Genetic Variants and Poor Sleep Quality: Can Tryptophan Help?

By Adin Smith, MS | Posted May 20, 2022

Gene variants impacting serotonin metabolism may impair sleep quality. Emerging research suggests that the serotonin precursor tryptophan improves sleep quality in those with certain genetic tendencies.

What is a gene variant?

A gene variant is an alteration in the DNA sequence (the biological process that makes up a gene). Gene variants influence how our cells function, but these changes to the DNA are often subtle and don’t always cause disease.[1]MedlinePlus. Genetics. Accessed April (2022).

Genetic variants can be either inherited or non-inherited.

Inherited genetic variants are passed down from parent to child and exist in virtually all cells. These in-born variants remain active throughout a person’s life.

Non-inherited genetic variants manifest in certain cells after birth, commonly resulting from environmental exposures (e.g., radiation, infection, drugs, toxins) but can also occur if DNA replication errors arise during cell division.[2]Mertz TM, et al. Risks at the DNA Replication Fork: Effects upon Carcinogenesis and Tumor Heterogeneity. Genes (Basel). 2017;8(1):46.

How might genetic variants impair sleep quality?

Some gene variants cause alterations in serotonin metabolism, which may lead to poor sleep quality.[3]Huang C, et al. Interaction between serotonin transporter gene-linked polymorphic region (5-HTTLPR) and job-related stress in insomnia. Sleep Med. 2014 Oct;15(10):1269-75.

For instance, a gene variant or “allele” known as the serotonin transporter gene-linked polymorphic region (5-HTTLPR) may predispose individuals to experience reductions in sleep quality. All humans inherit either a short copy (S-allele) or a long copy (L-allele) of the 5-HTTLPR from each parent.

Short Copy Reduces Serotonin Transporter Function

According to in-vitro research, the S-allele of the 5-HTTLPR decreases the function of the serotonin transporter (SERT).[4]Lesch KP, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996 Nov 29;274(5292):1527-31. The SERT is responsible for serotonin reuptake within the synaptic cleft (the meeting point between two neurons). Because reduced SERT function limits serotonin clearance, synaptic serotonin levels may increase.

While certain concentrations of synaptic serotonin are essential for optimal sleep, elevations in synaptic serotonin are involved in wakefulness.[5]Monti JM. Serotonin control of sleep-wake behavior. Sleep Med Rev. 2011 Aug;15(4):269-81. Chronic serotonin elevations due to the 5-HTTLPR S-allelic variant may cause more synaptic serotonin to accumulate—desensitizing the serotonin receptors and worsening sleep quality.

People with S-allele more likely to have sleep issues

In one of the first studies measuring the effect of 5-HTTLPR variants on sleep quality, researchers recruited individuals caring for people with various dementias and a group of non-caregivers serving as the control group.[6]Brummett BH, Krystal AD, Ashley-Koch A, et al. Sleep quality varies as a function of 5-HTTLPR genotype and stress. Psychosom Med. 2007;69(7):621-624. All participants underwent genetic testing to determine if they were carrying the S-allele or L-allele and had subjective sleep scores measured.

The post-data analysis showed that caregivers with the S-allele experienced reduced sleep quality compared to the control group. These results suggest that individuals carrying the S-allele are more likely to have sleep issues when exposed to chronic stress.

Can tryptophan help those with genetically related sleep impairments?

Tryptophan is an essential dietary amino acid serving as a building block for serotonin and melatonin synthesis—two vital compounds involved in sleep regulation.

While most people consume enough tryptophan in their diet, health factors ranging from age, exercise frequency, gut health, medical conditions such as COVID-19, and genetics may influence a person’s need for tryptophan.

In one study, researchers evaluated the sleep-promoting effects of tryptophan among people with different genetic variations in the serotonin transporter.[7]van Dalfsen JH, et al. The serotonin transporter gene-linked polymorphic region (5-HTTLPR) and the sleep-promoting effects of tryptophan. J Psychopharmacol. 2019;33(8):948-954.

Subjects were genotyped and randomly assigned to receive 1000 mg of tryptophan or placebo capsules each night before bed for one week, then switched treatments for another week.

All participants maintained a sleep diary for subjective evaluation and underwent activity-based sleep-wake monitoring (called actigraphy) for objective sleep assessment.

At trial completion, tryptophan treatment improved objective sleep efficiency and reduced the amount of awake time after sleep—irrespective of genetic variation.

However, individuals carrying the S-alleles had better improvements in subjective sleep quality and the number of nighttime awakenings than those with the L-alleles.


Genetic variants such as the 5-HTTLPR S-allele may cause reductions in serotonin transporter function and worsen sleep quality—especially among those exposed to chronic stress.

Research suggests that tryptophan’s sleep-promoting benefits are experienced in people regardless of genetic variation in the 5-HTTLPR. However, individuals with S-allelic variations appear to respond better to tryptophan intake.

    Image author credit: nesharm ©