Amino Acids

, Volume 45, Issue 3, pp 419–430 | Cite as

Large neutral amino acids: dietary effects on brain neurochemistry and function

  • John D. Fernstrom
Review Article


The ingestion of large neutral amino acids (LNAA), notably tryptophan, tyrosine and the branched-chain amino acids (BCAA), modifies tryptophan and tyrosine uptake into brain and their conversion to serotonin and catecholamines, respectively. The particular effect reflects the competitive nature of the transporter for LNAA at the blood–brain barrier. For example, raising blood tryptophan or tyrosine levels raises their uptake into brain, while raising blood BCAA levels lowers tryptophan and tyrosine uptake; serotonin and catecholamine synthesis in brain parallel the tryptophan and tyrosine changes. By changing blood LNAA levels, the ingestion of particular proteins causes surprisingly large variations in brain tryptophan uptake and serotonin synthesis, with minimal effects on tyrosine uptake and catecholamine synthesis. Such variations elicit predictable effects on mood, cognition and hormone secretion (prolactin, cortisol). The ingestion of mixtures of LNAA, particularly BCAA, lowers brain tryptophan uptake and serotonin synthesis. Though argued to improve physical performance by reducing serotonin function, such effects are generally considered modest at best. However, BCAA ingestion also lowers tyrosine uptake, and dopamine synthesis in brain. Increasing dopamine function in brain improves performance, suggesting that BCAA may fail to increase performance because dopamine is reduced. Conceivably, BCAA administered with tyrosine could prevent the decline in dopamine, while still eliciting a drop in serotonin. Such an LNAA mixture might thus prove an effective enhancer of physical performance. The thoughtful development and application of dietary proteins and LNAA mixtures may thus produce treatments with predictable and useful functional effects.


Tryptophan Serotonin Brain Diet Exercise 



Anorexia nervosa


Acute tryptophan depletion


Blood–brain barrier


Branched-chain amino acids


Large neutral amino acids


Non-esterified fatty acids


Conflict of interest

The author declares that he has no conflict of interest.


