Babies with phenylketonuria (PKU) are missing an enzyme called phenylalanine hydroxylase. Phenylalanine hydroxylase is needed to break down the essential amino acid phenylalanine. Phenylalanine is found in foods that contain protein. Without the phenylalanine hydroxylase enzyme, levels of phenylalanine build up in the body. This buildup can harm the central nervous system and cause brain damage, mental retardation and other serious problems.

Women who have high levels of phenylalanine during pregnancy are at high risk for having babies born with mental retardation, heart problems, small head size (microcephaly) and developmental delay. This is because the babies are exposed to their mother’s very high levels of phenylalanine before they are born.

Maintaining maternal blood phenylalanine between 120 and 360 μmol/l before and during pregnancy results in the best outcome for offspring ³. However, 30% of clinics surveyed recommend 120–240 μmol/l as the target range for maternal blood phenylalanine ⁴.

In the United States, phenylketonuria occurs in 1 in 10,000 to 1 in 15,000 newborn babies. Newborn screening has been used to detect phenylketonuria since the 1960’s. As a result, the severe signs and symptoms of phenylketonuria are rarely seen.

Phenylketonurics have elevated serum plasma levels of phenylalanine up to 400 times normal. High plasma concentrations of phenylalanine influence the blood-brain barrier transport of large neutral amino acids. The high plasma phenylalanine concentrations increase phenylalanine entry into the brain and restrict the entry of other large neutral amino acids ⁵. Phenylalanine has been found to interfere with different cerebral enzyme systems. Untreated phenylketonuria (PKU) can lead to intellectual disability, seizures, behavioral problems, and mental disorders. It may also result in a musty smell and lighter skin. Classic PKU dramatically affects myelination and white matter tracts in untreated infants; this may be one major cause of neurological disorders associated with phenylketonuria. Mild phenylketonuria can act as an unsuspected cause of hyperactivity, learning problems, and other developmental problems in children. It has been recently suggested that PKU may resemble amyloid diseases, such as Alzheimer’s disease and Parkinson’s disease, due to the formation of toxic amyloid-like assemblies of phenylalanine ⁶.

What are the symptoms of phenylketonuria?

Symptoms of phenylketonuria range from mild to severe. Severe phenylketonuria is called classic PKU. Infants born with classic PKU appear normal for the first few months after birth. However, without treatment with a low-phenylalanine diet, these infants will develop mental retardation and behavioral problems. Other common symptoms of untreated classic PKU include seizures, developmental delay, and autism. Boys and girls who have classic PKU may also have eczema of the skin and lighter skin and hair than their family members who do not have phenylketonuria.

Babies born with less severe forms of phenylketonuria (moderate or mild PKU) may have a milder degree of mental retardation unless treated with the special diet. If the baby has only a very slight degree of phenylketonuria, often called mild hyperphenylalaninemia, there may be no problems and the special dietary treatment may not be needed.

How is phenylketonuria diagnosed?

Phenylketonuria (PKU) is usually diagnosed through newborn screening testing that is done shortly after birth on a blood sample (heel stick). However, phenylketonuria (PKU) should be considered at any age in a person who has developmental delays or mental retardation. This is because, rarely, infants are missed by newborn screening programs.

Phenylketonuria prevention

An enzyme assay or genetic testing can determine if parents carry the gene for PKU. Chorionic villus sampling (CVS) or amniocentesis can be done during pregnancy to screen the unborn baby for phenylketonuria.

It is very important that women with PKU closely follow a strict low-phenylalanine diet both before becoming pregnant and throughout the pregnancy. Buildup of phenylalanine will damage the developing baby, even if the child has not inherited the defective gene.

Maintaining maternal blood phenylalanine between 120 and 360 μmol/l before and during pregnancy results in the best outcome for offspring ³. However, 30% of clinics surveyed recommend 120–240 μmol/l as the target range for maternal blood phenylalanine ⁴.

What is the treatment for phenylketonuria?

Phenylketonuria (PKU) is a treatable disease. Phenylketonuria (PKU) is treated by limiting the amount of protein (that contains phenylalanine) in the diet, particularly when the child is growing. The very low in phenylalanine diet must be strictly followed. Treatment also includes using special medical foods as well as special low-protein foods and taking vitamins and minerals. People who have PKU need to follow this diet for their lifetime. It is especially important for women who have phenylketonuria to follow the diet throughout their childbearing years. This requires close supervision by a registered dietitian or doctor.

Those who continue the very low in phenylalanine diet into adulthood have better physical and mental health than those who don’t stay on it. “Diet for life” has become the standard most experts recommend. Women who have PKU need to follow the diet before conception and throughout pregnancy.

Phenylketonuria prognosis

The outcome is expected to be very good if the very low in phenylalanine diet is closely followed, starting shortly after the child’s birth. If treatment is delayed or the condition remains untreated, brain damage will occur. School functioning may be mildly impaired.

If proteins containing phenylalanine are not avoided, PKU can lead to mental disability by the end of the first year of life.

Phenylketonuria possible complications

Severe mental disability occurs if the disorder is untreated. ADHD (attention-deficit hyperactivity disorder) appears to be a common problem in those who do not stick to a very low-phenylalanine diet.

What is DL-phenylalanine?

DL-Phenylalanine is a racemic mixture of phenylalanine, D-phenylalanine and L-phenylalanine, an aromatic amino acid that is marketed as a nutritional supplement for its purported antidepressant, analgesic and appetite suppressant properties ⁷. The reputed analgesic activity of DL-phenylalanine may be explained by the possible blockage by D-phenylalanine of enkephalin degradation by the enzyme carboxypeptidase A ⁸. The mechanism of DL-phenylalanine’s supposed antidepressant activity may be accounted for by the precursor role of L-phenylalanine in the synthesis of the neurotransmitters norepinephrine and dopamine. Elevated brain levels of norepinephrine and dopamine are thought to have an antidepressant effect. Elevated brain norepinephrine and dopamine levels are thought to be associated with antidepressant effects. D-Phenylalanine is absorbed from the small intestine and transported to the liver via the portal circulation. A small amount of D-phenylalanine appears to be converted to L-phenylalanine. D-Phenylalanine is distributed to the various tissues of the body via the systemic circulation. It appears to cross the blood–brain barrier less efficiently than L-phenylalanine, and so a small amount of an ingested dose of D-phenylalanine is excreted in the urine without penetrating the central nervous system. This agent also plays a role in alleviating mood swings of premenstrual syndrome (PMS), increasing energy and mental alertness and heighten the ability to focus in individuals with attention deficit hyperactivity disorder (ADHD) ⁷.

Is phenylalanine bad for you?

Phenylalanine isn’t a health concern for most people. However, for people who have the genetic disorder phenylketonuria (PKU) or certain other health conditions, phenylalanine can be a serious health concern.

Phenylalanine can cause intellectual disabilities, brain damage, seizures and other problems in people with PKU. Phenylalanine occurs naturally in many protein-rich foods, such as milk, eggs and meat. Phenylalanine also is sold as a dietary supplement.

The artificial sweetener aspartame (Equal, NutraSweet or E 951), which is added to many medications, diet foods and diet sodas, contains phenylalanine.

Federal regulations require that any food that contains aspartame bear this warning: “Phenylketonurics: Contains phenylalanine.” This warning helps people with PKU avoid products that are a source of phenylalanine. The current Acceptable Daily Intake (ADI) of aspartame (E 951) is 40mg/kg body weight per day is safe for the general population ².

If you don’t have PKU, you probably don’t need to worry about harmful health effects of phenylalanine with certain important exceptions. Aspartame in large doses can cause a rapid increase in the brain levels of phenylalanine. Because of this, use products with aspartame cautiously if you:

• Take certain medications, such as monoamine oxidase inhibitors, neuroleptics or medications that contain levodopa
• Have tardive dyskinesia (a muscle movement disorder)
• Have a sleep disorder, anxiety disorder or other mental health condition; phenylalanine may worsen feelings of anxiety and jitteriness

If you aren’t sure if phenylalanine or aspartame is a concern for you, talk to your doctor. A blood test to determine if you have PKU is available.

Foods high in phenylalanine

Table 1. Phenylalanine foods (ordered from highest to low)

Description	Phenylalanine (g) Value Per 100 grams
Egg, white, dried, powder, stabilized, glucose reduced	5.18
Egg, white, dried, stabilized, glucose reduced	5.13
Egg, white, dried, flakes, stabilized, glucose reduced	4.84
Egg, white, dried	4.74
Soy protein isolate	4.59
Soy protein isolate, potassium type	4.59
Soy protein concentrate, produced by alcohol extraction	3.28
Soy protein concentrate, produced by acid wash	3.28
Seeds, cottonseed flour, low fat (glandless)	3.1
Seeds, cottonseed meal, partially defatted (glandless)	3.06
Beverages, Protein powder soy based	2.96
Whale, beluga, meat, dried (Alaska Native)	2.95
Seaweed, spirulina, dried	2.78
Egg, whole, dried, stabilized, glucose reduced	2.72
Peanut flour, defatted	2.71
Seeds, sesame flour, low-fat	2.66
Seeds, cottonseed flour, partially defatted (glandless)	2.55
Egg, whole, dried	2.53
Seeds, sunflower seed flour, partially defatted	2.47
Soy flour, defatted	2.45
Fish, cod, Atlantic, dried and salted	2.45
Soy meal, defatted, raw	2.35
Tofu, dried-frozen (koyadofu)	2.33
Tofu, dried-frozen (koyadofu), prepared with calcium sulfate	2.33
Cheese, parmesan, shredded	2.23
Meat extender	2.18
Seeds, sesame flour, partially defatted	2.14
Soybeans, mature seeds, raw	2.12
Soybeans, mature seeds, dry roasted	2.07
Seeds, watermelon seed kernels, dried	2.03
Seeds, cottonseed kernels, roasted (glandless)	2.03
Snacks, pork skins, plain	1.94
Cheese, parmesan, hard	1.92
Snacks, pork skins, barbecue-flavor	1.88
Pigeon peas (red gram), mature seeds, raw	1.86
Soybeans, mature seeds, roasted, salted	1.84
Soybeans, mature seeds, roasted, no salt added	1.84
Soy flour, full-fat, roasted	1.82
Soy flour, full-fat, raw	1.8
Seeds, safflower seed meal, partially defatted	1.77
Peanut flour, low fat	1.75
Leavening agents, yeast, baker’s, active dry	1.75
Milk, dry, nonfat, regular, without added vitamin A and vitamin D	1.75
Milk, dry, nonfat, regular, with added vitamin A and vitamin D	1.75
Cheese, gruyere	1.74
Gelatins, dry powder, unsweetened	1.74
Seeds, pumpkin and squash seed kernels, dried	1.73
Milk, dry, nonfat, calcium reduced	1.71
Spices, parsley, dried	1.71
Seeds, pumpkin and squash seed kernels, roasted, without salt	1.71
Seeds, pumpkin and squash seed kernels, roasted, with salt added	1.71
Cheese, romano	1.71
Milk, dry, nonfat, instant, with added vitamin A and vitamin D	1.69
Milk, dry, nonfat, instant, without added vitamin A and vitamin D	1.69
Cheese, swiss	1.66
Milk, buttermilk, dried	1.66
Mollusks, whelk, unspecified, cooked, moist heat	1.65
Seeds, sesame flour, high-fat	1.63
Pork, cured, bacon, cooked, microwaved	1.62
Cheese, parmesan, dry grated, reduced fat	1.6
Cheese, parmesan, grated	1.54
Beef, variety meats and by-products, liver, cooked, braised	1.51
Cheese, fontina	1.5
Veal, leg (top round), separable lean only, cooked, braised	1.48
Chicken, broilers or fryers, giblets, cooked, fried	1.48
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	1.48
Mungo beans, mature seeds, raw	1.47
Egg, yolk, dried	1.47
Pork, cured, bacon, cooked, broiled, pan-fried or roasted, reduced sodium	1.47
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	1.46
Veal, leg (top round), separable lean and fat, cooked, braised	1.46
Peanuts, spanish, oil-roasted, with salt	1.45
Peanuts, spanish, oil-roasted, without salt	1.45
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	1.45
Seeds, hemp seed, hulled	1.45
Lamb, shoulder, arm, separable lean only, trimmed to 1/4″ fat, choice, cooked, braised	1.45
Beef, plate steak, boneless, inside skirt, separable lean only, trimmed to 0″ fat, select, cooked, grilled	1.45
Mung beans, mature seeds, raw	1.44
Nuts, butternuts, dried	1.44
Veal, shoulder, arm, separable lean only, cooked, braised	1.44
Veal, variety meats and by-products, liver, cooked, braised	1.44
Fast foods, chicken tenders	1.44
Lupins, mature seeds, raw	1.44
Cheese, edam	1.43
Game meat, bison, chuck, shoulder clod, separable lean only, cooked, braised	1.43
Cheese, gouda	1.43
Winged beans, mature seeds, raw	1.43
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	1.43
Peanuts, all types, oil-roasted, with salt	1.43
Peanuts, all types, oil-roasted, without salt	1.43
Pork, cured, bacon, pre-sliced, cooked, pan-fried	1.42
Yardlong beans, mature seeds, raw	1.42
Pork, cured, bacon, cooked, baked	1.42
Game meat, beaver, cooked, roasted	1.42
Beef, round, top round, separable lean only, trimmed to 0″ fat, choice, cooked, braised	1.41
Beef, round, top round, separable lean only, trimmed to 0″ fat, select, cooked, braised	1.41
Veal, cubed for stew (leg and shoulder), separable lean only, cooked, braised	1.41
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, all grades, cooked, braised	1.41
Beef, top loin filet, boneless, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	1.41
Peanuts, valencia, oil-roasted, with salt	1.4
Peanuts, valencia, oil-roasted, without salt	1.4
Fish, roe, mixed species, cooked, dry heat	1.4
Beef, loin, top loin steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	1.4
Mutton, cooked, roasted (Navajo)	1.4
Beef, loin, top loin steak, boneless, lip off, separable lean only, trimmed to 0″ fat, select, cooked, grilled	1.4
Cowpeas, catjang, mature seeds, raw	1.39
Beef, round, eye of round steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	1.39
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, choice, cooked, braised	1.39
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, select, cooked, braised	1.39
Veal, rib, separable lean only, cooked, braised	1.39
Lamb, Australian, imported, fresh, shoulder, arm, separable lean only, trimmed to 1/8″ fat, cooked, braised	1.39
Veal, variety meats and by-products, liver, cooked, pan-fried	1.39
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, grilled	1.39
Lamb, New Zealand, imported, frozen, shoulder, whole (arm and blade), separable lean only, cooked, braised	1.39
Beef, loin, top sirloin petite roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	1.38
Beef, variety meats and by-products, liver, cooked, pan-fried	1.38
Beef, round, bottom round, steak, separable lean only, trimmed to 0″ fat, select, cooked, braised	1.38
Beef, rib, back ribs, bone-in, separable lean only, trimmed to 0″ fat, select, cooked, braised	1.38
Peanuts, all types, raw	1.38
CRACKER BARREL, grilled sirloin steak	1.38
Cowpeas, common (blackeyes, crowder, southern), mature seeds, raw	1.37
Lamb, cubed for stew or kabob (leg and shoulder), separable lean only, trimmed to 1/4″ fat, cooked, braised	1.37
Veal, sirloin, separable lean only, cooked, braised	1.37
Beef, chuck, arm pot roast, separable lean only, trimmed to 1/8″ fat, choice, cooked, braised	1.37
Snacks, soy chips or crisps, salted	1.37
Beans, kidney, royal red, mature seeds, raw	1.37
Beef, chuck, arm pot roast, separable lean only, trimmed to 1/8″ fat, all grades, cooked, braised	1.37
Beef, chuck, arm pot roast, separable lean only, trimmed to 1/8″ fat, select, cooked, braised	1.37
Beef, rib eye steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	1.37
Beef, rib eye steak, boneless, lip off, separable lean only, trimmed to 0″ fat, select, cooked, grilled	1.37
Lamb, variety meats and by-products, liver, cooked, braised	1.36
Beef, round, bottom round, steak, separable lean only, trimmed to 1/8″ fat, select, cooked, braised	1.36
BURGER KING, Chicken Strips	1.36
Veal, shoulder, whole (arm and blade), separable lean only, cooked, braised	1.36
Cheese, tilsit	1.36
Beef, round, bottom round, steak, separable lean and fat, trimmed to 0″ fat, select, cooked, braised	1.36
Veal, shoulder, arm, separable lean and fat, cooked, braised	1.36
Peanuts, spanish, raw	1.36
Game meat, deer, shoulder clod, separable lean only, cooked, braised	1.36
Beef, round, bottom round, steak, separable lean only, trimmed to 1/8″ fat, all grades, cooked, braised	1.36
Veal, loin, separable lean only, cooked, braised	1.35
Game meat, rabbit, wild, cooked, stewed	1.35
Beef, rib eye roast, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, roasted	1.35
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	1.35
Beef, round, bottom round, steak, separable lean only, trimmed to 1/8″ fat, choice, cooked, braised	1.35
Beef, round, top round, separable lean and fat, trimmed to 1/8″ fat, select, cooked, braised	1.35
Beef, plate steak, boneless, outside skirt, separable lean only, trimmed to 0″ fat, select, cooked, grilled	1.35
Pork, ground, 96% lean / 4% fat, cooked, pan-broiled	1.35
Beef, round, bottom round, steak, separable lean only, trimmed to 0″ fat, all grades, cooked, braised	1.34
Beef, top loin petite roast, boneless, separable lean only, trimmed to 1/8″ fat, select, cooked, roasted	1.34

[Source ⁹]

Phenylalanine supplements

Experimental Therapy for Vitiligo (localized hypopigmentation): Oral or topical photochemotherapy with psoralens is generally considered to be the best available treatment for vitiligo (localized skin hypopigmentation), but experimental therapy includes UVA phototherapy with phenylalanine. Use of phenylalanine in oral doses of up to 100 mg/kg with UVA/sunlight led to beneficial results in more than 90% of 200 patients with vitiligo ¹⁰. Greatest benefit was noted in early disease, but prolonged use still induced repigmentation in long-standing cases. Repigmentation occurred mainly in areas rich in follicles. Such therapy is contraindicated in phenylketonuria (PKU) and in pregnancy. Similarly a further open study reported responses in 94 of 149 patients receiving 50 to 100 mg/kg daily of phenylalanine plus twice weekly UVA treatment. However, only 22% of responders had repigmentation in more than 60% of the affected area. Higher doses did not seem to be more effective than 50 mg/kg daily. Another group reported on 6 years of experience of treatment of vitiligo using 50 or 100 mg/kg daily of phenylalanine, with application of 10% phenylalanine gel and daily sun exposure. Although not ideal, they considered the treatment useful, especially for its ability to rapidly repigment the face. The same group performed an open study, adding topical 0.025% clobetasol propionate, and ultraviolet exposure during autumn and winter; 65.5% of patients achieved 100% repigmentation on the face. L-phenylalanine in combination with 0.025% clobetasol propionate and sunlight during sunny months or UVA lamps in winter, appears to improve evolutive vitiligo without side effects, and therefore is especially recommended on the face or for children ¹¹.

