The serotonin transporter gene-linked polymorphic region (5-HTTLPR) and the sleep-promoting effects of tryptophan: A randomized placebo-controlled crossover study

J Psychopharmacol. 2019 Aug;33(8):948-954. doi: 10.1177/0269881119855978. Epub 2019 Jun 25.


Background: The low-expressive short (S) allele of a functional polymorphism (5-HTTLPR) within the serotonin (5-hydroxytriptamine; 5-HT) transporter gene (SLC6A4) has been associated with a reduced functioning of the brain 5-HT system relative to the long (L) allele. As a consequence, the S-allele is found to predispose individuals to a higher risk of sleep quality reduction and clinical insomnia.

Aims: The present study investigated whether subchronic pre-sleep tryptophan administration could compensate for this predisposition by improving sleep in 5-HTTLPR S-allele carriers.

Methods: In a double-blind placebo-controlled crossover design a sample of homozygous 5-HTTLPR S-allele (n = 47) and L-allele (n = 51) carriers were assessed for subjective (sleep diary) and objective (actigraphy) sleep during a treatment protocol consisting of 1 week of placebo (1000 mg/day) and 1 week of tryptophan administration (1000 mg/day).

Results: The results support the sleep-promoting effects of tryptophan. Tryptophan improved objective sleep efficiency and objective wake after sleep onset irrespective of allelic variation. There was a marginally significant improvement of subjective sleep quality in the 5-HTTLPR S-allele group but not in the L-allele group following tryptophan relative to placebo intake. In contrast, a significantly poorer sleep quality in the S-allele as opposed to the L-allele group in the placebo condition was not observed in the tryptophan condition.

Conclusions: Tryptophan augmentation promises to be a valuable treatment strategy for sleep impairments related to genetic deficiencies in 5-HT functioning.

Keywords: 5-HTTLPR; Sleep; insomnia; serotonin; tryptophan.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Alleles
  • Brain / drug effects
  • Cross-Over Studies
  • Double-Blind Method
  • Female
  • Genotype
  • Humans
  • Male
  • Polymorphism, Genetic / genetics*
  • Serotonin / genetics
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • Sleep / drug effects*
  • Sleep / genetics*
  • Sleep Initiation and Maintenance Disorders / drug therapy
  • Sleep Initiation and Maintenance Disorders / genetics
  • Tryptophan / therapeutic use*
  • Young Adult


  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin
  • Tryptophan