  1. Ashley DV, Barclay DV, Chauffard FA, Moennoz D, Leathwood PD (1982) Plasma amino acid responses in humans to evening meals of differing nutritional composition. Am J Clin Nutr 36:143–153PubMedGoogle Scholar
  2. Ashley DV, Liardon R, Leathwood PD (1985) Breakfast meal composition influences plasma tryptophan to large neutral amino acid ratios of healthy lean young men. J Neural Transm 63:271–283PubMedCrossRefGoogle Scholar
  3. Bishop D (2010) Dietary supplements and team-sport performance. Sports Med 40:1017CrossRefGoogle Scholar
  4. Blomstrand E (2001) Amino acids and central fatigue. Amino Acids 20:25–34PubMedCrossRefGoogle Scholar
  5. Blomstrand E, Hassmen P, Ekblom B, Newsholme EA (1991) Administration of branched-chain amino acids during sustained exercise—effects on performance and on plasma concentration of some amino acids. Eur J Appl Physiol 63:83–88CrossRefGoogle Scholar
  6. Boadle-Biber MC (1993) Regulation of serotonin synthesis. Prog Biophys Mol Biol 60:1–15PubMedCrossRefGoogle Scholar
  7. Bouchard R, Weber AR, Geiger JD (2002) Informed decision-making on sympathomimetic use in sport and health. Clin J Sport Med 12:209–224PubMedCrossRefGoogle Scholar
  8. Carlsson A, Lindqvist M (1978) Dependence of 5-HT and catecholamine synthesis on concentrations of precursor amino acids in rat brain. Naunyn Schmied Arch Pharmacol 303:157–164CrossRefGoogle Scholar
  9. Chaouloff F, Elghozi JL, Guezennec Y, Laude D (1985) Effects of conditioned running on plasma, liver and brain tryptophan and on brain 5-hydroxytryptamine metabolism of the rat. Br J Pharmacol 86:33–41PubMedCrossRefGoogle Scholar
  10. Chaouloff F, Kennett GA, Serrurrier B, Merino D, Curzon G (1986) Amino acid analysis demonstrates that increased plasma free tryptophan causes the increase of brain tryptophan during exercise in the rat. J Neurochem 46:1647–1650PubMedCrossRefGoogle Scholar
  11. Choi S, DiSilvio B, Fernstrom MH, Fernstrom JD (2009) Meal ingestion, amino acids and brain neurotransmitters: effects of dietary protein source on serotonin and catecholamine synthesis rates. Physiol Behav 98:156–162PubMedCrossRefGoogle Scholar
  12. Colmenares JL, Wurtman RJ, Fernstrom JD (1975) Effects of ingestion of a carbohydrate-fat meal on the levels and synthesis of 5-hydroxyindoles in various regions of the rat central nervous system. J Neurochem 25:825–829PubMedCrossRefGoogle Scholar
  13. Crandall EA, Fernstrom JD (1980) Acute changes in brain tryptophan and serotonin after carbohydrate or protein ingestion by diabetic rats. Diabetes 29:460–466PubMedGoogle Scholar
  14. Crofford OB, Felts PW, Lacy WW (1964) Effect of glucose infusion on the individual plasma free amino acids in man. Proc Soc Exp Biol Med 117:11–14PubMedCrossRefGoogle Scholar
  15. Davis JM, Bailey SP (1997) Possible mechanisms of central nervous system fatigue during exercise. Med Sci Sports Exer 29:45–57Google Scholar
  16. Davis JM, Alderson NL, Welsh RS (2000) Serotonin and central nervous system fatigue: nutritional considerations. Am J Clin Nutr 72:573S–578SPubMedGoogle Scholar
  17. Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR (1990) Serotonin function and the mechanism of antidepressant action. Arch Gen Psychiatry 47:411–418PubMedCrossRefGoogle Scholar
  18. Evers EAT, Tillie DE, van der Veen FM, Lieben CK, Jolles J, Deutz NEP, Schmitt JAJ (2005) Effects of a novel method of acute tryptophan depletion on plasma tryptophan and cognitive performance in healthy volunteers. Psychopharmacology 178:92–99PubMedCrossRefGoogle Scholar