References

1. A different approach to breast-feeding of the infant with phenylketonuria. van Rijn M, Bekhof J, Dijkstra T, Smit PG, Moddermam P, van Spronsen FJ. Eur J Pediatr. 2003 May; 162(5):323-6.
2. EFSA completes full risk assessment on aspartame and concludes it is safe at current levels of exposure. http://www.efsa.europa.eu/en/press/news/131210
3. National Institutes of Health Consensus Development Conference Statement: phenylketonuria: screening and management, October 16-18, 2000. National Institutes of Health Consensus Development Panel. Pediatrics. 2001 Oct; 108(4):972-82. http://pediatrics.aappublications.org/content/108/4/972.full
4. GMDI Delphi Survey: Genetic Metabolic Dietitians International and Southeast Regional Newborn Screening and Genetics Collaborative. 2013.
5. Brain dysfunction in phenylketonuria: is phenylalanine toxicity the only possible cause? J Inherit Metab Dis. 2009 Feb;32(1):46-51. doi: 10.1007/s10545-008-0946-2. Epub 2009 Jan 13. https://www.ncbi.nlm.nih.gov/pubmed/19191004
6. Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria. Nat Chem Biol. 2012 Aug;8(8):701-6. doi: 10.1038/nchembio.1002. Epub 2012 Jun 17. https://www.ncbi.nlm.nih.gov/pubmed/22706200
7. DL-Phenylalanine. https://pubchem.ncbi.nlm.nih.gov/compound/dl-phenylalanine
8. Binding of D-phenylalanine and D-tyrosine to carboxypeptidase A. J Biol Chem. 1989 Aug 5;264(22):12849-53. http://www.jbc.org/content/264/22/12849.long
9. United States Department of Agriculture Agricultural Research Service. USDA Food Composition Databases. https://ndb.nal.usda.gov/ndb/search/list
10. Sweetman SC (ed), Martindale: The Complete Drug Reference. London: Pharmaceutical Press (2009), p.1960.
11. Camacho F, Mazuecos J; J Drugs Dermatol 1 (2): 127-31 (2002).

What is L-arginine

Arginine is an semi-essential or conditionally essential amino acid that is physiologically active in the L-form (L-arginine). Arginine is an essential amino acid in infants, because infants are unable to effectively synthesize arginine, making it nutritionally essential for infants, so infants must get arginine from their diet (see Table 1 below). However adults are able to synthesize arginine in the urea cycle. L-arginine is an amino acid that is obtained from the diet and is necessary for the body to make proteins. Arginine is found in plant and animal proteins, such as dairy products, meat, poultry, fish, and nuts. The ratio of L-arginine to lysine is also important: soy and other plant proteins have more L-arginine than animal sources of protein. L-arginine can also be made in a laboratory and used as medicine.

What does L-arginine do?

L-Arginine is an amino acid that has numerous functions in the body. L-Arginine helps dispose of ammonia, is used to make compounds such as nitric oxide (NO), creatine, L-glutamate, and L-proline, and it can be converted into glucose and glycogen if needed ¹. L-arginine is converted in the body into a chemical called nitric oxide (NO). Endothelial nitric oxide synthase (eNOS) stability plays a crucial role in regulating nitric oxide (NO) bioavailability and endothelial function. Endothelial nitric oxide (NO) is synthesized from its substrate L‐arginine, primarily by endothelial nitric oxide synthase (eNOS) and facilitated by the co‐factor tetrahydrobiopterin (BH₄) ². Endothelial nitric oxide synthase (eNOS) can become unstable and uncoupled if there are deficiencies in L‐arginine and/or any of its cofactors (e.g., tetrahydrobiopterin BH₄), resulting in an increased production of superoxide instead of nitric oxide and impaired endothelial function ³. Nitric oxide (NO) causes blood vessels to open wider for improved blood flow and for treating angina (chest pain) and other cardiovascular problems. Arginine may prevent or treat heart and circulatory diseases, combat fatigue, and stimulate the immune system. L-arginine also stimulates the release of growth hormone, insulin, and other substances in the body. Arginine is also an important intermediate in the urea cycle and in detoxification of nitrogenous wastes.

In large doses, L-arginine also stimulates the release of the hormones growth hormone and prolactin. Arginine is a known inducer of mTOR (mammalian target of rapamycin) and is responsible for inducing protein synthesis through the mTOR pathway. mTOR inhibition by rapamycin partially reduces arginine-induced protein synthesis ⁴. Catabolic disease states such as sepsis, injury, and cancer cause an increase in arginine utilization, which can exceed normal body production, leading to arginine depletion. Arginine also activates AMP kinase (AMPK) which then stimulates skeletal muscle fatty acid oxidation and muscle glucose uptake, thereby increasing insulin secretion by pancreatic beta-cells ⁵.

L‐arginine metabolism is complex and highly regulated. In addition to producing nitric oxide (NO) via endothelial nitric oxide synthase (eNOS), L‐arginine is metabolized by arginase to generate ornithine and urea. Because L‐arginine is a substrate for both endothelial nitric oxide synthase (eNOS) and arginase, high arginase activity may limit L‐arginine availability for eNOS ⁶. L‐arginine can also be methylated to produce asymmetric dimethylarginine (ADMA), N^G‐N^′G‐dimethyl‐l‐arginine (SDMA) and N^G‐mono‐methyl‐ւ‐arginine (L‐NMMA) ⁷. ADMA and L‐NMMA can compete with L‐arginine for eNOS, whereas all three methylarginines can interfere with L‐arginine transport into endothelial cells, resulting in a relative L‐arginine deficiency ⁷. Thus, increased metabolism of L‐arginine via the urea cycle and/or methylation could result in reduced L‐arginine bioavailability, eNOS uncoupling and reduced nitric oxide biosynthesis.

L-arginine is used for heart and blood vessel conditions including congestive heart failure, chest pain (angina), high blood pressure, high cholesterol, heart surgery, recovery after heart transplant, heart attack, and coronary artery disease. L-arginine is also used for recurrent pain in the legs due to blocked arteries (intermittent claudication), decreased mental capacity in the elderly (senile dementia), erectile dysfunction (ED), altitude sickness, nitrate tolerance, diabetes, diabetic nerve pain, kidney toxicity from cyclosporine, kidney disease, tuberculosis, critical illness, head and neck cancer, obesity, ovary disease (polycystic ovary syndrome), pressure ulcers, respiratory infections, sickle cell disease, stress, and male infertility.

Some people use L-arginine for preventing the common cold, improving kidney function after a kidney transplant, high blood pressure during pregnancy (pre-eclampsia), improving athletic performance, boosting the immune system, and preventing inflammation and tissue death of the digestive tract in premature infants (necrotizing enterocolitis) and preventing slowing of growth of the baby within the uterus.

L-arginine is used in combination with a number of over-the-counter and prescription medications for various conditions. For example, L-arginine is used along with ibuprofen for migraine headaches; with conventional chemotherapy drugs for treating breast cancer; with other amino acids for treating weight loss in people with AIDS; and with fish oil and other supplements for reducing infections, improving wound healing, and shortening recovery time after surgery.

Some people apply L-arginine to the skin to speed wound healing, healing of small rips of the anus, and for increasing blood flow to cold hands and feet, especially in people with diabetes. It is also used as a cream for sexual problems in both men and women. Arginine has also been used for dental caries and dental hypersensitivity.

Data from an uncontrolled open-label study conducted over a 25 year period supports the use of intravenous arginine (in combination with sodium benzoate, sodium phenylacetate and adequate caloric provision) for the treatment of acute hyperammonemia associated with urea-cycle disorders resulting in increased survival. Clinical experience also suggests the utility of intravenous arginine for the management of this condition. Based on the National Organization for Rare Disorders ⁸, the use of arginine (in combination with sodium benzoate, sodium phenylacetate and adequate caloric provision) is effective and recommended for the management of patients with urea-cycle disorders.

Finally, arginine has been injected into the vein for recurrent pain in the legs due to blocked arteries (intermittent claudication), reduced blood flow to the limbs (peripheral artery disease), for detecting growth hormone deficiency, disease due to defective mitochondria (mitochondrial encephalomyopathies), chest pain due to gastric problems, re-stenosis, kidney transplant, nutrition for the critically ill, metabolic acidosis, and increased blood pressure in the artery of the lungs (pulmonary hypertension) in newborns.

L-arginine foods

Table 1. L-arginine rich foods (ordered from highest to low)

Description	Arginine (g) Value Per 100 gram
Seeds, sesame flour, low-fat	7.44
Seeds, cottonseed flour, low fat (glandless)	6.73
Soy protein isolate	6.67
Soy protein isolate, potassium type	6.67
Seeds, cottonseed meal, partially defatted (glandless)	6.63
Gelatins, dry powder, unsweetened	6.62
Peanut flour, defatted	6.24
Seeds, sesame flour, partially defatted	5.98
Seeds, cottonseed flour, partially defatted (glandless)	5.53
Seeds, pumpkin and squash seed kernels, dried	5.35
Seeds, pumpkin and squash seed kernels, roasted, without salt	5.28
Seeds, pumpkin and squash seed kernels, roasted, with salt added	5.28
Seeds, sunflower seed flour, partially defatted	5.07
Mollusks, whelk, unspecified, cooked, moist heat	4.94
Seeds, watermelon seed kernels, dried	4.9
Egg, white, dried, stabilized, glucose reduced	4.89
Nuts, butternuts, dried	4.86
Snacks, pork skins, plain	4.84
Egg, white, dried, powder, stabilized, glucose reduced	4.81
Gelatin desserts, dry mix, reduced calorie, with aspartame, added phosphorus, potassium, sodium, vitamin C	4.78
Gelatin desserts, dry mix, reduced calorie, with aspartame, no added sodium	4.78
Soy protein concentrate, produced by alcohol extraction	4.64
Soy protein concentrate, produced by acid wash	4.64
Seeds, sesame flour, high-fat	4.57
Seeds, hemp seed, hulled	4.55
Snacks, pork skins, barbecue-flavor	4.55
Egg, white, dried, flakes, stabilized, glucose reduced	4.49
Egg, white, dried	4.41
Seeds, cottonseed kernels, roasted (glandless)	4.4
Beverages, Protein powder soy based	4.27
Seaweed, spirulina, dried	4.15
Peanut flour, low fat	4.04
Lupins, mature seeds, raw	3.88
Seeds, safflower seed meal, partially defatted	3.85
Whale, beluga, meat, dried (Alaska Native)	3.84
Fish, cod, Atlantic, dried and salted	3.76
Soy flour, defatted	3.65
Nuts, walnuts, black, dried	3.62
Soy meal, defatted, raw	3.49
Spices, garlic powder	3.37
Peanuts, spanish, oil-roasted, with salt	3.35
Peanuts, spanish, oil-roasted, without salt	3.35
Seeds, sesame seed kernels, dried (decorticated)	3.25
Peanuts, all types, oil-roasted, with salt	3.25
Peanuts, all types, oil-roasted, without salt	3.25
Peanuts, valencia, oil-roasted, with salt	3.23
Peanuts, valencia, oil-roasted, without salt	3.23
Tofu, dried-frozen (koyadofu)	3.19
Tofu, dried-frozen (koyadofu), prepared with calcium sulfate	3.19
Soybeans, mature seeds, raw	3.15
Peanuts, spanish, raw	3.13
Meat extender	3.12
Peanuts, virginia, oil-roasted, with salt	3.09
Peanuts, virginia, oil-roasted, without salt	3.09
Peanuts, all types, raw	3.08
Egg, whole, dried, stabilized, glucose reduced	3.08
Egg, whole, dried	3.07
Soybeans, mature seeds, dry roasted	3.07
Seeds, pumpkin and squash seeds, whole, roasted, without salt	3.05
Seeds, pumpkin and squash seeds, whole, roasted, with salt added	3.05
Peanuts, virginia, raw	3.01
Peanuts, valencia, raw	3
Nuts, mixed nuts, oil roasted, with peanuts, without salt added	2.96
Nuts, mixed nuts, oil roasted, with peanuts, with salt added	2.96
Nuts, mixed nuts, oil roasted, with peanuts, lightly salted	2.96
Peanuts, all types, dry-roasted, with salt	2.83
Peanuts, all types, dry-roasted, without salt	2.83
Peanut butter, smooth style, with salt (Includes foods for USDA’s Food Distribution Program)	2.77
Peanut butter, smooth style, without salt	2.77
Peanut Butter, smooth (Includes foods for USDA’s Food Distribution Program)	2.73
Soybeans, mature seeds, roasted, salted	2.73
Soybeans, mature seeds, roasted, no salt added	2.73
Peanut butter, chunk style, with salt	2.73
Peanut butter, chunk style, without salt	2.73
Soy flour, full-fat, roasted	2.7
Seeds, sesame butter, paste	2.68
Soy flour, full-fat, raw	2.68
Seeds, sesame butter, tahini, from unroasted kernels (non-chemically removed seed coat)	2.66
Seeds, sesame butter, tahini, from raw and stone ground kernels	2.64
Seeds, sesame seeds, whole, dried	2.63
Seeds, sesame butter, tahini, from roasted and toasted kernels (most common type)	2.52
Seeds, sesame seeds, whole, roasted and toasted	2.52
Seeds, sesame seed kernels, toasted, without salt added (decorticated)	2.52
Seeds, sesame meal, partially defatted	2.52
Seeds, sesame seed kernels, toasted, with salt added (decorticated)	2.52
Pork, cured, bacon, cooked, microwaved	2.51
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	2.51
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	2.49
Nuts, almonds, blanched	2.48
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	2.47
Mollusks, whelk, unspecified, raw	2.47
Spices, fenugreek seed	2.46
Nuts, almonds	2.46
Nuts, almonds, oil roasted, without salt added	2.46
Nuts, almonds, oil roasted, with salt added	2.46
Nuts, almonds, oil roasted, lightly salted	2.46
Beef, plate steak, boneless, inside skirt, separable lean only, trimmed to 0″ fat, select, cooked, grilled	2.46
Nuts, almonds, dry roasted, without salt added	2.44
Nuts, almonds, dry roasted, with salt added	2.44
Nuts, pine nuts, dried	2.41
Broadbeans (fava beans), mature seeds, raw	2.41
Seeds, sunflower seed kernels, dried	2.4
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	2.4
Pork, cured, bacon, cooked, broiled, pan-fried or roasted, reduced sodium	2.4
Beef, top loin filet, boneless, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	2.4
Nuts, almond butter, plain, without salt added	2.38
Nuts, almond butter, plain, with salt added	2.38
Beef, loin, top loin steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	2.38
Beef, loin, top loin steak, boneless, lip off, separable lean only, trimmed to 0″ fat, select, cooked, grilled	2.38
Mollusks, cuttlefish, mixed species, cooked, moist heat	2.37
Beef, round, eye of round steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	2.37
Nuts, mixed nuts, dry roasted, with peanuts, without salt added	2.36
Beef, loin, top sirloin petite roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	2.36
Beef, rib, back ribs, bone-in, separable lean only, trimmed to 0″ fat, select, cooked, braised	2.35
Cereals ready-to-eat, wheat germ, toasted, plain	2.35
Egg, yolk, dried	2.34
Beef, rib eye steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	2.33
Beef, rib eye steak, boneless, lip off, separable lean only, trimmed to 0″ fat, select, cooked, grilled	2.33
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, grilled	2.32
Pork, cured, bacon, cooked, baked	2.31
Beef, rib eye roast, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, roasted	2.31
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, all grades, cooked, braised	2.3
Crustaceans, spiny lobster, mixed species, cooked, moist heat	2.3
Game meat, bison, chuck, shoulder clod, separable lean only, cooked, braised	2.3
Beef, plate steak, boneless, outside skirt, separable lean only, trimmed to 0″ fat, select, cooked, grilled	2.3
Turkey, ground, fat free, pan-broiled crumbles	2.3
Beef, top loin petite roast, boneless, separable lean only, trimmed to 1/8″ fat, select, cooked, roasted	2.29
Beef, round, top round, separable lean only, trimmed to 0″ fat, choice, cooked, braised	2.28
Beef, round, top round, separable lean only, trimmed to 0″ fat, select, cooked, braised	2.28
Nuts, walnuts, english	2.28
Beef, ribeye petite roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	2.28
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	2.28
Beef, loin, top sirloin cap steak, boneless, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	2.28
Beef, New Zealand, imported, brisket point end, separable lean only, cooked, braised	2.27
Beef, round, top round steak, boneless, separable lean and fat, trimmed to 0″ fat, select, cooked, grilled	2.27
Beef, round, bottom round, steak, separable lean only, trimmed to 0″ fat, select, cooked, braised	2.26
Formulated bar, MARS SNACKFOOD US, SNICKERS MARATHON Protein Performance Bar, Caramel Nut Rush	2.26
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, braised	2.26
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	2.25
Beef, loin, tenderloin steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	2.25
Nuts, pine nuts, pinyon, dried	2.25
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, choice, cooked, braised	2.25
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, select, cooked, braised	2.25
Crustaceans, shrimp, mixed species, cooked, moist heat (may contain additives to retain moisture)	2.25
Beef, chuck, arm pot roast, separable lean only, trimmed to 1/8″ fat, choice, cooked, braised	2.25
Beef, rib eye steak, bone-in, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	2.24
Lamb, New Zealand, imported, fore-shank, separable lean only, cooked, braised	2.24
Nuts, mixed nuts, dry roasted, with peanuts, with salt added	2.24
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	2.24
Beef, chuck, arm pot roast, separable lean only, trimmed to 1/8″ fat, all grades, cooked, braised	2.24

