Tryptophan Genes: Serotonin, Melatonin, and Kynurenine

For a lot of people, tryptophan brings to mind napping on the couch after eating a huge amount of Thanksgiving turkey. (Turns out that it isn’t really true that the tryptophan in turkey makes you sleepy – but the post Thanksgiving dinner nap phenomenon is definitely real at our house.) Tryptophan metabolism influences mood, sleep, neurotransmitters, and immune response.

What is tryptophan and why do we need it?

Tryptophan is an essential amino acid. ‘Essential’ here means that your body can’t produce it, and thus you need to get tryptophan through your diet.

Once you consume tryptophan in foods, your body can use it through a couple of different pathways.

First, tryptophan can be used to make serotonin, which is a neurotransmitter in the brain and in the intestines. Serotonin is the precursor for melatonin, so tryptophan eventually can become melatonin (thus the tie into being sleepy from the Thanksgiving turkey).

The other pathway that uses tryptophan is the kynurenic acid pathway. This eventually leads to tryptophan being converted into niacin. But there are lots of steps along the way and intermediate molecules with a variety of implications for mental health.

tryptophan pathway

Kynurenine pathway: One route for tryptophan

Tryptophan can be converted to kynurenine, and >90% of tryptophan that isn’t used for protein synthesis goes down this pathway.  This occurs with the help of the  IDO (indoleamine 2,3-dioxygenase) enzymes, which are expressed throughout the body, and the TDO enzyme in the liver.[ref]

The IDO enzymes are induced by inflammatory cytokines, such as interferon-gamma. So inflammation may cause tryptophan to be used even more for kynurenine and less for serotonin.

Most commonly, tryptophan is converted to kynurenine by the TDO (tryptophan 2,3 dioxygenase) enzyme. This is mainly expressed in the liver and is induced by cortisol (stress) and steroids.[ref]

Thus, when you are stressed with high cortisol levels or when you are fighting off a pathogen, the kynurenine pathway will dominate, with little tryptophan available for conversion to serotonin.

The metabolites, or what kynurenine is broken down into, are a key to why the body shunts tryptophan towards this path. For the most part, I will focus on the effects of these metabolites in the brain.

Quinolinic acid from kynurenine:

Kynurenine can be converted, through a couple of intermediate steps, to quinolinic acid. 

Quinolinic acid is a neurotoxin that binds to the NMDA receptor. It causes neurodegeneration and apoptosis. It is unable to pass through the blood-brain barrier, so it is only neurotoxic to the brain when produced in the brain by macrophages or microglial cells (as long as the blood-brain barrier is intact).[ref]

Too much quinolinic acid in the brain is associated with Alzheimer’s disease, ALS, Huntington’s, autism, depression, and suicide attempts. The excess quinolinic acid in the brain causes overactivation of the NMDA receptor. This leads to oxidative stress, not enough energy in the brain, and eventual cell death of the neurons.[ref][ref]

The link between quinolinic acid and depression has been the subject of quite a few recent research papers.

One 2016 paper theorizes a cause of depression may be due to tryptophan metabolism being shunted to the kynurenine pathway – which could increase quinolinic acid and, at the same time, decrease serotonin. This shift would be promoted by either an inflammatory response and/or stress hormones, both of which activate the IDO enzyme.[ref][ref]

There are quite a few studies linking inflammation with depression and bipolar disorder, and some studies that include data showing the kynurenine pathway activation.[ref][ref]

Niacin insufficiency:

Quinolinic acid is converted by the body into a form of niacin called NAD+ (nicotinamide adenine dinucleotide).

  • NAD+ is essential in the production of ATP in the mitochondria.
  • Magnesium is a cofactor in this conversion.
  • We also get niacin through our diet.

Tryptophan –> Serotonin –> Melatonin Pathway:

Your body also uses tryptophan to make the neurotransmitter serotonin. While we often think of serotonin as a happy molecule in the brain, it also acts as a neurotransmitter elsewhere in the body, such as in the intestines, where it regulates gut motility.