  19. Fernstrom JD (1983) Role of precursor availability in the control of monoamine biosynthesis in brain. Physiol Rev 63:484–546PubMedGoogle Scholar
  20. Fernstrom MH, Fernstrom JD (1987) Protein consumption increases tyrosine concentration and in vivo tyrosine hydroxylation rate in the light-adapted rat retina. Brain Res 401:392–396PubMedCrossRefGoogle Scholar
  21. Fernstrom MH, Fernstrom JD (1995a) Brain tryptophan concentrations and serotonin synthesis remain responsive to food consumption after the ingestion of sequential meals. Am J Clin Nutr 61:312–319PubMedGoogle Scholar
  22. Fernstrom MH, Fernstrom JD (1995b) Effect of chronic protein ingestion on rat central nervous system tyrosine levels and in vivo tyrosine hydroxylation rate. Brain Res 672:97–103PubMedCrossRefGoogle Scholar
  23. Fernstrom JD, Fernstrom MH (2006) Exercise, serum free tryptophan, and central fatigue. J Nutr 136:553S–559SPubMedGoogle Scholar
  24. Fernstrom JD, Wurtman RJ (1971a) Brain serotonin content: increase following ingestion of carbohydrate diet. Science 174:1023–1025PubMedCrossRefGoogle Scholar
  25. Fernstrom JD, Wurtman RJ (1971b) Brain serotonin content: physiological dependence on plasma tryptophan levels. Science 173:149–152PubMedCrossRefGoogle Scholar
  26. Fernstrom JD, Wurtman RJ (1972a) Brain serotonin content: physiological regulation by plasma neutral amino acids. Science 178:414–416PubMedCrossRefGoogle Scholar
  27. Fernstrom JD, Wurtman RJ (1972b) Elevation of plasma tryptophan by insulin in rat. Metabolism 21:337–342PubMedCrossRefGoogle Scholar
  28. Fernstrom MH, Volk EA, Fernstrom JD, Iuvone PM (1986) Effect of tyrosine administration on dopa accumulation in light- and dark-adapted retinas from normal and diabetic rats. Life Sci 39:2049–2057PubMedCrossRefGoogle Scholar
  29. Fernstrom MH, Massoudi MS, Fernstrom JD (1990) Effect of 8-hydroxy-2-(di-n-propylamino)-tetralin on the tryptophan-induced increase in 5-hydroxytryptophan accumulation in rat brain. Life Sci 47:283–289PubMedCrossRefGoogle Scholar
  30. Fernstrom JD, DiSilvio B, Choi S, Fernstrom MH (2008) Branched-chain amino acid administration reduces both serotonin and catecholamine synthesis rates in rat brain. Med Sci Sports Exer 40:S299Google Scholar
  31. Fernstrom JD, Langham KA, Marcelino LM, Fernstrom MH, Kaye WH (2011) The effect in humans of ingesting different dietary proteins on plasma tryptophan, tyrosine, and the amino acid ratios that predict their brain uptake. FASEB J 25(1 meeting abstracts):983.8Google Scholar
  32. Feurte S, Gerozissis K, Regnault A, Paul FM (2001) Plasma Trp/LNAA ratio increases during chronic ingestion of an alpha-lactalbumin diet in rats. Nutr Neurosci 4:413–418PubMedGoogle Scholar
  33. Filip V, Krulik R, Haskovec L, Hyanek J (1974) The effect of insulin load on plasma tryptophan levels in schizophrenic patients. Acta Nerv Super (Praha) 16:174–175Google Scholar
  34. Fukagawa NK, Minaker KL, Young VR, Rowe JW (1986) Insulin dose-dependent reduction in plasma amino acids in man. Am J Physiol 250:E13–E17PubMedGoogle Scholar
  35. Gandevia SC, Allen GM, Butler JE, Taylor JL (1996) Supraspinal factors in human muscle fatigue: evidence for suboptimal output from the motor cortex. J Physiol (Lond) 490:529–536Google Scholar
  36. Gartside SE, Cowen PJ, Sharp T (1992) Evidence that the large neutral amino acid l-valine decreases electrically-evoked release of 5-HT in rat hippocampus in vivo. Psychopharmacology 109:251–253PubMedCrossRefGoogle Scholar
  37. Gessa GL, Biggio G, Fadda F, Corsini GU, Tagliamonte A (1974) Effect of the oral administration of tryptophan-free amino acid mixtures on serum tryptophan, brain tryptophan and serotonin metabolism. J Neurochem 22:869–870PubMedCrossRefGoogle Scholar