[Source ⁹]

What is L-arginine good for

L-arginine possibly effective for:

• Chest pain (angina). Taking L-arginine seems to decrease symptoms and improve exercise tolerance and quality of life in people with angina. However, L-arginine does not seem to help widen the blood vessels that are narrowed in angina.
• Erectile dysfunction (ED). Taking 5 grams of L-arginine by mouth daily seems to improve sexual function in men with ED. Taking lower doses might not be effective. However, there is some early evidence that taking L-arginine with maritime pine bark extract and other ingredients, might improve the effectiveness of low-dose L-arginine for ED.
• High blood pressure. There is early evidence that taking L-arginine by mouth can reduce blood pressure in healthy people, people with high blood pressure, and people with slightly high blood pressure with or without diabetes.
• Inflammation and tissue death in the digestive tract in premature infants (necrotizing enterocolitis). Adding L-arginine to formula seems to prevent inflammation of the digestive tract in premature infants. A total of 5 premature infants need to receive arginine to prevent one instance of digestive tract inflammation.
• Nitrate tolerance. Taking L-arginine by mouth seems to prevent nitrate tolerance in people taking nitroglycerin for chest pain (angina pectoris).
• Leg pain associated with poor blood flow (peripheral arterial disease). Research suggests that taking L-arginine by mouth or intravenously (by IV) for up to 8 weeks increases blood flow in people with peripheral arterial disease. However, long-term use (up to 6 months) does not improve walking speed or distance in people with peripheral arterial disease.
• Improving recovery after surgery. Taking L-arginine with ribonucleic acid (RNA) and eicosapentaenoic acid (EPA) before surgery or afterwards seems to help reduce the recovery time, reduce the number of infections, and improve wound healing after surgery.
• High blood pressure during pregnancy (pre-eclampsia). Most research shows that L-arginine can reduce blood pressure in women with this condition. L-arginine might also prevent this condition in pregnant women.

L-arginine possibly ineffective for:

• Kidney disease. Most early research suggests that taking L-arginine by mouth or intravenously (by IV) does not improve kidney function in most people with kidney failure or kidney disease. However, taking L-arginine by mouth might improve kidney function and reverse anemia in elderly people with kidney disease-associated anemia.
• Heart attack. Taking L-arginine does not seem to help prevent a heart attack. It also does not seem to be beneficial for treating a heart attack after it has occurs. In fact, there is concern that L-arginine might be harmful for people after a recent heart attack. Do not take L-arginine if you have had a recent heart attack.
• Tuberculosis. Adding arginine to standard treatment for tuberculosis does not seem to help improve symptoms or clear the infection.
• Wound healing. Taking L-arginine does not seem to improve wound healing.

Insufficient evidence to rate effectiveness for:

• AIDS-related wasting. Taking L-arginine by mouth, along with hydroxymethylbutyrate (HMB) and glutamine, for 8 weeks seems to increase body weight and improve immune function in people with HIV/AIDS. However, taking L-arginine by mouth, along with omega-3 fatty acids and a balanced nutritional supplement, for 6 months does not improve body weight or fat mass, energy intake, or immune function in people who are HIV-positive.
• Altitude sickness. Early research suggests that L-arginine does not reduce altitude sickness.
• Anal fissures. There is inconsistent evidence about that effects of L-arginine for treating anal fissures. Applying a topical gel containing L-arginine for at least 12 weeks might heal anal fissures in people who do not respond to traditional care. However, applying L-arginine to the skin does not seem to be better than surgery for anal fissures.
• Breast cancer. Early research shows that taking L-arginine before chemotherapy does not improve the response rate in people with breast cancer.
• Heart failure. Taking L-arginine by mouth, together with conventional treatment, seems to improve kidney function in people with heart failure. However, it might not improve the ability to exercise, quality of life, or blood circulation. L-arginine should not be used in place of conventional treatment.
• Coronary artery bypass graft (CABG) surgery. There is mixed evidence about the effects of L-arginine in protecting the heart during CABG. Some research suggests that giving L-arginine intravenously (by IV) may be helpful in people undergoing CABG. Other research shows that it does not help.
• Clogged blood vessels (coronary artery disease). Early research suggests that taking L-arginine intravenously (by IV) before exercising can improve blood vessel function in people with coronary artery disease. However, it does not improve blood flow to the heart.
• Critical illness (trauma). Research shows that taking L-arginine by mouth with glutamine, nucleotides, and omega-3 fatty acids reduces the recovery time, the need for help with breathing, and risk of infections in people who are critically ill. However, it does not reduce the risk of death.
• Memory loss (dementia). Early research suggests that L-arginine might improve memory loss related to aging.
• Cavities. Early research suggests that using a sugarless mint containing an arginine complex (CaviStat) for one year reduces the number of cavities in molars of children compared with sugarless mints that do not contain arginine.
• Sensitive teeth. Early research suggests that using a toothpaste containing arginine, calcium, and fluoride reduces tooth sensitivity when used twice daily.
• Diabetes. Taking L-arginine by mouth seems to improve blood sugar control in people with existing diabetes. However, it is unclear if arginine helps prevent people with pre-diabetes from developing diabetes.
• Diabetic foot ulcers. Early research shows that applying L-arginine to the feet daily can improve circulation in people with diabetes, which might be helpful in preventing diabetic foot ulcers. However, if there is already an ulcer on the foot, injecting L-arginine under the skin near the ulcer does not seem to shorten healing time or lower the chance of needing an amputation in the future.
• Nerve damage due to diabetes. Early research suggests that taking L-arginine daily for 3 months does not improve nerve damage related to diabetes.
• Muscle problems in the esophagus. Early research suggests that taking L-arginine by mouth or as an infusion can reduces the number and intensity of chest pain attacks in people with chest pain that is not related to the heart.
• Exercise performance. There is inconsistent evidence about the effects of L-arginine on exercise performance. Some evidence shows that taking 6 grams of L-arginine in a drink increases exercise time until becoming tired. Also taking arginine with grape seed extract appears to improve working ability in men and decreases their tiredness. However, taking arginine 6 grams once does not affect strength during exercise.
• Head and neck cancer. Supplementing a feeding tube with L-arginine does not seem to improve immune function, reduce tumor size, or improve healing in people with head and neck cancer.
• Heart transplant. Early research suggests that taking L-arginine by mouth for 6 weeks increases walking distance and improves breathing in people with a heart transplant.
• Infertility. There is inconsistent evidence about the effectiveness of L-arginine for infertility. Some early research suggests that taking 16 grams of L-arginine daily increases egg counts collected in women undergoing IVF. However, it does not seem to improve pregnancy rates. Other research suggests that taking L-arginine does not improve semen quality in men with unexplained infertility.
• Bladder inflammation. Taking L-arginine by mouth seems to reduce pain and some symptoms of bladder inflammation, although improvements may take 3 months to occur. However, L-arginine does not seem to reduce the need to urinate at night or improve the frequency of urination.
• Poor growth of fetus during pregnancy. Early research suggests that taking L-arginine during pregnancy can increase the birthweight of babies who show poor growth while still in their mother’s womb. However, L-arginine does not seem to increase birthweight or reduce the risk of the baby dying if the baby has extremely poor growth while in the womb.
• Mitochondrial encephalomyopathies (a group of disorders that lead to muscle and nervous system problems). There is some interest in using L-arginine to improve symptoms associated with MELAS (myoclonic epilepsy with lactic acidosis and stroke-like episodes) syndrome. Early research suggests that administering L-arginine intravenously (by IV) within one hour of stroke-like symptoms improves headaches, nausea, vomiting, blindness, and the appearance of bright spots in people with this condition.
• Migraine headache. Taking L-arginine by mouth along with the painkiller ibuprofen seems to be effective for treating migraine headache. This combination sometimes starts to work within 30 minutes. However, it is hard to know how much of the pain relief is due to L-arginine, since ibuprofen can relieve migraine pain on its own.
• Obesity. Early research suggests that taking a specific arginine supplement (NOW Foods, Bloomingdale, IL) 3 grams three times daily may decrease waist size and weight in women.
• Ovarian disease (polycystic ovarian syndrome). Early research suggests that taking N-acetyl-cysteine and L-arginine daily for 6 months can improve menstrual function and reduces insulin resistance in people with polycystic ovarian syndrome.
• Pressure ulcers. Taking L-arginine by mouth along with the painkiller ibuprofen seems to be effective for treating migraine headache. This combination sometimes starts to work within 30 minutes. However, it is hard to know how much of the pain relief is due to L-arginine, since ibuprofen can relieve migraine pain on its own.
• Restricted blood flow (restenosis). Some research suggests that giving L-arginine during stent implantation followed by L-arginine supplementation by mouth for 2 weeks after stent implantation does not reduce the risk of restricted blood flow. However, other evidence suggests that administering L-arginine at the site of stent implantation may reduce artery wall thickening.
• Kidney transplant. There is conflicting evidence about the effects of L-arginine for people with kidney transplants. It is unclear if it helps.
• Respiratory infections. Early research suggests that taking L-arginine by mouth for 60 days prevents the recurrence of respiratory infections in children.
• Sickle-cell disease. Early research suggests that taking L-arginine for 5 days might be useful for people with sickle cell disease who have high blood pressure in the lungs.
• Stress. Some early research suggests that taking a combination of L-lysine and L-arginine for up to 10 days reduces stress and anxiety in healthy people and those prone to stress.
• Prevention of the common cold.
• Female sexual problems.

More evidence is needed to rate the effectiveness of L-arginine for these uses.

L-arginine dosage

The following doses have been studied in scientific research:

By mouth:

• For chest pain associated with coronary artery disease (angina pectoris): 3-6 grams three times per day for up to one month.
• For preventing the loss of the effectiveness of nitroglycerin in relieving pain in people with chest pain due to coronary artery disease (angina pectoris): 700 mg four times daily.
• For organic erectile dysfunction (ED): 5 grams per day. Taking lower doses might not be effective.
• For high blood pressure: 4-24 grams per day for 2-24 weeks.
• For preventing inflammation of the digestive tract in premature infants: 261 mg/kg added to oral feedings daily for the first 28 days of life.
• For reducing pain when walking in people with a disease called peripheral arterial disease: 6 grams for up to 8 weeks.
• For preventing high blood pressure during pregnancy: 3 grams daily for 3 weeks. Two bars of a medical food (Heart Bars) with arginine 6.6 grams and antioxidant vitamins daily starting at 14-32 weeks gestation and continuing until delivery. 4 grams arginine (Bioarginina, Damor, Italy) daily for 10-12 weeks.

By IV (intravenously):

• For reducing pain when walking in people with a disease called peripheral arterial disease: 6 grams for up to 8 weeks.

L-arginine supplement side effects

L-arginine is POSSIBLY SAFE for most people when taken appropriately by mouth, administered as a shot, or applied to the skin, short-term. It can cause some side effects such as abdominal pain, bloating, diarrhea, gout, blood abnormalities, allergies, airway inflammation, worsening of asthma, and low blood pressure.

Check with your doctor or nurse immediately if any of the following side effects occur while taking arginine:

Rare side effects

• redness or discoloration of the skin
• swelling of the hands and face

Incidence Not Known

• blood in the urine
• cough
• difficulty swallowing
• dizziness
• fast heartbeat
• hives, itching, skin rash
• pain or redness at the injection site
• pale skin at the injection site
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• tightness in the chest
• unusual tiredness or weakness

Get emergency help immediately if any of the following symptoms of overdose occur while taking arginine:

Symptoms of L-arginine overdose

• confusion
• deep or fast breathing with dizziness
• drowsiness
• muscle tremors
• numbness of the feet, hands, and around the mouth
• rapid, deep breathing
• restlessness
• stomach cramps

Some side effects of arginine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common side effects

• bleeding, blistering, burning, coldness, discoloration of skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, rash, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
• headache
• nausea
• numbness
• vomiting

Special precautions and warnings

Pregnancy and breast-feeding: L-arginine is POSSIBLY SAFE when taken by mouth appropriately for a short-term during pregnancy. Not enough is known about using L-arginine long-term in pregnancy or during breast-feeding. Stay on the safe side and avoid use.

Children: L-arginine is POSSIBLY SAFE when used by mouth in premature infants in appropriate doses. However, L-arginine is POSSIBLY UNSAFE when used in high doses. Doses that are too high can cause serious side effects including death in children.

Allergies or asthma: L-arginine can cause an allergic response or make swelling in the airways worse. If you are prone to allergies or asthma and decide to take L-arginine, use it with caution.

Cirrhosis: L-arginine should be used with caution in people with cirrhosis.

Guanidinoacetate methyltransferase deficiency: People with this inherited condition are unable to convert arginine and other similar chemicals into creatine. To prevent complications associated with this condition, these people should not take arginine.

Herpes: There is a concern that L-arginine might make herpes worse. There is some evidence that L-arginine is needed for the herpes virus to multiply.

Low blood pressure: L-arginine might lower blood pressure. This could be a problem if you already have low blood pressure.

Recent heart attack: There is a concern that L-arginine might increase the risk of death after a heart attack, especially in older people. If you have had a heart attack recently, don’t take L-arginine.

Kidney disease: L-arginine has caused high potassium levels when used by people with kidney disease. In some cases, this has resulted in a potentially life-threatening irregular heartbeat.

Surgery: L-arginine might affect blood pressure. There is a concern that it might interfere with blood pressure control during and after surgery. Stop taking L-arginine at least 2 weeks before a scheduled surgery.

L-arginine interactions with medications

Major interactions

Do NOT take this combination.

Medications for high blood pressure (Antihypertensive drugs)

• L-arginine seems to decrease blood pressure. Taking L-arginine along with medications for high blood pressure might cause your blood pressure to go too low.
• Some medications for high blood pressure include captopril (Capoten), enalapril (Vasotec), losartan (Cozaar), valsartan (Diovan), diltiazem (Cardizem), amlodipine (Norvasc), hydrochlorothiazide (HydroDIURIL), furosemide (Lasix), and many others.

Moderate interactions

Be cautious with this combination.