The TPH2 enzyme is the limiting factor in converting tryptophan into serotonin.

Crossing the blood-brain barrier: In the brain, serotonin needs to be made from tryptophan that has crossed the blood-brain barrier.

Tryptophan needs a transporter to cross the blood-brain barrier, and that transport is shared with other branch-chain amino acids. So when tryptophan is consumed along with other proteins, all of it may not reach the brain.[ref]

Consuming carbohydrates, though, can increase the amount of tryptophan that reaches the brain. Eating carbohydrates tends to increase insulin levels, which alters the ratio of tryptophan to other amino acids in the bloodstream. This allows more tryptophan to reach the brain and be converted into serotonin.[ref][ref]

Serotonin in the brain can be converted to melatonin, a hormone that is important for circadian rhythm, glucose regulation, and sleep.

Depression: low serotonin or high quinolinic acid?

While it is often thought that decreased serotonin levels in the brain causes depression, the science is not exactly cut-and-dry here. It turns out it is really hard to measure serotonin levels in human brains. There is definitely a connection between biomarkers of serotonin and depression, and increasing serotonin can help with depression for some people… but it isn’t as simple as depression is caused by low serotonin for everyone.[ref][ref]

Researchers have created a mouse model of reduced TPH2 enzyme activity. They have shown that this significantly decreases serotonin levels in the brain and causes mouse depression and anxiety symptoms.[ref] And other researchers have shown that this decreased TPH2 activity causes mice to be susceptible to psychosocial stress.[ref]  Decreased serotonin synthesis in adult mice also causes circadian disruption and hyperactivity.[ref] Thus, tryptophan conversion in the brain into serotonin is likely to play some role in mood, anxiety, and circadian rhythm.

Keep in mind that one cause of tryptophan conversion being shunted away from serotonin and towards kynurenine is increased inflammation. This causes a double whammy – lower serotonin and higher quinolinic acid. Quinolinic acid acts on NMDA receptors and too much can kill off brain cells.  Studies show that depression scores correlate to higher quinolinic acid in the blood, and postmortem studies show more cells in the brain producing quinolinic acid in suicide victims.[ref]

Never forget the gut microbiome…

The graphic above shows the various ways the body can convert tryptophan.  However, it leaves out one big player in this game – the gut microbiome. Your gut bacteria can also use some of the same enzymes that your body makes in order to convert tryptophan into metabolites. This makes my nifty flow chart really messy.[ref]

Dietary sources of tryptophan:

The estimated recommended daily intake for adults is between 250- 425 mg/day of tryptophan — which is not a lot.  Most people consume more than this amount daily.

Common sources of tryptophan in the diet include oatmeal, bananas, milk, tuna, chicken, turkey, peanuts, chocolate, and cheese.[ref]

Is too much tryptophan bad? A study of 29,000 people found that high levels of tryptophan in the diet are not a problem for kidney or liver function. The study did find that higher tryptophan intake correlated to lower levels of depression and better sleep.[ref]

Pellagra: a niacin deficiency disease

A lack of niacin (vitamin B3) causes pellagra, which is a disease that causes diarrhea, dementia, and dermatitis.

People get niacin either through eating foods that contain it or through converting tryptophan via the kynurenine pathway into niacin.

Historically, pellagra was a problem in the southern US after the Civil War due to the nutritional deficiency of niacin from eating a diet mainly consisting of corn.  Corn doesn’t contain tryptophan, and the niacin in corn is bound up in such a way that it needs to be nixtamalized before eating it. This is why native populations in Mexico soaked corn with lime water (or another alkaline solution) before making the tortillas. This nixtamalization process makes the niacin available.

