Tryptophan supplementation and serotonin function: genetic variations in behavioural effects

Proc Nutr Soc. 2018 May;77(2):174-188. doi: 10.1017/S0029665117004451. Epub 2018 Jan 25.


The neurotransmitter serotonin has a role in affective disorders such as depression and anxiety, as well as sleep, cognitive function and appetite. This review examines the evidence that serotonin-related genotypes may moderate the behavioural effects of supplementation with the serotonin precursor amino acid l-tryptophan (TRP), on which synthesis of serotonin (or 5-hydroxytryptamine; 5-HT) depends. However, 95 % of serotonin is synthesised and used in the periphery, and TRP is also metabolised via non-5-HT routes such as the kynurenine pathway. Moreover, understanding of genotypes involved in regulation of serotonin raises questions over the generalisability of TRP effects on behaviour across individuals with varied serotonergic genotypes. To date, only differences between variants of the 5-HT transporter-linked promoter region (5-HTTLPR) have been investigated in relation to behavioural effects of TRP supplementation. Effects of 5-HTTLPR genotypes are usually compared between the alleles that are either high (L/L') or low (S/S') expressing of mRNA for the 5-HT transporter receptor. Yet, another key genetic variable is sex: in women, the S/S' genotype predicts sensitivity to improved mood and reduced cortisol by TRP supplementation, during stressful challenges, whereas the L/L' genotype protects against stress-induced mood deterioration. In men, the L/L' genotype may confer risk of stress-induced increases in negative affect; there are insufficient data to assess effects on male S/S' genotypes. However, better-powered studies to detect sex by genotype by stress by TRP interactions, as well as consideration of more genotypes, are needed before strong conclusions and recommendations for behavioural effects of TRP treatment can be reached.

Keywords: 5-HT 5-hydroxytryptamine; 5-HTTLPR 5-HT transporter-linked promoter region; ATD acute tryptophan depletion; CNS central nervous systems; CSF cerebrospinal fluid; LNAA large neutral amino acids; MAO monoamine oxidase; TDO tryptophan 2; TPH TRP hydroxylase; TRP l-tryptophan; 3-dioxygenase; 5-HT transporter-linked promoter region; Genetic polymorphism; Serotonin and behaviour; Stress; Tryptophan supplementation.

Publication types

  • Review

MeSH terms

  • Affect / drug effects
  • Alleles
  • Behavior
  • Depression / drug therapy
  • Depression / genetics*
  • Dietary Supplements*
  • Female
  • Genetic Variation*
  • Genotype*
  • Humans
  • Hydrocortisone / blood
  • Male
  • Receptors, Serotonin / genetics
  • Serotonin / blood
  • Serotonin / genetics*
  • Stress, Psychological / drug therapy
  • Stress, Psychological / genetics*
  • Tryptophan / pharmacology*
  • Tryptophan / therapeutic use


  • Receptors, Serotonin
  • Serotonin
  • Tryptophan
  • Hydrocortisone