Medications for diabetes (Antidiabetes drugs)

• L-arginine seems to decrease blood sugar in people with type 2 diabetes. Diabetes medications are also used to lower blood sugar. Taking L-arginine along with diabetes medications might cause your blood sugar to go too low. Monitor your blood sugar closely. The dose of your diabetes medication might need to be changed.
• Some medications used for diabetes include glimepiride (Amaryl), glyburide (DiaBeta, Glynase PresTab, Micronase), insulin, pioglitazone (Actos), rosiglitazone (Avandia), chlorpropamide (Diabinese), glipizide (Glucotrol), tolbutamide (Orinase), and others.

Medications for high blood pressure (ACE inhibitors)

• L-arginine seems to decrease blood pressure. Taking L-arginine along with certain medications for high blood pressure, called ACE inhibitors might cause your blood pressure to go too low. Also, ACE inhibitors can increase potassium levels. L-arginine may also increase potassium levels. Taking L-arginine with ACE inhibitors might cause potassium levels to become too high.
• Some ACE inhibitors include benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik).

Medications for high blood pressure [Angiotensin receptor blockers (ARBs)]

• L-arginine seems to decrease blood pressure. Taking L-arginine along with medications for high blood pressure might cause your blood pressure to go too low.
• The ARBs include losartan (Cozaar), valsartan (Diovan), irbesartan (Avapro), candesartan (Atacand), telmisartan (Micardis), and eprosartan (Teveten).

Medications for high blood pressure (Isoproterenol)

• L-arginine seems to decrease blood pressure. Isoproterenol is a drug that is used to lower blood pressure. Taking L-arginine along with isoproterenol might cause your blood pressure to go too low.

Medications that increase blood flow to the heart (Nitrates)

• L-arginine increases blood flow. Taking L-arginine with medications that increase blood flow to the heart might increase the chance of dizziness and lightheadedness.
• Some of these medications that increase blood flow to the heart include nitroglycerin (Nitro-Bid, Nitro-Dur, Nitrostat), and isosorbide (Imdur, Isordil, Sorbitrate).

Medications that slow blood clotting (Anticoagulant / Antiplatelet drugs)

• L-arginine seems to slow blood clotting. Taking L-arginine along with medications that also slow clotting might increase the chances of bruising and bleeding.
• Some medications that slow blood clotting include aspirin, clopidogrel (Plavix), dalteparin (Fragmin), enoxaparin (Lovenox), heparin, ticlopidine (Ticlid), warfarin (Coumadin), and others.

Sildenafil (Viagra)

• Sildenafil (Viagra) can lower blood pressure. L-arginine can also lower blood pressure. Taking sildenafil (Viagra) and L-arginine together might cause the blood pressure to go too low. Blood pressure that is too low can cause dizziness and other side effects.

Water pills (Potassium-sparing diuretics)

• L-arginine might increase potassium levels in the body. Some “water pills” might also increase potassium in the body. In theory, taking L-arginine along with some “water pills” might cause too much potassium to be in the body. Some water pills include amiloride (Midamor), spironolactone (Aldactone), and triamterene (Dyrenium).

Some “water pills” that increase potassium in the body include spironolactone (Aldactone), triamterene (Dyrenium), and amiloride (Midamor).

Interactions with herbs and supplements

Herbs and supplements that might lower blood pressure

• L-arginine seems to lower blood pressure. Using it along with other herbs and supplements that have this same effect might increase the risk of blood pressure dropping too low in some people. Some of these products include andrographis, casein peptides, cat’s claw, coenzyme Q-10, fish oil, L-arginine, lycium, stinging nettle, theanine, and others.

Herbs and supplements that might lower blood sugar

• L-arginine seems to lower blood sugar. Using it along with other herbs and supplements that have the same effect might cause blood sugar to become too low in some people. Some of these products include devil’s claw, fenugreek, guar gum, Panax ginseng, Siberian ginseng, and others.

Herbs and supplements that might slow blood clotting

• Using L-arginine along with herbs that can slow blood clotting could increase the risk of bleeding in some people. These herbs include angelica, clove, danshen, garlic, ginkgo, Panax ginseng, red clover, turmeric, and others.

Xylitol

• L-arginine can cause an organ in the body called the pancreas to release a hormone called glucagon. Glucagon comes to the rescue when blood sugar levels are too low. Glucagon makes the liver convert stored sugar to useable sugar that is released into the bloodstream. Using L-arginine along with xylitol can keep L-arginine from stimulating the pancreas to release glucagon.

References

1. Wu G , Morris SM .Arginine metabolism: nitric oxide and beyond.Biochem J 336: 1-17, 1998.
2. Klawitter J, Hildreth KL, Christians U, Kohrt WM, Moreau KL. A relative L‐arginine deficiency contributes to endothelial dysfunction across the stages of the menopausal transition. Physiological Reports. 2017;5(17):e13409. doi:10.14814/phy2.13409. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599867/
3. Zhang Y., Janssens S. P., Wingler K., Schmidt H. H. H. W., and Moens A. L.. 2011. Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy. Am. J. Physiol. Heart Circ. Physiol. 301:H634–H646
4. Arginine-induced stimulation of protein synthesis and survival in IPEC-J2 cells is mediated by mTOR but not nitric oxide. Am J Physiol Endocrinol Metab. 2010 Dec;299(6):E899-909. doi: 10.1152/ajpendo.00068.2010. Epub 2010 Sep 14. https://www.physiology.org/doi/full/10.1152/ajpendo.00068.2010
5. Effect of l-arginine infusion on glucose disposal during exercise in humans. Med Sci Sports Exerc. 2011 Sep;43(9):1626-34. doi: 10.1249/MSS.0b013e318212a317. https://www.ncbi.nlm.nih.gov/pubmed/21311355
6. Santhanam L., Christianson D. W., Nyhan D., and Berkowitz D. E.. 2008. Arginase and vascular aging. J. Appl. Physiol. (1985) 105:1632–1642.
7. Bode‐Böger S. M., Scalera F., and Ignarro L. J.. 2007. The l‐arginine paradox: importance of the l‐arginine/asymmetrical dimethylarginine ratio. Pharmacol. Ther. 114:295–306.
8. Urea Cycle Disorders (UCD). https://rarediseases.org/physician-guide/urea-cycle-disorders/
9. United States Department of Agriculture Agricultural Research Service. USDA Food Composition Databases. https://ndb.nal.usda.gov/ndb/search/list

What is tryptophan

Tryptophan or L-tryptophan is an essential amino acid and a precursor of serotonin (5-hydroxytryptamine) and consequently melatonin; substances that are considered important in the modulation of several essential behaviors and psychological functions including sleep, mood, cognition, and circadian rhythms ¹. Tryptophan is an essential amino acid, which means your body cannot produce it, so you must get tryptophan from your diet (see Tables 1 and 2 below). Tryptophan is an essential amino acid found in many protein-based foods and dietary proteins ² including meats, dairy, fruits, and seeds. High-glycemic index (high GI) and high-glycemic load (high GL) meals also increase the availability of tryptophan ³. Levels of plasma tryptophan are determined by a balance between dietary intake ⁴ and its removal from the plasma as a part of its essential role in protein biosynthesis ⁵. Aside from its role in protein formation, tryptophan is a precursor for a number of metabolites, most notably kynurenine and the neurotransmitters, serotonin and melatonin.

Melatonin is a hormone that is produced by the pineal gland in human, which regulates sleep and wakefulness. Serotonin is a brain neurotransmitter, platelet clotting factor, and neurohormone found in organs throughout your body. Metabolism of tryptophan into serotonin requires nutrients such as vitamin B6, niacin, and glutathione. Niacin (also known as vitamin B3) is an important metabolite of tryptophan. It is synthesized via kynurenine and quinolinic acids, which are products of tryptophan degradation ⁶.

For all amino acids, including L-tryptophan, only the L isomer is used in protein synthesis ⁷ and can pass across the blood-brain barrier ⁸. In humans, tryptophan has relatively low tissue storage ⁹ and the overall tryptophan concentration in the body is the lowest among all amino acids ¹⁰, although only small amounts are necessary for general healthy nutrition ¹¹. While typical intake for many individuals is approximately 900 to 1000 mg daily, the recommended daily allowance for adults is estimated to be between 250 mg/day ¹¹ and 425 mg/day ¹², which translates to a dietary intake of 3.5 to 6.0 mg/kg of body weight per day. Some common sources of tryptophan are oats, bananas, dried prunes, milk, tuna fish, cheese, bread, chicken, turkey, peanuts, and chocolate (see Table 1).

Table 1. L-tryptophan found in common foods

	L-tryptophan*(mg)	Sum of Competing Amino Acids (CAAs)** (mg)	Ratio
Turkey, Skinless, Boneless, Light Meat (per pound, raw)	410	9525	0.043
Chicken, Skinless, Boneless, Light Meat (per pound, raw)	238	5122	0.046
Turkey, Skinless, Boneless, Dark Meat (per pound, raw)	303	7036	0.043
Chicken, Skinless, Boneless, Dark Meat (per pound, raw)	256	5492	0.047
Whole Milk (per quart)	732	8989	0.081
2% Milk (per quart)	551	12516	0.044
Wheat Bread (per slice)	19	317	0.06
White Bread (per slice)	22	439	0.05
Semisweet Chocolate (per ounce)	18	294	0.061
Sweet Chocolate (per ounce)	16	270	0.059
Canned Tuna (per ounce)	472	10591	0.045
Cheddar Cheese (per ounce)	91	2298	0.04
Peanuts (per ounce)	65	1574	0.041
Oats for Oatmeal (per cup)	147	2617	0.056
Dried Prune (one)	2	27	0.074
Banana (one medium)	11	237	0.046
Apple (one medium)	2	70	0.029

Footnotes:

The L-tryptophan/competing amino acid (CAA) ratio represents the relative availability of plasma L-tryptophan for crossing the blood-brain barrier and is thought to be the best indicator of brain serotonin synthesis.
^*e.g. The recommended daily allowance for a 79 kg (175 lb) adult is 278 to 476 mg.
^**CAAs = Isoleucine, Leucine, Phenylalanine, Tyrosine, and Valine, the five large neutral amino acids typically included in the tryptophan/competing amino acid (CAA) ratio.

[Source ¹³]

In humans acute tryptophan depletion inhibits serotonin synthesis ¹⁴ and also lowers cerebrospinal fluid concentrations of tryptophan ¹⁵ and 5-hydroxyindoleacetic acid (5-HIAA), the major serotonin metabolite ¹⁶.

Tryptophan is the sole precursor of peripherally and centrally produced serotonin (5-hydroxytryptamine) ¹³. However, the second most prevalent metabolic pathway of tryptophan after protein synthesis is the synthesis of kynurenine, which accounts for approximately 90% of tryptophan metabolism ¹⁷. Kynurenine is the precursor of kynurenic acid, an antagonist at glutamate ionotropic receptors. There is strong evidence implicating the kynurenines in behavioral and cognitive symptoms of neurological disease ¹⁸, however the relationship between the central effects of tryptophan depletion/supplementation and the kynurenine pathway is as yet not clear ¹⁹.

It is estimated that 95% of mammalian serotonin is found within the gastrointestinal tract ²⁰ and only 3% of dietary tryptophan is used for serotonin synthesis throughout the body ²¹. Nevertheless, serotonin synthesis is one of the most important tryptophan pathways and a topic of intense research. It is estimated that only 1% of dietary tryptophan is used for serotonin synthesis in the brain ²², but despite the relatively low concentration of brain serotonin compared to that in the rest of the body, it has a broad impact as a neurotransmitter and neuromodulator and has been implicated in numerous psychiatric conditions and psychological processes.

After protein synthesis, the second most prevalent metabolic pathway of tryptophan is for the synthesis of kynurenine, which accounts for approximately 90% of tryptophan catabolism ²³. Kynurenine is a key component in the synthesis of a number of metabolites, but most importantly, it is the precursor of kynurenic and quinolinic acids. Each of these metabolites has the potential to affect other neurotransmitters; specifically kynurenic acid is a glutamate receptor antagonist, while quinolinic acid is a glutamate receptor agonist ²⁴. Among other pathways, kynurenine is known to be involved in acting as an ultra violet (UV) filter which protects the retina of the eye from UV damage ²⁵. The effectiveness of this protection deteriorates with age, contributing to the normal changes in coloration and fluorescence of the lens that interfere with visual function and may, in some individuals, play a role in cataract formation.

In addition to tryptophan’s three major activities of protein, kynurenine, and serotonin synthesis, tryptamine is another biologically active compound that is derived from tryptophan. The immediate decarboxylation of tryptophan results in the synthesis of trace amounts of tryptamine (i.e. ng/g), which is an important neuromodulator of serotonin.45 Numerous animal studies have indicated that tryptamine acts as a control for the balance between excitatory and inhibitory functions of serotonin, and in other instances, tryptamine acts as a neurotransmitter with specific receptors that are independent of serotonin function ²⁶.

Melatonin is a hormone produced in the tryptophan/serotonin pathway, which regulates diurnal rhythms and influences the reproductive and immune systems,47 as well as digestive processes and gastrointestinal motility.48 Melatonin synthesis is regulated by the blue light spectrum (i.e. 446 to 477 nm) in both artificial and sun light ²⁷. During periods of darkness, it is actively secreted from the pineal gland to induce neural and endocrine effects that regulate circadian rhythms of behavior, physiology, and sleep patterns ²⁸.

Tryptophan also plays a role as a substrate for synthesis of the coenzymes nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP) ²⁹. NAD and NADP are coenzymes essential for electron transfer reactions (i.e. redox reactions) in all living cells. These enzymes can be synthesized de novo from ingested tryptophan, or from ingestion of niacin (i.e. vitamin B3).

There are a number of conditions or diseases that are characterized tryptophan deficiencies. For instance, fructose malabsorption causes improper absorption of tryptophan in the intestine, which reduces levels of tryptophan in the blood and leads to depression. High corn or other tryptophan-deficient diets can cause pellagra, which is a niacin-tryptophan deficiency disease with symptoms of dermatitis, diarrhea, and dementia ⁶. Hartnup’s disease is a disorder in which tryptophan and other amino acids are not absorbed properly. Symptoms of Hartnup’s disease include skin rashes, difficulty coordinating movements (cerebellar ataxia), and psychiatric symptoms such as depression or psychosis ⁶. Tryptophan supplements may be useful for treating Hartnup’s disease. Assessment of tryptophan deficiency is done through studying excretion of tryptophan metabolites in the urine or blood. Blood may be the most sensitive test because the amino acid tryptophan is transported in a unique way. Increased urination of tryptophan breakdown products (such as kynurenine) correlates with increased tryptophan degradation, which occurs with oral contraception, depression, mental retardation, hypertension, and anxiety states ⁶.

The requirement for tryptophan and protein decreases with age ⁶. The minimum daily requirement for adults is 3 mg/kg body weight per day or about 200 mg a day. There is 400 mg of tryptophan in a cup of wheat germ ⁶. A cup of low fat cottage cheese contains 300 mg of tryptophan and chicken and turkey contain up to 600 mg of tryptophan per pound (see Table 1 below).

Tryptophan plays a role in “feast-induced” drowsiness. Ingestion of a meal rich in carbohydrates triggers the release of insulin. Insulin, in turn, stimulates the uptake of large neutral branched-chain amino acids (BCAAs) into muscle, increasing the ratio of tryptophan to branched-chain amino acid in the bloodstream. The increased tryptophan ratio reduces competition at the large neutral amino acid transporter (which transports both branched-chain amino acids and tryptophan), resulting in greater uptake of tryptophan across the blood-brain barrier into the cerebrospinal fluid (CSF). Once in the cerebrospinal fluid (CSF), tryptophan is converted into serotonin and the resulting serotonin is further metabolized into melatonin by the pineal gland, which promotes sleep ⁶.

Under certain situations, tryptophan can be a neurotoxin and a metabotoxin ⁶. A neurotoxin is a compound that causes damage to the brain and nerve tissues. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels. Chronically high levels of tryptophan can be found in glutaric aciduria type I (glutaric acidemia type I or GA1). GA1 is an inherited disorder in which the body is unable to completely break down the amino acids lysine, hydroxylysine, and tryptophan ⁶. Babies with glutaric acidemia type I are often born with unusually large heads (macrocephaly). Affected individuals may also have difficulty moving and may experience spasms, jerking, rigidity or decreased muscle tone, and muscle weakness. High levels of tryptophan have also been implicated in eosinophilia-myalgia syndrome, an incurable and sometimes fatal flu-like neurological condition linked to the ingestion of large amounts of L-tryptophan. The risk of developing eosinophilia-myalgia syndrome increases with larger doses of tryptophan and increasing age. Some research suggests that certain genetic polymorphisms may be related to the development of eosinophilia-myalgia syndrome. The presence of eosinophilia is a core feature of eosinophilia-myalgia syndrome, along with unusually severe myalgia (muscle pain). It is thought that both tryptophan and certain unidentified tryptophan contaminants may contribute to eosinophilia-myalgia syndrome ³⁰. It has also been suggested that excessive tryptophan or elevation of its metabolites could play a role in amplifying some of the pathological features of eosinophilia-myalgia syndrome ³¹. This pathological damage is further augmented by metabolites of the kynurenine pathway (a tryptophan degradation pathway).