  38. Gijsman HJ, Scarna A, Harmer CJ, McTavish SB, Odontiadis J, Cowen PJ, Goodwin GM (2002) A dose-finding study on the effects of branch chain amino acids on surrogate markers of brain dopamine function. Psychopharmacology 160:192–197PubMedCrossRefGoogle Scholar
  39. Gomez-Merino D, Bequet F, Berthelot M, Chennaoui M, Guezennec CY (2001a) Site-dependent effects of an acute intensive exercise on extracellular 5-HT and 5-HIAA levels in rat brain. Neurosci Lett 301:143–146PubMedCrossRefGoogle Scholar
  40. Gomez-Merino D, Bequet F, Berthelot M, Riverain S, Chennaoui M, Guezennec CY (2001b) Evidence that the branched-chain amino acid l-valine prevents exercise-induced release of 5-HT in rat hippocampus. Int J Sports Med 22:317–322PubMedCrossRefGoogle Scholar
  41. Gwirtsman HE, Kaye WH, Curtis SR, Lyter LM (1989) Energy intake and dietary macronutrient content in women with anorexia nervosa and volunteers. J Am Diet Assoc 89:54–57PubMedGoogle Scholar
  42. Iuvone PM, Galli CL, Garrison-Gund CK, Neff NH (1978) Light stimulates tyrosine hydroxylase activity and dopamine synthesis in retinal amacrine neurons. Science 202:901–902PubMedCrossRefGoogle Scholar
  43. Iuvone PM, Rauch AL, Marshburn PB, Glass DB, Neff NH (1982) Activation of retinal tyrosine hydroxylase in vitro by cyclic AMP-dependent protein kinase: characterization and comparison to activation in vivo by photic stimulation. J Neurochem 39:1632–1640PubMedCrossRefGoogle Scholar
  44. Jensen K, Fruensgaard K, Alfors UG, Pihkanen TA, Tuomikoski S, Ose E, Dencker SJ, Lindberg D, Nagy A (1975) Tryptophan/imipramine in depression. Lancet 2:920PubMedCrossRefGoogle Scholar
  45. Kaufman S, Kaufman EE (1985) Tyrosine hydroxylase. In: Blakley RL, Benkovic SJ (eds) Folates and pterins, vol 2, Chemistry and biochemistry of the pterins. Wiley, New York, pp 251–352Google Scholar
  46. Kaufman LD, Philen RM (1993) Tryptophan: current status and future trends for oral administration. Drug Saf 8:89–98PubMedCrossRefGoogle Scholar
  47. Kaye WH, Barbarich NC, Putnam K, Gendall KA, Fernstrom J, Fernstrom M, McConaha CW, Kishore A (2003) Anxiolytic effects of acute tryptophan depletion in anorexia nervosa. Int J Eat Disord 33:257–267PubMedCrossRefGoogle Scholar
  48. Kaye WH, Frank GK, Bailer UF, Henry SE, Meltzer CC, Price JC, Mathis CA, Wagner A (2005) Serotonin alterations in anorexia and bulimia nervosa: new insights from imaging studies. Physiol Behav 85:73–81PubMedCrossRefGoogle Scholar
  49. Klein DA, Walsh BT (2003) Eating disorders. Int Rev Psychiatry 15:205–216PubMedCrossRefGoogle Scholar
  50. Laties VG, Weiss B (1981) The amphetamine margin in sports. Fed Proc 40:2689–2692PubMedGoogle Scholar
  51. Le Floc’h N, Otten W, Merlot E (2011) Tryptophan metabolism, from nutrition to potential therapeutic applications. Amino Acids 41:1195–1205PubMedCrossRefGoogle Scholar
  52. Lieben CKJ, Blokland A, Westerink B, Deutz NEP (2004) Acute tryptophan and serotonin depletion using an optimized tryptophan-free protein-carbohydrate mixture in the adult rat. Neurochem Int 44:9–16PubMedCrossRefGoogle Scholar
  53. Lipsett D, Madras BK, Wurtman RJ, Munro HN (1973) Serum tryptophan level after carbohydrate ingestion: selective decline in non-albumin-bound tryptophan coincident with reduction in serum free fatty acids. Life Sci 12(2):57–64CrossRefGoogle Scholar