Tryptophan and depression

Tryptophan depletion studies in never-depressed individuals are variable, with no or little overall effect on lowering of mood ³². Interestingly, reports of moderate mood lowering are seen more often in studies with healthy women than in studies with healthy men ³³. However in never-depressed healthy volunteers who are at high risk for depression through a familial risk factor, acute tryptophan depletion produces clear abnormalities in mood control ³⁴. Finally, in depressed patients in remission, temporarily lowering tryptophan levels can result in an acute depressive relapse ³⁵ with transient exacerbation of symptoms associated with patients taking serotonergic anti-depressants ³⁶. These studies reveal that subjects with a pre-existing vulnerability in the serotonergic system may be most susceptible to a tryptophan challenge. Moreover, low serotonin can indeed contribute to a lowered mood state, however this cannot occur in isolation—it must be in concert with some other unknown system (perhaps neurotransmitter or genetic) that interacts with the reduced serotonin to decrease mood ³⁷.

A comprehensive meta-analysis of over fifty tryptophan depletion studies in man from 1966 through to 2008 was published by Mendelsohn and colleagues in 2009 ³⁸. The effects of acute tryptophan depletion on psychomotor processing, declarative memory, working memory, executive functions, and attention were evaluated with the most robust finding that lowering tryptophan impaired the consolidation of episodic memory for verbal information ³⁹. Semantic memory appeared to be unaffected by acute tryptophan depletion as were verbal, spatial, and affective working memory, executive function, and attention ³⁸.

Many of the studies covered in the Mendelsohn et al. review ³⁸ focus on healthy volunteers, or those with susceptibility to depression. Latter work published after Mendelsohn’s review has demonstrated some interesting findings concerning emotional processing. In a small study of depressed patients, a bimodal symptom response to acute tryptophan depletion was shown to be preceded by a bimodal emotional processing bias in the same direction; that is, patients whose depressive symptoms improved 24 hour after depletion showed more positive emotional processing bias 5 hour after depletion, while the reverse was true for patients whose mood symptoms worsened ⁴⁰. Asymptomatic individuals at high familial risk for depression also showed abnormalities in emotional processing while undergoing acute tryptophan depletion ³⁴. Interestingly in normal subjects, acute tryptophan depletion elicited significantly lower intensity and arousal ratings for angry faces in an unconscious perception task ⁴¹. In another study involving tryptophan depletion in postmenopausal women, there was an increase in brain activation in the orbital frontal cortex and bilateral amygdala, as measured by functional magnetic resonance imaging, during an emotional processing task as compared to untreated controls ⁴².

Manipulating central tryptophan levels using acute tryptophan depletion is also used as a tool to investigate the role of serotonin in neurological disorders. In Parkinson’s disease patients, a demonstrable reduction in global cognitive function and verbal recognition during acute tryptophan depletion is observed compared with placebo and control patients suggesting an interaction between serotonergic and cholinergic impairment ⁴³. No deficits in memory were observed in tryptophan-depleted young persons with attention deficit hyperactivity disorder ⁴⁴, in reward response tests with alcoholic males ⁴⁵, or in cognitive testing of Alzheimer’s patients that could not be attributed to old age ⁴⁶. Interestingly it was observed that the detrimental effects of acute tryptophan depletion on working memory were more common in an elderly, compared to young, group of healthy volunteers ³².

Manipulating tryptophan levels using acute tryptophan depletion has also been used to investigate the role of serotonin in other disorders. Kennedy and colleagues have used acute tryptophan depletion to demonstrate that impaired hippocampal-mediated cognitive performance in irritable bowel syndrome ⁴⁷ is modulated by peripheral tryptophan levels ⁴⁸. Moreover, in breast cancer survivors, acute tryptophan depletion was used to model serotonin loss which is a common side effect of oestrogen withdrawal in this disease population. This study demonstrated specific impairment in episodic memory and motor speed suggesting a critical role for serotonin in cognitive impairment in these patients ⁴⁹.

L-tryptophan and depression

In 13 adults with recovered depression, tryptophan depletion by a tryptophan-free drink was associated with shorter rapid eye movement (REM) latency (i.e. time span between bedtime and start of REM sleep) as compared to the control drink ⁵⁰. The evidence relating tryptophan to mental well-being is presently mixed. A meta-analysis ⁵¹ and a 2002 Cochrane review ⁵² concluded that supplementation with tryptophan or serotonin significantly improved depressive symptoms as compared to the placebo treatment in patients with depression. This was further confirmed in a mega-analysis of five trials concluding that acute tryptophan depletion evokes depressive symptoms in 50% of the remitted depressed patients ⁵³. However, a separate review of 13 trials in healthy and depressed adults, indicated mixed results and no clear conclusion ¹.

Studies of tryptophan in combination with electroconvulsive therapy (ECT) have also produced inconsistent findings. One study demonstrated that patients with depression who received combined doses of tryptophan (3 g/day) and nicotinamide for 4 weeks reported significantly lower ratings of depression compared to those who received electroconvulsive therapy (ECT) twice weekly ⁵⁴. Conversely, in another study, patients with a severe primary depressive illness treated with ECT improved significantly compared to those receiving tryptophan (6 to 8 g) plus pyridoxine daily ⁵⁵. Similarly, patients receiving ECT twice daily improved significantly compared to patients receiving daily doses of combined tryptophan (6 g) and pyridoxine ⁵⁶. In yet another study, there were no significant differences in depressed patients treated with tryptophan alone (6 g/day) compared to ECT alone ⁵⁷.

In contrast to the mixed results of the effects of tryptophan with tricyclic antidepressants or ECT, tryptophan has been shown to be more effective in combination with monoamine oxidase inhibitors (MAOI). For example, depressed patients who were unresponsive to a 60 mg/day dose of the MAOI phenelzine received supplements of 12, 15, or 18 g of tryptophan or placebo. A significantly higher percentage of the patients on the combined therapy (i.e. MAOI plus tryptophan) improved compared to those receiving the MAOI alone or with placebo ⁵⁸. Patients who received a combined therapy of tryptophan (6 g/day) and a different MAOI, nialamide, also improved significantly compared to those who received nialamide alone.185 In another study, compared to patients who received doses of the MAOI tranylcypromine plus placebo for one week, those who received a 214 mg/kg/day supplement of tryptophan reported a significant decrease in depression ratings during that week, as well as during the 2 weeks after tryptophan supplements were discontinued ⁵⁹.

Although the results of the therapeutic combination of tryptophan with MAOIs have demonstrated the most successful results for treatment of depression, most clinical studies have produced mixed results as to the efficacy of tryptophan for treatment of depression ⁶⁰. These mixed results are due, in part, to flawed study designs and trials using insufficient lengths of time to allow determination of efficacy. Methodological differences such as inconsistent diagnostics within and across studies ²¹ have also produced mixed results. Taken together, there is evidence that tryptophan is effective for ameliorating mild to moderate depressive symptoms, but not severe depressive symptoms ⁶¹.

L-tryptophan and sleep

The relationship between tryptophan and sleep quality has, to date, only been investigated in intervention trials. A review including 21 trials in humans with and without sleep disorders concluded that increasing brain tryptophan by dietary treatments appeared to improve subjective measures of sleepiness and reduce sleep latency (i.e. time span between bedtime and sleep onset) ¹. This improved quality of sleep is associated with an improvement in hedonic and cognitive measures ⁶², improved morning alertness and brain measures of attention ⁶³. In addition, a 7-day trial with tryptophan-enriched cereals at breakfast and dinner showed beneficial effects on sleep/wake cycle in 35 elderly with sleep problems ⁶⁴.

Acute tryptophan depletion studies in humans demonstrate inhibition of rapid eye movement (REM) latency and prolonged REM sleep ⁶⁵, with further work from animal studies demonstrating the importance of serotonin in this association [88]. Serotonin is also a precursor to melatonin in the pineal gland.

Patients with depression suffer from poor sleep quality ⁶⁶, with associated antidepressant treatment often exacerbating sleep inefficiency with insomnia and decreased total sleep time being common side-effects ⁶⁷. The effect of tryptophan depletion on sleep in depression has largely focused on remitted patients, who were still taking antidepressants, tryptophan depletion resulted in reduced sleep and REM latencies but increased density ⁶⁸, demonstrating that depleting tryptophan did not alter the antidepressant side-effects. Interestingly, in a population of patients with obsessive compulsive disorder (OCD), tryptophan depletion induced a worsening of sleep continuity, but no changes of REM or slow wave sleep ⁶⁹.

Tryptophan supplement benefits

L-tryptophan supplement is possibly effective for:

• Premenstrual dysphoric disorder. Taking 6 grams of L-tryptophan per day seems to decrease mood swings, tension, and irritability in women with premenstrual dysphoric disorder.
• To help people quit smoking. Taking L-tryptophan seems to help people quit smoking when used with conventional treatment.

L-tryptophan supplement is possibly ineffective for:

• Teeth grinding (bruxism). Taking L-tryptophan by mouth doesn’t help treat teeth grinding.
• Facial pain. Taking L-tryptophan by mouth doesn’t help reduce facial pain.

Insufficient evidence to rate effectiveness for:

• Improving athletic ability. Some research shows that taking L-tryptophan for 3 days before exercising can improve power during exercise. This improvement in power helps increase the distance an athlete can go in the same amount of time. But other early research shows that taking L-tryptophan during exercise doesn’t improve endurance during a cycling exercise. Reasons for the conflicting results are not clear. It is possible that L-tryptophan improves some measures of athletic ability but not others. On the other hand, L-tryptophan might need to be taken for a few days before exercise in order to see any benefit.
• Attention deficit-hyperactivity disorder (ADHD). There is some evidence that L-tryptophan levels are lower in children with ADHD. But taking L-tryptophan supplements does not appear to improve ADHD symptoms.
• Problems with mental function in the elderly. Taking a mixture of L-tryptophan and other ingredients can slightly improve mental function in older people. But the improvement is very small, so it might not be meaningful. Also, it’s not known if any potential benefit is due to L-tryptophan or another ingredient.
• Depression. Early research suggests that L-tryptophan might improve the effectiveness of common medications for depression.
• Healing ulcers caused by the bacteria Helicobacter pylori (H pylori). Research shows that taking L-tryptophan in combination with the ulcer medication omeprazole improves ulcer healing rates compared to taking omeprazole alone.
• Treating sleep disorders. Taking L-tryptophan might decrease the amount of time it takes to fall asleep and improve mood in healthy people with sleep problems.
• Seasonal affective disorder (SAD). Early research suggests L-tryptophan might be helpful in SAD.
• Treating sleep apnea. There is some evidence that taking L-tryptophan might decrease episodes in some people who periodically stop breathing during sleep (sleep apnea).
• Anxiety.
• Other conditions.

More evidence is needed to rate L-tryptophan for these uses.

L-tryptophan dosage

The following doses have been studied in scientific research:

Adults By mouth:

• Premenstrual dysphoric disorder: Doses of 6 grams of L-tryptophan have been taken daily from ovulation to the third day of the period.
• To help people quit smoking: Doses of 50 mg/kg of L-tryptophan have been taken daily.
• For depression: Adults 8 to 12 grams per day, given in 3 to 4 equally divided doses
• Evening oral doses of tryptophan as low as 250 mg have been shown to improve sleep quality, although the typical dosage range for sleep disorders is 1-3 g daily. Safe and effective dosages for other disorders range from 0.5-4 g daily, while potentially higher doses (50 mg/kg/day) have been used short term as a smoking cessation intervention.

The intraperitoneal median lethal dose of tryptophan was determined to be 1600 mg/kg body weight in rats but was drastically decreased to a median lethal dose of 11–25 mg/kg body weight when corticosteroid production was inhibited ⁷⁰. These observations suggested that the rate of tryptophan catabolism is a factor in the excess dietary intake that results in adverse effects. Thus, the upper limit of tryptophan catabolism may be a possible marker of the intake above which increasing intake increases the risk of adverse effects. In the rat experiment ⁷⁰, the urinary excretory ratio of anthranilic acid:kynurenic acid was specified as a possible marker of the intake above which increasing intake increases the risk of adverse effects.

In rat ⁷¹ and pig ⁷⁰ studies with tryptophan, symptoms of excess tryptophan intake in pigs ⁷⁰ include reduced food intake and growth rate, which were described as manifestations of amino acid imbalance. In growing animals, it appears that tryptophan intakes of >10 times the requirement are necessary before there are detrimental effects on growth performance ⁷². Symptoms of tryptophan excess may include development of fatty liver and fibrotic changes in muscles, lung, and pancreas and the serotonin syndrome (in rats: tremors, hyper-reactivity, hyper-tonicity). Similar to leucine ⁷³, the effects of tryptophan excess are attenuated by higher protein intake. Although the dietary tryptophan requirement appears to vary widely across species when compared on the basis of g/kg body weight or g/kg of diet, the ratio of tryptophan:lysine requirement is fairly similar in many mono-gastric species. The small differences among species are more likely due to differences in techniques and outcome measurements than a true difference in the ratio of tryptophan:lysine in body proteins ⁷².

Tryptophan supplement side effects

L-tryptophan can cause some side effects such as heartburn, stomach pain, belching and gas, nausea, vomiting, diarrhea, and loss of appetite. L-tryptophan can also cause headache, lightheadedness, drowsiness, dry mouth, visual blurring, muscle weakness, dry mouth, blurred vision, sedation, euphoria, and nystagmus (involuntary eye movements) and sexual problems ⁷⁴.

It was also noted, that because tryptophan raises brain serotonin production, its ingestion with drugs that stimulate serotonin function (e.g., certain antidepressants, monoamine oxidase inhibitors) can produce a medically important condition termed the “serotonin syndrome,” for which medical attention is required. Serotonin syndrome is a potentially life-threatening drug reaction. It causes the body to have too much serotonin ⁷⁵.

You can develop serotonin syndrome if you take tryptophan supplement together with antidepressants called selective serotonin reuptake inhibitors (SSRIs), selective serotonin/norepinephrine reuptake inhibitors (SSNRIs) and monoamine oxidase inhibitors.

Common selective serotonin reuptake inhibitors (SSRIs) include citalopram (Celexa), sertraline (Zoloft), fluoxetine (Prozac), paroxetine (Paxil), and escitalopram (Lexapro). Selective serotonin/norepinephrine reuptake inhibitors (SSNRIs) include duloxetine (Cymbalta) and venlafaxine (Effexor). Common monoamine oxidase inhibitors include isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Emsam) and tranylcypromine (Parnate).

If you take these medicines, be sure to read the warning on the packaging. It tells you about the potential risk of serotonin syndrome. However, do not stop taking your medicine. Talk to your doctor about your concerns first.

People with serotonin syndrome will likely stay in the hospital for at least 24 hours for close observation.

Serotonin syndrome treatment may include:

• Benzodiazepine medicines, such as diazepam (Valium) or lorazepam (Ativan) to decrease agitation, seizure-like movements, and muscle stiffness
• Cyproheptadine (Periactin), a drug that blocks serotonin production
• Intravenous (through the vein) fluids
• Withdrawal of medicines that caused the syndrome

In life-threatening cases, medicines that keep the muscles still (paralyze them), and a temporary breathing tube and breathing machine will be needed to prevent further muscle damage.

Serotonin syndrome prognosis

People may get slowly worse and can become severely ill if not quickly treated. Untreated, serotonin syndrome can be deadly. With treatment, symptoms usually go away in less than 24 hours.

Uncontrolled muscle spasms can cause severe muscle breakdown. The products produced when the muscles break down are released into the blood and eventually go through the kidneys. This can cause severe kidney damage if serotonin syndrome isn’t recognized and treated properly.

Serotonin syndrome symptoms occur within minutes to hours, and may include ⁷⁵:

• Agitation or restlessness
• Diarrhea
• Fast heartbeat and high blood pressure
• Hallucinations
• Increased body temperature
• Loss of coordination
• Nausea and vomiting
• Overactive reflexes
• Rapid changes in blood pressure

Special precautions and warnings

Pregnancy and breast-feeding: L-tryptophan is likely UNSAFE in pregnancy because it may harm the unborn child. Not enough is known about the safety of L-tryptophan during breast-feeding. Avoid using L-tryptophan during pregnancy and breast-feeding.

A white blood cell disorder called eosinophilia: L-tryptophan might make this condition worse. L-tryptophan has been associated with the development of eosinophilia-myalgia syndrome (EMS).

Liver or kidney disease: L-tryptophan might make these conditions worse since it has been associated with the development of eosinophilia-myalgia syndrome (EMS).