  54. Markus CR, Olivier B, Panhuysen GE, Van Der GJ, Alles MS, Tuiten A, Westenberg HG, Fekkes D, Koppeschaar HF, de Haan EE (2000) The bovine protein alpha-lactalbumin increases the plasma ratio of tryptophan to the other large neutral amino acids, and in vulnerable subjects raises brain serotonin activity, reduces cortisol concentration, and improves mood under stress. Am J Clin Nutr 71:1536–1544PubMedGoogle Scholar
  55. Markus CR, Firk C, Gerhardt C, Kloek J, Smolders G (2008) Effect of different tryptophan sources on amino acids availability to the brain and mood in healthy volunteers. Psychopharmacology 201:107–114PubMedCrossRefGoogle Scholar
  56. McMenamy RH, Oncley JL (1958) The specific binding of l-tryptophan to serum albumin. J Biol Chem 233:1436–1447PubMedGoogle Scholar
  57. Meeusen R, Thorre K, Chaouloff F, Sarre S, De MK, Ebinger G, Michotte Y (1996) Effects of tryptophan and/or acute running on extracellular 5-HT and 5-HIAA levels in the hippocampus of food-deprived rats. Brain Res 740:245–252PubMedCrossRefGoogle Scholar
  58. Meeusen R, Watson P, Hasegawa H, Roelands B, Piacentini MF (2006) Central fatigue: the serotonin hypothesis and beyond. Sports Med 36:881–909PubMedCrossRefGoogle Scholar
  59. Mitchell ES, Slettenaar M, Quadt F, Giesbrecht T, Kloek J, Gerhardt C, Bot A, Eilander A, Wiseman S (2011) Effect of hydrolysed egg protein on brain tryptophan availability. Brit J Nutr 105:611–617PubMedCrossRefGoogle Scholar
  60. Moir ATB, Eccleston D (1968) The effects of precursor loading in the cerebral metabolism of 5-hydroxyindoles. J Neurochem 15:1093–1108PubMedCrossRefGoogle Scholar
  61. Orosco M, Rouch C, Beslot F, Feurte S, Regnault A, Dauge V (2004) Alpha-lactalbumin-enriched diets enhance serotonin release and induce anxiolytic and rewarding effects in the rat. Behav Brain Res 148:1–10PubMedCrossRefGoogle Scholar
  62. Pardridge WM, Oldendorf WH (1975) Kinetic analysis of blood brain barrier transport of amino acids. Biochim Biophys Acta 401:128–136PubMedCrossRefGoogle Scholar
  63. Raghunath M, Rao BSN (1984) Relationship between relative protein value and some in vitro indices of protein quality. J Biosci 6:655–661CrossRefGoogle Scholar
  64. Rao B, Broadhurst AD (1976) Tryptophan and depression. Brit Med J 1:460PubMedCrossRefGoogle Scholar
  65. Reeves PG, Nielsen FH, Fahey GC Jr (1993) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 123:1939–1951PubMedGoogle Scholar
  66. Rennie MJ, Tipton KD (2000) Protein and amino acid metabolism during and after exercise and the effects of nutrition. Annu Rev Nutr 20:457–483PubMedCrossRefGoogle Scholar
  67. Roelands B, Hasegawa H, Watson P, Piacentini MF, Buyse L, De Schutter G, Meeusen R (2008) The effects of acute dopamine reuptake inhibition on performance. Med Sci Sports Exer 40:879–885CrossRefGoogle Scholar
  68. Rosenwasser AM, Boulos Z, Terman M (1981) Circadian organization of food intake and meal patterns in the rat. Physiol Behav 27:33–39PubMedCrossRefGoogle Scholar
  69. Sambeth A, Riedel WJ, Tillie DE, Blokland A, Postma A, Schmitt JAJ (2009) Memory impairments in humans after acute tryptophan depletion using a novel gelatin-based protein drink. J Psychopharmacol 23:56–64PubMedCrossRefGoogle Scholar
  70. Scally MC, Ulus I, Wurtman RJ (1977) Brain tyrosine level controls striatal dopamine synthesis in haloperidol-treated rats. J Neural Transm 41:1–6PubMedCrossRefGoogle Scholar
  71. Scarna A, Gijsman HJ, McTavish SF, Harmer CJ, Cowen PJ, Goodwin GM (2003) Effects of a branched-chain amino acid drink in mania. Br J Psychiatry 182:210–213PubMedCrossRefGoogle Scholar