Eosinophilia myalgia syndrome

In 1989, reports began appearing that over-the-counter tryptophan use was associated with a serious condition, eosinophilia myalgia syndrome ⁷⁴. High levels of tryptophan have also been implicated in eosinophilia-myalgia syndrome, an incurable and sometimes fatal flu-like neurological condition linked to the ingestion of large amounts of L-tryptophan. Eosinophilia myalgia syndrome is a neurological condition with symptoms that include fatigue; intense muscle pain; nerve pain; skin changes; baldness; rash; and pain and swelling affecting the joints, connective tissue, lungs, heart, and liver. Symptoms tend to improve over time, but some people may still experience symptoms up to 2 years after they develop eosinophilia myalgia syndrome. Some people report that their symptoms have never gone away completely. The risk of developing eosinophilia-myalgia syndrome increases with larger doses of tryptophan and increasing age. Some research suggests that certain genetic polymorphisms may be related to the development of eosinophilia-myalgia syndrome. The presence of eosinophilia is a core feature of eosinophilia-myalgia syndrome, along with unusually severe myalgia (muscle pain). It is thought that both tryptophan and certain unidentified tryptophan contaminants may contribute to eosinophilia-myalgia syndrome ³⁰. It has also been suggested that excessive tryptophan or elevation of its metabolites could play a role in amplifying some of the pathological features of eosinophilia-myalgia syndrome ³¹. This pathological damage is further augmented by metabolites of the kynurenine pathway (a tryptophan degradation pathway).

Over a period of several months, the Centers for Disease Control and Prevention (CDC) identified 1531 eosinophilia-myalgia syndrome cases and 37 deaths in the U.S. population; given the seriousness of the condition, the FDA banned over-the-counter tryptophan ⁷⁶. Once the ban was in place, eosinophilia-myalgia syndrome occurrence dropped to zero. Eosinophilia-myalgia syndrome symptoms were a high peripheral eosinophil count and disabling myalgias (note that the side effect profile associated with tryptophan use prior to 1989 does not overlap with these symptoms.) It subsequently became evident that almost all cases were traceable to the tryptophan produced by a single company (about 95% of all eosinophilia-myalgia syndrome cases were traced to L-tryptophan produced by a single manufacturer in Japan). Cases of eosinophilia-myalgia syndrome were not associated with the use of tryptophan from other manufacturers ⁷⁷. A contaminant in the tryptophan, rather than tryptophan itself, was therefore considered the likely cause. Multiple contaminants were found in the suspected lot of tryptophan ⁷⁸, but none faithfully reproduced eosinophilia-myalgia syndrome in animals. Currently, under the Dietary Supplement Health and Education Act (DSHEA) of 1994, L-tryptophan is available and marketed as a dietary supplement.

Interactions with medications

Major interactions

Do NOT take this combination.

Sedative medications (CNS depressants)

L-tryptophan might cause sleepiness and drowsiness. Medications that cause sleepiness are called sedatives. Taking L-tryptophan along with sedative medications might cause too much sleepiness.

Some sedative medications include clonazepam (Klonopin), lorazepam (Ativan), phenobarbital (Donnatal), zolpidem (Ambien), and others.

Moderate interactions

Be cautious with this combination.

Dextromethorphan (Robitussin DM, and others)

• L-tryptophan can affect a brain chemical called serotonin. Dextromethorphan (Robitussin DM, others) can also affect serotonin. Taking L-tryptophan along with dextromethorphan (Robitussin DM, others) might cause there to be too much serotonin in the brain and serious side effects including heart problems, shivering and anxiety could occur. Do not take L-tryptophan if you are taking dextromethorphan (Robitussin DM, others).

Medications for depression (Antidepressant drugs)

• L-tryptophan increases a brain chemical called serotonin. Some medications for depression also increase the brain chemical serotonin. Taking L-tryptophan along with these medications for depression might increase serotonin too much and cause serious side effects including heart problems, shivering, and anxiety. Do not take L-tryptophan if you are taking medications for depression.

Some of these medications for depression include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), amitriptyline (Elavil), clomipramine (Anafranil), imipramine (Tofranil), and others.

Medications for depression (MAOIs)

• L-tryptophan increases a chemical in the brain. This chemical is called serotonin. Some medications used for depression also increase serotonin. Taking L-tryptophan with these medications used for depression might cause there to be too much serotonin. This could cause serious side effects including heart problems, shivering, and anxiety.

Some of these medications used for depression include phenelzine (Nardil), tranylcypromine (Parnate), and others.

Meperidine (Demerol)

L-tryptophan increases a chemical in the brain called serotonin. Meperidine (Demerol) can also increase serotonin in the brain. Taking L-tryptophan along with meperidine (Demerol) might cause too much serotonin in the brain and serious side effects including heart problems, shivering, and anxiety.

Pentazocine (Talwin)

L-tryptophan increases a brain chemical called serotonin. Pentazocine (Talwin) also increases serotonin. Taking L-tryptophan along with pentazocine (Talwin) might cause serious side effects including heart problems, shivering, and anxiety. Do not take L-tryptophan if you are taking pentazocine (Talwin).

Phenothiazines

Taking L-tryptophan with phenothiazines can cause serious side effects including movement disorders.

Some phenothiazines include chlorpromazine (Thorazine), fluphenazine (Prolixin), trifluoperazine (Stelazine), thioridazine (Mellaril), and others.

Sedative medications (Benzodiazepines)

Sedative medications can affect the nervous system. L-tryptophan can also affect the nervous system. Taking L-tryptophan along with sedative medications can cause serious side effects. Do not take L-tryptophan if you are taking sedative medications.

Some of these sedative medications include clonazepam (Klonopin), diazepam (Valium), lorazepam (Ativan), and others.

Tramadol (Ultram)

Tramadol (Ultram) can affect a chemical in the brain called serotonin. L-tryptophan can also affect serotonin. Taking L-tryptophan along with tramadol (Ultram) might cause too much serotonin in the brain and side effects including confusion, shivering, and stiff muscles could result.

Interactions with herbs and supplements

Herbs and supplements that act like sedatives

• L-tryptophan can cause drowsiness and relaxation. Using it along with other herbs and supplements that also have sedative effects might cause too much drowsiness. Some of these herbs and supplements include 5-HTP, calamus, California poppy, catnip, hops, Jamaican dogwood, kava, St. John’s wort, skullcap, valerian, yerba mansa, and others.

Herbs and supplements that increase serotonin levels

• L-tryptophan seems to raise the level of serotonin, a hormone that transmits signals between nerve cells and affects mood. There is a concern that using it with other herbs and supplements that increase serotonin, might increase the effects and side effects of those herbs and supplements. Some of those include 5-HTP, Hawaiian baby woodrose, and S-adenosylmethionine (SAMe).

St. John’s wort

• Combining L-tryptophan with St. John’s wort might increase the risk of serotonin syndrome, a possibly fatal condition that occurs when there is too much serotonin in the body. There is a report of serotonin syndrome in a patient who took L-tryptophan and high doses of St. John’s wort.

Tryptophan rich foods

Table 2. Foods high in tryptophan (ordered from highest to low)

Description	Tryptophan (g) Value Per 100 grams
Egg, white, dried, stabilized, glucose reduced	1.43
Egg, white, dried, powder, stabilized, glucose reduced	1.27
Egg, white, dried, flakes, stabilized, glucose reduced	1.18
Soy protein isolate	1.12
Soy protein isolate, potassium type	1.12
Seeds, sesame flour, low-fat	1.1
Egg, white, dried	1
Seaweed, spirulina, dried	0.93
Seeds, sesame flour, partially defatted	0.88
Soy protein concentrate, produced by alcohol extraction	0.83
Soy protein concentrate, produced by acid wash	0.83
Whale, beluga, meat, dried (Alaska Native)	0.8
Egg, whole, dried	0.78
Egg, whole, dried, stabilized, glucose reduced	0.77
Winged beans, mature seeds, raw	0.76
Seeds, cottonseed flour, low fat (glandless)	0.75
Tofu, dried-frozen (koyadofu)	0.75
Tofu, dried-frozen (koyadofu), prepared with calcium sulfate	0.75
Seeds, cottonseed meal, partially defatted (glandless)	0.74
Seeds, sunflower seed flour, partially defatted	0.73
Beverages, Protein powder soy based	0.72
Fish, cod, Atlantic, dried and salted	0.7
Soy flour, defatted	0.68
Seeds, sesame flour, high-fat	0.67
Soy meal, defatted, raw	0.65
Pork, fresh, variety meats and by-products, pancreas, cooked, braised	0.62
Seeds, cottonseed flour, partially defatted (glandless)	0.62
Mollusks, whelk, unspecified, cooked, moist heat	0.62
Soybeans, mature seeds, raw	0.59
Seeds, pumpkin and squash seed kernels, dried	0.58
Soybeans, mature seeds, dry roasted	0.57
Meat extender	0.57
Seeds, pumpkin and squash seed kernels, roasted, without salt	0.57
Seeds, pumpkin and squash seed kernels, roasted, with salt added	0.57
Cheese, parmesan, shredded	0.56
Cheese, mozzarella, low moisture, part-skim	0.55
Cheese, cheddar (Includes foods for USDA’s Food Distribution Program)	0.55
Game meat, elk, cooked, roasted	0.55
Leavening agents, yeast, baker’s, active dry	0.54
Parsley, freeze-dried	0.52
Cheese, mozzarella, whole milk	0.52
Soybeans, mature seeds, roasted, salted	0.51
Soybeans, mature seeds, roasted, no salt added	0.51
Milk, dry, nonfat, regular, without added vitamin A and vitamin D	0.51
Milk, dry, nonfat, regular, with added vitamin A and vitamin D	0.51
Peanut flour, defatted	0.51
Soy flour, full-fat, roasted	0.51
Soy flour, full-fat, raw	0.5
Milk, dry, nonfat, calcium reduced	0.5
Milk, dry, nonfat, instant, with added vitamin A and vitamin D	0.49
Milk, dry, nonfat, instant, without added vitamin A and vitamin D	0.49
Seeds, cottonseed kernels, roasted (glandless)	0.49
Milk, buttermilk, dried	0.48
Cheese, parmesan, hard	0.48
Spices, parsley, dried	0.47
Pork, cured, bacon, cooked, microwaved	0.46
Game meat, caribou, cooked, roasted	0.46
Seeds, chia seeds, dried	0.44
Game meat, rabbit, wild, cooked, stewed	0.44
Cheese, romano	0.43
Cheese, gruyere	0.42
Lamb, shoulder, arm, separable lean only, trimmed to 1/4″ fat, choice, cooked, braised	0.41
T.G.I. FRIDAY’S, classic sirloin steak (10 oz)	0.41
Game meat, elk, raw	0.41
CRACKER BARREL, grilled sirloin steak	0.41
Pork, ground, 96% lean / 4% fat, cooked, pan-broiled	0.41
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	0.41
Pork, fresh, variety meats and by-products, pancreas, raw	0.41
Pork, cured, bacon, pre-sliced, cooked, pan-fried	0.41
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	0.41
Beef, round, top round, separable lean only, trimmed to 0″ fat, choice, cooked, braised	0.41
Beef, round, top round, separable lean only, trimmed to 0″ fat, select, cooked, braised	0.41
Chicken, broiler or fryers, breast, skinless, boneless, meat only, cooked, braised	0.4
Goose, domesticated, meat only, cooked, roasted	0.4
Seeds, safflower seed meal, partially defatted	0.4
Game meat, goat, cooked, roasted	0.4
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	0.4
Cheese, swiss	0.4
Game meat, rabbit, domesticated, composite of cuts, cooked, stewed	0.4
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	0.4
Duck, young duckling, domesticated, White Pekin, leg, meat only, bone in, cooked without skin, braised	0.4
Beef, plate steak, boneless, inside skirt, separable lean only, trimmed to 0″ fat, select, cooked, grilled	0.4
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, choice, cooked, braised	0.4
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, select, cooked, braised	0.4
Lamb, Australian, imported, fresh, shoulder, arm, separable lean only, trimmed to 1/8″ fat, cooked, braised	0.4
Cereals ready-to-eat, wheat germ, toasted, plain	0.4
Lamb, New Zealand, imported, frozen, shoulder, whole (arm and blade), separable lean only, cooked, braised	0.4
Seeds, sesame butter, paste	0.4
Pork, ground, 96% lean / 4% fat, cooked, crumbles	0.39
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, grilled	0.39
Lamb, cubed for stew or kabob (leg and shoulder), separable lean only, trimmed to 1/4″ fat, cooked, braised	0.39
Seeds, sesame butter, tahini, from unroasted kernels (non-chemically removed seed coat)	0.39
Restaurant, family style, sirloin steak	0.39
Spices, fenugreek seed	0.39
Egg, yolk, dried	0.39
Chicken, broilers or fryers, breast, meat only, cooked, fried	0.39
Seeds, watermelon seed kernels, dried	0.39
Seeds, sesame butter, tahini, from raw and stone ground kernels	0.39
Beef, top loin filet, boneless, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	0.39
Seeds, sesame seeds, whole, dried	0.39
Beef, round, top round, separable lean and fat, trimmed to 1/8″ fat, select, cooked, braised	0.39
Beef, loin, top loin steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	0.39
Chicken, stewing, light meat, meat only, cooked, stewed	0.39
Pork, fresh, loin, tenderloin, separable lean only, cooked, broiled	0.39
Beef, loin, top loin steak, boneless, lip off, separable lean only, trimmed to 0″ fat, select, cooked, grilled	0.39
Chicken, broiler or fryers, breast, skinless, boneless, meat only, cooked, grilled	0.39
Beef, round, top round, separable lean and fat, trimmed to 1/8″ fat, all grades, cooked, braised	0.39
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, braised	0.39
Beef, round, eye of round steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	0.39
Game meat, rabbit, domesticated, composite of cuts, cooked, roasted	0.38
Cheese, parmesan, grated	0.38
Chicken, broilers or fryers, light meat, meat only, cooked, fried	0.38
Lamb, shoulder, whole (arm and blade), separable lean only, trimmed to 1/4″ fat, choice, cooked, braised	0.38
Beef, loin, top sirloin petite roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	0.38
Beef, round, top round, separable lean and fat, trimmed to 1/8″ fat, choice, cooked, braised	0.38
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, braised	0.38
Beef, rib, back ribs, bone-in, separable lean only, trimmed to 0″ fat, select, cooked, braised	0.38
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	0.38
Duck, young duckling, domesticated, White Pekin, breast, meat only, boneless, cooked without skin, broiled	0.38
Game meat, boar, wild, cooked, roasted	0.38
DENNY’S, top sirloin steak	0.38
Lamb, shoulder, blade, separable lean only, trimmed to 1/4″ fat, choice, cooked, braised	0.38
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, braised	0.38
Beef, rib eye steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	0.38
Beef, rib eye steak, boneless, lip off, separable lean only, trimmed to 0″ fat, select, cooked, grilled	0.38
Beef, shank crosscuts, separable lean only, trimmed to 1/4″ fat, choice, cooked, simmered	0.38
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	0.38
Pork, fresh, loin, tenderloin, separable lean and fat, cooked, broiled	0.38
Snacks, soy chips or crisps, salted	0.38
Fish, roe, mixed species, cooked, dry heat	0.38
Beef, rib eye roast, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, roasted	0.38
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	0.38
Pork, fresh, leg (ham), whole, separable lean only, cooked, roasted	0.37
Pork, fresh, loin, center rib (chops), boneless, separable lean only, cooked, broiled	0.37
Pork, fresh, composite of trimmed retail cuts (loin and shoulder blade), separable lean only, cooked	0.37
Beef, plate steak, boneless, outside skirt, separable lean only, trimmed to 0″ fat, select, cooked, grilled	0.37
Chicken, broilers or fryers, giblets, cooked, fried	0.37
Beef, chuck for stew, separable lean and fat, choice, cooked, braised	0.37
Turkey, retail parts, wing, meat only, cooked, roasted	0.37
Chicken, broiler or fryers, breast, skinless, boneless, meat only, with added solution, cooked, grilled	0.37
Ham and cheese spread	0.37
Seeds, sesame butter, tahini, from roasted and toasted kernels (most common type)	0.37
Veal, leg (top round), separable lean only, cooked, braised	0.37
Beef, chuck for stew, separable lean and fat, all grades, cooked, braised	0.37
Milk, dry, whole, with added vitamin D	0.37
Milk, dry, whole, without added vitamin D	0.37
Seeds, sesame seeds, whole, roasted and toasted	0.37
Seeds, sesame seed kernels, toasted, without salt added (decorticated)	0.37
Seeds, sesame meal, partially defatted	0.37
Seeds, sesame seed kernels, toasted, with salt added (decorticated)	0.37

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What is lysine

Lysine or L-lysine is one of nine essential amino acids (building block of protein) in humans required for growth and tissue repair. The human body cannot synthesize lysine, so it is essential in humans and must be obtained from the diet. For all amino acids, including L-lysine, only the L isomer is used in protein synthesis ¹ and can pass across the blood-brain barrier ². Lysine is supplied by many foods, especially red meats, fish, and dairy products (see Table 1 below). Normal requirements for lysine have been found to be about 8 g per day or 12 mg/kg body weight in adults. Children and infants need more, 44 mg/kg per day for an eleven to-twelve-year old, and 97 mg/kg per day for three-to six-month old ³. Lysine is highly concentrated in muscle compared to most other amino acids. Lysine is high in foods such as wheat germ, cottage cheese and chicken. Of meat products, wild game and pork have the highest concentration of lysine. Fruits and vegetables contain little lysine, except avocados. Normal lysine metabolism is dependent upon many nutrients including niacin, vitamin B6, riboflavin, vitamin C, glutamic acid and iron. Excess arginine antagonizes lysine. Several inborn errors of lysine metabolism are known, such as cystinuria, hyperdibasic aminoaciduria I, lysinuric protein intolerance, propionic acidemia, and tyrosinemia I. Most are marked by mental retardation with occasional diverse symptoms such as absence of secondary sex characteristics, undescended testes, abnormal facial structure, anemia, obesity, enlarged liver and spleen, and eye muscle imbalance.

Lysine deficiency is seen in non-western societies and manifests as protein-energy malnutrition, which has profound and systemic effects on the health of the individual ⁴. This double-blind randomized study in poor peri-urban communities of Accra, Ghana, showed significant benefits of 16 weeks of lysine supplementation on diarrhea morbidity and weight gain in children ⁴. A positive effect of lysine on respiratory disease outcomes was found in men. The results suggest that lysine could be a useful nutritional intervention for decreasing diarrhea morbidity and improving the nutritional status of populations in some developing countries.

Upon digestion from dietary proteins, lysine is transported to the liver from the gut via portal circulation. Its metabolism involves protein synthesis and oxidative catabolism. Lysine catabolism occurs almost exclusively in the liver. It does not undergo transamination ⁵. Lysine is rapidly transported to muscle tissue, and within 5 to 7 hours following ingestion, is highly concentrated in the muscle. Lysine improves calcium assimilation.

Like other amino acids, the metabolism of free lysine follows two principal paths: protein synthesis and oxidative catabolism. Lysine is required for biosynthesis of such substances as carnitine, collagen ⁶ and elastin ⁷. Lysine plays several roles in humans, most importantly proteinogenesis, but also in the crosslinking of collagen polypeptides, uptake of essential mineral nutrients, and in the production of carnitine, which is key in fatty acid metabolism.

A second major role of lysine is in epigenetic regulation by means of histone modification ⁸. There are several types of covalent histone modifications, which commonly involve lysine residues found in the protruding tail of histones. Modifications often include the addition or removal of an acetyl (-CH3CO) forming acetyllysine or reverting to lysine, up to three methyl (‑CH3), ubiquitin or a sumo protein group ⁸. The various modifications have downstream effects on gene regulation, in which genes can be activated or repressed.

Lysine has also been implicated to play a key role in other biological processes including; structural proteins of connective tissues, calcium homeostasis, and fatty acid metabolism ⁶. Lysine has been shown to be involved in the crosslinking between the three helical polypeptides in collagen, resulting in its stability and tensile strength ⁶. This mechanism is akin to the role of lysine in bacterial cell walls, in which lysine (and meso-diaminopimelate) are critical to the formation of crosslinks, and therefore, stability of the cell wall ⁹. Lysine has also been proposed to be involved in calcium intestinal absorption and renal retention, and thus, may play a role in calcium homeostasis ¹⁰. Finally, lysine has been shown to be a precursor for carnitine, which transports fatty acids to the mitochondria, where they can be oxidised for the release of energy ¹¹. Carnitine is synthesised from trimethyllysine, which is a product of the degradation of certain proteins, as such lysine must first be incorporated into proteins and be methylated prior to being converted to carnitine ¹². It must be noted however, that in mammals the primary source of carnitine is through dietary sources, rather than through lysine conversion ¹².

Due to its importance in several biological processes, a lack of lysine can lead to several disease states including defective connective tissues, impaired fatty acid metabolism, anaemia, and systemic protein-energy deficiency. In contrast, an overabundance of lysine, caused by ineffective catabolism, can cause severe neurological issues.

Lysine is present in many forms of dietary supplements. Lysine is also known as L-2,6-diaminohexanoic acid, Lisina, Lys, Lysine Hydrochloride, Lysine Monohydrochloride, and other names.

L-Lysine is a food additive permitted for direct addition to food for human consumption, as long as 1) the quantity of the substance added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food, and 2) any substance intended for use in or on food is of appropriate food grade and is prepared and handled as a food ingredient ¹³.

Lysine has been used in alternative medicine for the prevention and treatment of herpes infections and cold sores due to herpes simplex viruses (HSV) ¹⁴. Lysine itself does not have antiviral properties, but was believed to act by lowering arginine levels (lysine-arginine antagonism). The mechanism underlying this effect is believed to be based on the virus need for amino acid arginine; lysine competes with arginine for absorption and entry into cells. Lysine inhibits herpes simplex virus (HSV) growth by knocking out arginine. Because herpes simplex virus (HSV) proteins are richer in arginine and poorer in lysine than the cells they infect, lysine supplements have been tried as a treatment. Since the two amino acids are taken up in the intestine, reclaimed in the kidney, and moved into cells by the same amino acid transporters, an abundance of lysine would, in theory, limit the amount of arginine available for viral replication ¹⁴. Clinical studies do not provide good evidence for effectiveness as a prophylactic or in the treatment for herpes simplex viruses (HSV) outbreaks ¹⁵, ¹⁶. In response to product claims that lysine could improve immune responses the HSV, a review by the European Food Safety Authority found no evidence of a cause-effect relationship. The same review, published in 2011, found no evidence to support claims that lysine could lower cholesterol, increase appetite, contribute to protein synthesis in any role other than as an ordinary nutrient, or increase calcium absorption or retention ¹⁷.

Lysine also increases the intestinal absorption of calcium and eliminates its renal excretion, suggesting lysine also may be a useful adjunct in the treatment of osteoporosis. Lysine has been investigated for its effects on increasing muscle mass, lowering glucose, and improving anxiety. Case reports suggest lysine may ameliorate angina pectoris. Lysine acetylsalicylate has been used to treat pain and to detoxify the body after heroin use. Lysine clonixinate has been used for its analgesic properties for the treatment of migraine headaches and other painful conditions. However, limited clinical trials exist for these conditions.

Other uses not proven with research have included canker sores, diabetes, stress, and for athletic performance improvement.

It is not certain whether lysine is effective in treating any medical condition including cold sores due to herpes simplex viruses. Medicinal use of this product has not been approved by the FDA. Lysine should not be used in place of medication prescribed for you by your doctor.

Lysine is often sold as an herbal supplement. There are no regulated manufacturing standards in place for many herbal compounds and some marketed supplements have been found to be contaminated with toxic metals or other drugs. Herbal/health supplements should be purchased from a reliable source to minimize the risk of contamination.

Studies of lysine tolerance of human infants have not found adverse effects ¹⁸. In one study, six infants (4 to 11 months of age) were given 60 to 1,080 mg of lysine monohydrochloride per 8 ounces of milk in a series of seven incremental doses for 3 to 4 days at each dose. No behavioral effects were observed, nor was there anorexia, diarrhea, or other signs of gastrointestinal upset, and no evidence of cystinuria. Similarly, no adverse effects were reported when 1- to 5-month-old infants were given up to 220 mg/kg body weight of lysine for 15 days ¹⁸.

Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA) for Lysine for Children Ages 7 Months Through 18 Years

Age and Gender/Amino Acid	Maintenance (mg/kg/day)	Amino Acid Deposition (mg/kg/day)	Total = EAR (mg/kg/day)	RDA (mg/kg/day)
7-12 months, Boys, Girls	31	18	62	89
1-3 years, Boys, Girls	31	8	45	58
4-8 years, Boys, Girls	31	3	37	46
9-13 years, Boys	31	4	37	46
9-13 years, Girls	31	2	35	43
14-18 years, Boys	31	2	35	43
14-18 years, Girls	31	1	32	40

Footnotes:

There are essentially no data with regard to amino acid requirements during pregnancy, so it is generally assumed that indispensable amino acid needs increase in proportion to the increased protein needs during pregnancy. Estimated Average Requirement (EAR) for Pregnancy For all ages: 41 mg/kg/day of lysine.

There are essentially no data with regard to amino acid requirements during lactation, so it is generally assumed that indispensable amino acid needs will increase over the nonlactating needs by the amount of amino acids found in human milk. Estimated Average Requirement (EAR) for Lactation, For all ages: 42 mg/kg/day of lysine

• Recommended Dietary Allowance (RDA): Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.
• Adequate Intake (AI): Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.
• Estimated Average Requirement (EAR): Average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals.
• Tolerable Upper Intake Level (UL): Maximum daily intake unlikely to cause adverse health effects.

[Source ³]

Lysine benefits

Unproven uses and benefits: The most common use of supplemental lysine is for preventing and treating episodes of herpes simplex virus. Lysine has been used in conjunction with calcium to prevent and treat osteoporosis. It has also been used for treating pain, aphthous ulcers, migraine attacks, rheumatoid arthritis, and opiate withdrawal. Many “body-building” formulations contain lysine to aid in muscle repair.

There has been a long discussion that lysine, when administered intravenously or orally, can significantly increase the release of growth hormones ¹⁹. This has led to athletes using lysine as a means of promoting muscle growth while training, however, no significant evidence to support this application of lysine has been found to date ¹⁹.

Experimental Therapy: A major contributing factor to the loss of mobility in elderly people is the gradual and continuous loss of lean body mass. Elderly (76 +/-1.6 years) women (n = 39) and men (n = 38) were recruited for a double-blinded controlled study. Study participants were randomly assigned to either an isonitrogenous control-supplement (n = 37) or a treatment-supplement consisting of beta-hydroxy-beta-methylbutyrate, L-arginine, and L-lysine (n = 40) for the 1-year study ²⁰. In subjects taking the beta-hydroxy-beta-methylbutyrate, L-arginine, and L-lysine supplement, lean tissue increased over the year of study while in the control group, lean tissue did not change. Consumption of a simple amino acid-related cocktail increased protein turnover and lean tissue in elderly individuals in a year-long study ²⁰.

Although high protein diets result in loss of large amounts of calcium in urine, so does lysine deficiency. Lysine may be an adjunct therapy because it reduces calcium losses in urine. Lysine deficiency also may result in immunodeficiency. Requirements for this amino acid are probably increased by stress. Lysine toxicity has not occurred with oral doses in humans. Lysine dosages are presently too small and may fail to reach the concentrations necessary to prove potential therapeutic applications. Lysine metabolites, amino caproic acid and carnitine have already shown their therapeutic potential. Thirty grams daily of amino caproic acid has been used as an initial daily dose in treating blood clotting disorders, indicating that the proper doses of lysine, its precursor, have yet to be used in medicine. Low lysine levels have been found in patients with Parkinson’s, hypothyroidism, kidney disease, asthma and depression. The exact significance of these levels is unclear, yet lysine therapy can normalize the level and has been associated with improvement of some patients with these conditions. Abnormally elevated hydroxylysines have been found in virtually all chronic degenerative diseases and coumadin therapy. The levels of this stress marker may be improved by high doses of vitamin C. Lysine is particularly useful in therapy for marasmus (wasting) and herpes simplex. Dosing has not been adequately studied, but beneficial clinical effects occur in doses ranging from 100 mg to 4 g a day. Higher doses may also be useful, and toxicity has not been reported in doses as high as 8 g per day.

Lysine for cold sores

Human herpesvirus 1 (HSV type 1) and feline herpesvirus 1 (FHSV type 1) are members of different genera (Simplexvirus and Varicellovirus, respectively), but both belong to the alphaherpesvirinae, a subfamily of the herpesviruses ²¹. Publications claiming a positive effect of lysine supplementation on the treatment or prevention of herpes labialis or genitalis outbreaks in humans were at the basis of research on the efficacy of lysine supplementation in cats infected with FHV-1, both in test tubes ²² and in cats ²³, ²⁴. In this section we will therefore critically evaluate all clinical studies investigating the efficacy of lysine supplementation in humans infected with human herpes simplex virus 1 (HSV type 1), in a chronological order.

The first publication suggesting a possible role for lysine in the treatment of herpetic lesions was a letter written by Dr. Kagan ²⁵ in 1974. Four years later a first study appeared, under the leadership of Dr. Kagan, in which the authors claimed a beneficial effect of lysine supplementation on the treatment and prevention of herpes simplex outbreaks ²⁶. However, this study by Griffith et al. ²⁶ was not blind (patients knew which medication they received and what the goal of the study was) and there was no control group receiving a placebo. These types of studies are of no scientific value. Indeed, shortly after this study by Griffith et al. ²⁶ was published, a group in Denmark reported that they were unable to replicate these findings. Milman et al. ²⁷ investigated if lysine supplementation was effective to treat herpetic lesions. The results of this randomized, double-blind, placebo-controlled case–control study in which 119 patients were followed for almost a full year showed there was no difference in the recurrence of herpes outbreaks between the group receiving 1000 mg lysine per day (500 mg twice a day) and the group receiving a placebo ²⁷. Patients were instructed to start taking their pills (for the duration of about a week) when they first started noticing symptoms. The authors argued that they may have missed an effect of lysine in their study because virus replication may have started before the first symptoms were noticed. But also after 65 patients were given 1000 mg lysine (500 mg twice daily) or a placebo every day for a period of almost half a year in a randomized, double-blind, cross-over study (2 × 12 weeks), no prophylactic effect of lysine on the recurrence of herpes simplex labialis (cold sores on lips) was observed ²⁸.

Walsh et al. ²⁹ claimed that lysine reduced the number of attacks and shortened healing time. Walsh et al. ²⁹ article, however, describes the results of a questionnaire given to people who bought lysine in a nutrition store. It was uncontrolled and therefore, like other, similar reports ³⁰, results are not reliable. These papers cannot be used to help determine the efficacy of lysine on the prevention or treatment of herpetic lesions. Despite the poor quality of these articles, some authors, unfortunately, still cite these publications, sometimes selectively, using their untrustworthy results to support their claims.

A small (n = 20), but well controlled (randomized, double-blind, placebo-controlled case–control) study ³¹ in which the effect of 1200 mg lysine per day on recurrence, duration and severity of herpetic lesions was investigated for 4–5 months, confirmed the negative findings of Milman et al. ²⁷. A study performed by McCune et al. ³² had a size (n = 20) and design somewhat similar (double-blind, placebo-controlled cross-over) to the study performed by DiGiovanna et al. ³¹. The authors did not find a positive effect of lysine on healing rate, but did describe that oral ingestion of 1250 mg lysine daily for a period of 24 weeks lowered the number of recurrences when lysine was taken as compared to when the patients took a placebo ³².

Thein and colleagues ³³ were the first to study if there was a correlation between both plasma lysine and arginine levels, and the number of herpetic lesions. In this double-blind, placebo-controlled cross-over study (n = 26) that lasted for 1 year, it was attempted to control for dietary factors to determine efficacy of lysine supplementation, as was also suggested by Algert et al. ³⁴. In all studies, dietary changes were suggested or recommended, but diet has never been well controlled for. Thein et al. ³³ found a reduction in the number of lesions, but it was independent of the treatment type (1 g lysine/day or placebo). It was hypothesized that lysine may be effective only when a certain minimum level of lysine in the plasma is reached. Algert’s paper ³⁴ described that there is no difference in dietary intake for lysine and arginine between a group of patients with initial or recurrent herpes genitalis infections and a control group, although it is not clear how many persons in the control group were latently infected. In addition, the authors mention that the American diet is rich in lysine (6–10 g per day), which makes deficiencies rare since the recommended intake is about 2 g per day ³⁵.

In two randomized, double-blind, placebo-controlled case–control studies, Simon et al. ³⁶ (1 g/day for 3 months, n = 31) and Griffith et al. ³⁷ (3 g/day for 6 months, n = 52) claimed positive results of lysine supplementation. However, both studies compared the number of herpetic outbreaks with self-reported predicted recurrence rates based on the patient’s history, thereby introducing unnecessary bias ³⁸. When the number of outbreaks was compared between the group that received 3000 mg lysine daily and the group receiving a placebo, no difference was seen ³⁷. No new study results on this subject were published after this publication in 1987 ²¹.

In addition to the small sample sizes, poor study designs and improper analyses, scientists have other concerns that need to be addressed. Several of the researchers who published about lysine and herpes simplex virus-1 held a position at a pharmaceutical company manufacturing lysine supplements (Lilly and GNC), and therefore there was a conflict of interest. All their publications described a positive effect of lysine supplementation. Furthermore, there may be a publication bias, since journals are less willing to reports negative findings (e.g. a study describing the absence of an effect) than studies with statistically significant results ³⁹. There may have been other research groups that were unable to demonstrate the efficacy of lysine, whose results were not published.

Lysine supplementation is not effective for the treatment or prevention of herpetic lesions in humans infected with human herpesvirus 1 ²¹. Futhermore, 2015 Cochrane Review ¹⁶ found based on available evidence no preventative effects of lysine, LongoVital® supplementation, gamma globulin, herpes virus vaccine, and yellow fever vaccine for cold sores.