  72. Schweiger U, Warnhoff M, Pahl J, Pirke KM (1986) Effects of carbohydrate and protein meals on plasma large neutral amino acids, glucose, and insulin plasma levels of anorectic patients. Metabolism 35:938–943PubMedCrossRefGoogle Scholar
  73. Sharp T, Bramwell SR, Grahame-Smith DG (1992) Effect of acute administration of l-tryptophan on the release of 5-HT in rat hippocampus in relation to serotoninergic neuronal activity: an in vivo microdialysis study. Life Sci 50:1215–1223PubMedCrossRefGoogle Scholar
  74. Smriga M, Kameishi M, Tanaka T, Kondoh T, Torii K (2002) Preference for a solution of branched-chain amino acids plus glutamine and arginine correlates with free running activity in rats: involvement of serotonergic-dependent processes of lateral hypothalamus. Nutr Neurosci 5:189–199PubMedCrossRefGoogle Scholar
  75. Spector S, Gordon R, Sjoerdsma A, Udenfriend S (1967) End-product inhibition of tyrosine hydroxylase as a possible mechanism for regulation of norepinephrine synthesis. Mol Pharmacol 3:549–555PubMedGoogle Scholar
  76. Tarnopolsky M (2004) Protein requirements for endurance athletes. Nutrition 20:662–668PubMedCrossRefGoogle Scholar
  77. Taylor JL, Gandevia SC (2008) A comparison of central aspects of fatigue in submaximal and maximal voluntary contractions. J Appl Physiol 104:542–550PubMedCrossRefGoogle Scholar
  78. Teff KL, Young SN, Blundell JE (1989a) The effect of protein or carbohydrate breakfasts on subsequent plasma amino acid levels, satiety and nutrient selection in normal males. Pharmacol Biochem Behav 34:829–837PubMedCrossRefGoogle Scholar
  79. Teff KL, Young SN, Marchand L, Botenz MI (1989b) Acute effect of protein or carbohydrate breakfasts on human cerebrospinal fluid monoamine precursor and metabolite levels. J Neurochem 52:235–241PubMedCrossRefGoogle Scholar
  80. US Department of Agriculture and Agricultural Research Service (2011) USDA national nutrient database for standard reference, release 24. Accessed Jan 11 2012
  81. van Praag HM (1982) Serotonin precursors in the treatment of depression. In: Ho BT, Schoolar JC, Usdin E (eds) Serotonin in biological psychiatry. Raven Press, New York, pp 259–286Google Scholar
  82. Williams WA, Shoaf SE, Hommer D, Rawlings R, Linnoila M (1999) Effects of acute tryptophan depletion on plasma and cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers. J Neurochem 72:1641–1647PubMedCrossRefGoogle Scholar
  83. Wurtman RJ (2011) Non-nutritional uses of nutrients. Eur J Pharmacol 668:S10–S15PubMedCrossRefGoogle Scholar
  84. Wurtman JJ, Wurtman RJ (1979) Drugs that enhance serotoninergic transmission diminish elective carbohydrate consumption by rats. Life Sci 24:895–904PubMedCrossRefGoogle Scholar
  85. Wurtman RJ, Larin F, Mostafapour S, Fernstrom JD (1974) Brain catechol synthesis: control by brain tyrosine concentration. Science 185:183–184PubMedCrossRefGoogle Scholar
  86. Wurtman RJ, Hefti F, Melamed E (1980) Precursor control of neurotransmitter synthesis. Pharmacol Rev 32:315–335PubMedGoogle Scholar
  87. Wurtman J, Wurtman R, Reynolds S, Tsay R, Chew B (1987) Fenfluramine suppresses snack intake among carbohydrate cravers but not among noncarbohydrate cravers. Int J Eat Disord 6:687–699CrossRefGoogle Scholar
  88. Young SN, Smith SE, Pihl RO, Ervin FR (1985) Tryptophan depletion causes a rapid lowering of mood in normal males. Psychopharmacology 87:173–177PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Department of PsychiatryUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Department of Pharmacology and Chemical BiologyUniversity of Pittsburgh School of MedicinePittsburghUSA

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