Lysine supplement side effects

Gastrointestinal side effects, such as diarrhea, nausea, and abdominal pain, have been reported with lysine ingestion. A case report described the development of Fanconi syndrome and tubulointerstitial nephritis associated with lysine supplementation taken over a 5-year period.

Acute intake of high levels of lysine interferes with dietary protein metabolism and competes with the transport of arginine, suggesting that adverse effects from high levels of lysine are more likely to occur if protein intake or dietary arginine intake is low ¹⁸.

Patients with hypercholesterolemia should be aware that supplemental lysine has been linked to increased cholesterol levels in animal studies. However, other studies have shown lysine can also decrease cholesterol levels ⁷. Increased liver total lipids, triacylglycerol, and cholesterol concentrations were seen in rats fed 5% L-lysine and 15% casein for 2 weeks, an effect that can be reversed by feeding arginine ¹⁸.

Lysine supplementation is contraindicated in patients with hyperlysinemia/hyperlysinuria. Patients with liver and kidney disease should avoid supplementation with lysine ⁷. If use is warranted, patients should consult a health care provider ⁵.

Drug interactions

Concomitant use of calcium supplements with lysine may be associated with increased absorption and reduced elimination of calcium. Aminoglycoside toxicity may be enhanced in patients taking lysine supplementation.

Lysine rich foods

Table 1. Foods high in lysine (ordered from high to low)

Description	Lysine (g) Value Per 100 gram
Whale, beluga, meat, dried (Alaska Native)	6.31
Egg, white, dried, stabilized, glucose reduced	5.9
Fish, cod, Atlantic, dried and salted	5.77
Egg, white, dried	5.51
Soy protein isolate	5.33
Soy protein isolate, potassium type	5.33
Egg, white, dried, powder, stabilized, glucose reduced	5.08
Egg, white, dried, flakes, stabilized, glucose reduced	4.74
Soy protein concentrate, produced by alcohol extraction	3.93
Soy protein concentrate, produced by acid wash	3.93
Cheese, parmesan, shredded	3.84
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	3.61
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	3.58
Beverages, Protein powder soy based	3.55
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	3.55
Beef, plate steak, boneless, inside skirt, separable lean only, trimmed to 0″ fat, select, cooked, grilled	3.54
Pork, cured, bacon, cooked, microwaved	3.47
Gelatins, dry powder, unsweetened	3.46
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	3.44
Beef, top loin filet, boneless, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	3.44
Beef, loin, top loin steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	3.42
Beef, loin, top loin steak, boneless, lip off, separable lean only, trimmed to 0″ fat, select, cooked, grilled	3.41
Beef, round, eye of round steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	3.4
Beef, loin, top sirloin petite roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	3.39
Beef, rib, back ribs, bone-in, separable lean only, trimmed to 0″ fat, select, cooked, braised	3.38
Beef, rib eye steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	3.34
Beef, rib eye steak, boneless, lip off, separable lean only, trimmed to 0″ fat, select, cooked, grilled	3.34
Egg, whole, dried	3.34
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, grilled	3.32
Beef, rib eye roast, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, roasted	3.31
Cheese, parmesan, hard	3.31
Beef, plate steak, boneless, outside skirt, separable lean only, trimmed to 0″ fat, select, cooked, grilled	3.31
Beef, top loin petite roast, boneless, separable lean only, trimmed to 1/8″ fat, select, cooked, roasted	3.29
Leavening agents, yeast, baker’s, active dry	3.28
Beef, ribeye petite roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	3.27
Beef, loin, top sirloin cap steak, boneless, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	3.27
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	3.26
Egg, whole, dried, stabilized, glucose reduced	3.25
Game meat, beaver, cooked, roasted	3.24
Beef, loin, tenderloin steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	3.24
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	3.23
Beef, rib eye steak, bone-in, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	3.23
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	3.21
Beef, round, top round steak, boneless, separable lean and fat, trimmed to 0″ fat, select, cooked, grilled	3.21
Beef, ribeye filet, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	3.19
Beef, loin, tenderloin roast, separable lean only, boneless, trimmed to 0″ fat, select, cooked, roasted	3.18
Tofu, dried-frozen (koyadofu)	3.16
Tofu, dried-frozen (koyadofu), prepared with calcium sulfate	3.16
Beef, short loin, t-bone steak, bone-in, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	3.15
Beef, plate steak, boneless, inside skirt, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	3.15
Beef, short loin, porterhouse steak, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	3.14
Lamb, shoulder, arm, separable lean only, trimmed to 1/4″ fat, choice, cooked, braised	3.14
Beef, round, eye of round steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	3.14
Game meat, bison, chuck, shoulder clod, separable lean only, cooked, braised	3.13
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	3.13
Soy flour, defatted	3.13
Beef, round, top round steak, boneless, separable lean and fat, trimmed to 0″ fat, all grades, cooked, grilled	3.13
Beef, rib eye roast, bone-in, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, roasted	3.12
Parsley, freeze-dried	3.12
Turkey, retail parts, wing, meat only, cooked, roasted	3.11
Beef, round, top round steak, boneless, separable lean and fat, trimmed to 0″ fat, choice, cooked, grilled	3.11
Beef, loin, top loin steak, boneless, lip off, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	3.1
CRACKER BARREL, grilled sirloin steak	3.1
Chicken, broiler or fryers, breast, skinless, boneless, meat only, cooked, braised	3.08
Beef, top loin filet, boneless, separable lean only, trimmed to 1/8″ fat, all grades, cooked, grilled	3.08
Pork, cured, bacon, cooked, broiled, pan-fried or roasted, reduced sodium	3.07
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, roasted	3.07
Beef, round, top round roast, boneless, separable lean and fat, trimmed to 0″ fat, select, cooked, roasted	3.06
Beef, loin, top sirloin petite roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	3.06
Beef, loin, top loin steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, all grades, cooked, grilled	3.06
Turkey, retail parts, breast, meat only, cooked, roasted	3.04
Pork, cured, bacon, pre-sliced, cooked, pan-fried	3.04
Beef, round, eye of round roast, boneless, separable lean and fat, trimmed to 0″ fat, select, cooked, roasted	3.04
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, roasted	3.04
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, grilled	3.04
Seaweed, spirulina, dried	3.02
Veal, leg (top round), separable lean only, cooked, braised	3.02
Beef, ribeye filet, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	3.02
Lamb, Australian, imported, fresh, shoulder, arm, separable lean only, trimmed to 1/8″ fat, cooked, braised	3.02
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, braised	3.02
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, all grades, cooked, braised	3.01
Lamb, New Zealand, imported, frozen, shoulder, whole (arm and blade), separable lean only, cooked, braised	3.01
Beef, round, top round, separable lean only, trimmed to 0″ fat, choice, cooked, braised	3.01
Beef, round, top round, separable lean only, trimmed to 0″ fat, select, cooked, braised	3.01
Mutton, cooked, roasted (Navajo)	3
Beef, loin, tenderloin steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	3
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, braised	3
Soy meal, defatted, raw	2.99
Beef, round, eye of round steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, grilled	2.98
Beef, rib, back ribs, bone-in, separable lean only, trimmed to 0″ fat, all grades, cooked, braised	2.98
Veal, leg (top round), separable lean and fat, cooked, braised	2.98
Beef, composite of trimmed retail cuts, separable lean only, trimmed to 0″ fat, select, cooked	2.98
Beef, top loin petite roast, boneless, separable lean only, trimmed to 1/8″ fat, all grades, cooked, roasted	2.98
Lamb, cubed for stew or kabob (leg and shoulder), separable lean only, trimmed to 1/4″ fat, cooked, braised	2.98
Beef, plate steak, boneless, inside skirt, separable lean and fat, trimmed to 0″ fat, select, cooked, grilled	2.97
Beef, loin, top sirloin cap steak, boneless, separable lean only, trimmed to 1/8″ fat, all grades, cooked, grilled	2.97
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, braised	2.96
Beef, rib eye roast, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, all grades, cooked, roasted	2.96
Pork, cured, bacon, cooked, baked	2.96
Chicken, broilers or fryers, rotisserie, original seasoning, breast, meat and skin, cooked	2.96
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, choice, cooked, braised	2.96
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, select, cooked, braised	2.96
Beef, short loin, porterhouse steak, separable lean only, trimmed to 1/8″ fat, all grades, cooked, grilled	2.96
Beef, ribeye petite roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	2.96
Beef, round, top round roast, boneless, separable lean and fat, trimmed to 0″ fat, all grades, cooked, roasted	2.96
Beef, rib eye steak, boneless, lip off, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	2.96
Beef, round, bottom round, steak, separable lean only, trimmed to 0″ fat, select, cooked, braised	2.95
Turkey, retail parts, drumstick, meat only, cooked, roasted	2.95
Beef, plate steak, boneless, inside skirt, separable lean only, trimmed to 0″ fat, choice, cooked, grilled	2.95
Veal, shoulder, arm, separable lean only, cooked, braised	2.94
Cheese, romano	2.94
Beef, rib eye steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, all grades, cooked, grilled	2.94
Chicken, broiler or fryers, breast, skinless, boneless, meat only, cooked, grilled	2.94
Beef, chuck, arm pot roast, separable lean only, trimmed to 1/8″ fat, choice, cooked, braised	2.93
Mollusks, whelk, unspecified, cooked, moist heat	2.93
Beef, chuck, arm pot roast, separable lean only, trimmed to 1/8″ fat, all grades, cooked, braised	2.93
Beef, chuck, arm pot roast, separable lean only, trimmed to 1/8″ fat, select, cooked, braised	2.92
Beef, chuck for stew, separable lean and fat, choice, cooked, braised	2.92
Beef, chuck for stew, separable lean and fat, all grades, cooked, braised	2.92
Beef, ribeye cap steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	2.92
Game meat, deer, shoulder clod, separable lean only, cooked, braised	2.91
Beef, round, top round roast, boneless, separable lean and fat, trimmed to 0″ fat, choice, cooked, roasted	2.91
Beef, round, eye of round steak, boneless, separable lean and fat, trimmed to 0″ fat, select, cooked, grilled	2.91
Beef, round, bottom round, steak, separable lean only, trimmed to 1/8″ fat, select, cooked, braised	2.91
Beef, composite of trimmed retail cuts, separable lean only, trimmed to 0″ fat, all grades, cooked	2.91
Lamb, New Zealand, imported, fore-shank, separable lean only, cooked, braised	2.91
Beef, plate steak, boneless, outside skirt, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	2.91
Chicken, broilers or fryers, rotisserie, original seasoning, breast, meat only, cooked	2.91
Beef, round, bottom round, steak, separable lean and fat, trimmed to 0″ fat, select, cooked, braised	2.91
Beef, round, eye of round roast, boneless, separable lean and fat, trimmed to 0″ fat, all grades, cooked, roasted	2.91
Beef, chuck for stew, separable lean and fat, select, cooked, braised	2.9
Beef, round, bottom round, steak, separable lean only, trimmed to 1/8″ fat, all grades, cooked, braised	2.9
Beef, loin, top loin steak, boneless, lip off, separable lean and fat, trimmed to 0″ fat, select, cooked, grilled	2.9
Lamb, shoulder, whole (arm and blade), separable lean only, trimmed to 1/4″ fat, choice, cooked, braised	2.9
Beef, round, bottom round, steak, separable lean only, trimmed to 1/8″ fat, choice, cooked, braised	2.89
Game meat, rabbit, wild, cooked, stewed	2.89
Beef, top loin filet, boneless, separable lean only, trimmed to 1/8″ fat, choice, cooked, grilled	2.89
Beef, loin, tenderloin roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	2.89
Beef, round, eye of round roast, boneless, separable lean and fat, trimmed to 0″ fat, choice, cooked, roasted	2.89
Beef, loin, top sirloin petite roast, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, roasted	2.89
Beef, chuck eye Country-Style ribs, boneless, separable lean only, trimmed to 0″ fat, select, cooked, braised	2.89
Beef, loin, tenderloin steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, grilled	2.89
Beef, loin, top loin steak, boneless, lip off, separable lean only, trimmed to 0″ fat, choice, cooked, grilled	2.88
Turkey, retail parts, breast, meat and skin, cooked, roasted	2.88
Beef, chuck, under blade steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, braised	2.88
Beef, rib eye steak, bone-in, lip-on, separable lean only, trimmed to 1/8″ fat, all grades, cooked, grilled	2.88
Veal, cubed for stew (leg and shoulder), separable lean only, cooked, braised	2.88
Beef, round, top round, separable lean and fat, trimmed to 1/8″ fat, select, cooked, braised	2.88
Beef, round, bottom round, steak, separable lean only, trimmed to 0″ fat, all grades, cooked, braised	2.87
Milk, dry, nonfat, regular, without added vitamin A and vitamin D	2.87

[Source ⁴⁰]

Table 2. Plants with the highest amount of Lysine

Genus species	Common name(s)	Concentration	Area of plant
Cucurbita foetidissima HBK.	Buffalo Gourd	10,130 – 33,000 ppm	Seed
Nasturtium officinale R. BR.	Berro, Watercress	1,340 – 26,800 ppm	Herb
Glycine max (L.) MERR.	Soybean	24,290 – 26,560 ppm	Seed
Ceratonia siliqua L.	Carob, Locust Bean, St.John’s-Bread	26,320 ppm	Seed
Phaseolus vulgaris subsp. var. vulgaris	Black Bean, Dwarf Bean, Field Bean, Flageolet Bean, French Bean, Garden Bean, Green Bean, Haricot, Haricot Bean, Haricot Vert, Kidney Bean, Navy Bean, Pop Bean, Popping Bean, Snap Bean, String Bean, Wax Bean	2,390 – 25,700 ppm	Sprout Seedling
Moringa oleifera LAM.	Ben Nut, Benzolive Tree, Drumstick Tree, Horseradish Tree, Jacinto (Sp.), Moringa, West Indian Ben	5,370 – 25,165 ppm	Shoot
Lens culinaris MEDIK.	Lentil	7,120 – 23,735 ppm	Sprout Seedling
Psophocarpus tetragonolobus (L.) DC.	Asparagus Pea, Goa Bean, Winged Bean	21,360 – 23,304 ppm	Seed
Chenopodium album L.	Lambsquarter	3,540 – 22,550 ppm	Seed
Lens culinaris MEDIK.	Lentil	19,570 – 22,035 ppm	Seed
Lupinus albus L.	White Lupine	19,330 – 21,585 ppm	Seed
Nigella sativa L.	Black Caraway, Black Cumin, Fennel-Flower, Nutmeg-Flower, Roman Coriander	16,200 – 20,700 ppm	Seed
Spinacia oleracea L.	Spinach	1,740 – 20,664 ppm	Plant
Mucuna pruriens (L.) DC.	Cowage, Velvetbean	9,700 – 20,564 ppm	Seed
Acacia farnesiana (L.) WILLD.	Cassie, Huisache, Opopanax, Popinac, Sweet Acacia	3,760 – 20,170 ppm	Leaf
Pisum sativum L.	Pea	2,020 – 19,980 ppm	Fruit
Cucurbita pepo L.	Pumpkin	18,330 – 19,693 ppm	Seed
Vicia faba L.	Broadbean, Faba Bean, Habas	3,660 – 19,265 ppm	Seed
Brassica chinensis L.	Bok-Choy, Celery Cabbage, Celery Mustard, Chinese Cabbage, Chinese Mustard, Chinese White Cabbage, Pak-Choi	890 – 19,019 ppm	Leaf
Phaseolus lunatus L.	Butter Bean, Lima Bean	4,520 – 19,010 ppm	Seed
Petroselinum crispum (MILLER) NYMAN EX A. W. HILLL	Parsley	2,190 – 18,724 ppm	Plant
Asparagus officinalis L.	Asparagus	1,450 – 18,710 ppm	Shoot
Trigonella foenum-graecum L.	Alholva (Sp.), Bockshornklee (Ger.), Fenugreek, Greek Clover, Greek Hay	15,310 – 18,525 ppm	Seed
Vigna radiata (L.) WILCZEK	Green Gram, Mungbean	16,640 – 18,296 ppm	Seed
Lablab purpureus (L.) SWEET	Bonavist Bean, Hyacinth Bean, Lablab Bean	190 – 18,000 ppm	Seed
Triticum aestivum L.	Wheat	15,000 – 18,000 ppm	Plant
Vigna unguiculata subsp. sesquipedalis (L.) VERDC.	Asparagus Bean, Pea Bean, Yardlong Bean	16,460 – 17,975 ppm	Seed
Corchorus olitorius L.	Jew’s Mallow, Mulukiya, Nalta Jute	1,540 – 17,825 ppm	Leaf
Vigna radiata (L.) WILCZEK	Green Gram, Mungbean	1,666 – 17,437 ppm	Sprout Seedling
Vigna angularis (WILLD.) OHWI & H. OHASHI	Adzuki Bean	14,970 – 17,294 ppm	Seed

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