Not only does corn lack tryptophan or bioavailable niacin, but it also contains a lot of leucine, a branched-chain amino acid (BCAA).  Leucine (and other BCAA) compete with tryptophan for uptake through the blood-brain barrier. Thus, it is thought that high leucine along with low tryptophan contributes to pellagra.

Genetic Variants in the Tryptophan Genes:

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Tryptophan -> Kynurenine

IDO1 gene: codes for the enzyme that converts tryptophan to kynurenine.

Check your genetic data for rs3808606 (23andMe v4, v5; AncestryDNA):

  • A/A: decreased susceptibility to vaginal Candida, enhanced IDO1[ref]
  • A/G: typical IDO1
  • G/G: typical IDO1

Members: Your genotype for rs3808606 is .

Check your genetic data for rs9657182 (23andMe v5; AncestryDNA):

  • C/C: more likely to have depression with IFN-alpha treatment[ref][ref]
  • C/T: intermediate effect
  • T/T: typical IDO1

Members: Your genotype for rs9657182 is .

KMO gene: codes for the enzyme that converts kynurenine to 3-OH-kynurenine

Check your genetic data for rs1053230 (23andMe v4, v5; AncestryDNA):

  • C/C: typical genotype, higher risk of depression[ref]
  • C/T: increased 3-OH-kynurenine, decreased risk of bipolar with psychotic[ref]
  • T/T: increased 3-OH-kynurenine, decreased risk of bipolar with psychotic[ref]

Members: Your genotype for rs1053230 is .

Tryptophan -> Serotonin:

TPH2 gene: codes for the enzyme that converts tryptophan to 5-HTP, which then gets converted to serotonin in the brain.

Check your genetic data for rs4570625 (23andMe v4, v5; AncestryDNA):

  • G/G: typical, less tryptophan conversion to serotonin, slightly higher risk of ADHD[ref] a higher risk of depression, suicidal depression[ref][ref]
  • G/T: somewhat decreased risk of depression
  • T/T: generally decreased risk of depression[ref], less aggressiveness and lower anxiety[ref] lower neuroticism[ref]

Members: Your genotype for rs4570625 is .

Check your genetic data for rs11178997 (23andMe v4; AncestryDNA):

  • T/T: typical
  • A/T: somewhat increased risk of depression
  • A/A: increased risk of depression and suicide[ref][ref]

Members: Your genotype for rs11178997 is .

Check your genetic data for rs1843809 (23andMe v5; AncestryDNA):

  • G/G: decreased risk of depression[ref]
  • G/T: decreased risk of depression
  • T/T: typical

Members: Your genotype for rs1843809 is .

Check your genetic data for rs1386494 (23andMe v5; AncestryDNA):

  • T/T:  better response to ECT[ref]
  • C/T: increased risk of depression
  • C/C: typical, increased risk of depression[ref]

Members: Your genotype for rs1386494 is .

Check your genetic data for rs4290270 (23andMe v4; AncestryDNA):

  • T/T: circadian disruption in people with depression[ref]
  • A/T: typical
  • A/A: higher risk of depression (Chinese study)[ref]

Members: Your genotype for rs4290270 is .


SLC6A4 gene: codes for the serotonin transporter

The serotonin transporter has a common variation that can either produce more (long form) or less (short form) of the transporter, known as 5-HTTLPR short or long (read more here).[ref]

People with the short-short version of the 5-HTTLPR were found in a study to have impaired verbal recall when on a tryptophan-depleted diet. Thus, the study concluded that dietary tryptophan levels are more important for people with the short-short version of the serotonin transporter.[ref]

To find out if you are likely to carry the 5-HTTLPR short version, check the following variants:

Look for the T allele on rs2129785 (23andMe v4, v5; AncestryDNA) combined with the A allele on rs11867581 (23andMe v4, v5; AncestryDNA).
T+A = 5-HTTLPR short version

Lifehacks for tryptophan conversion:

Before we go any further, let me explain serotonin syndrome…
More is not always better, and too much serotonin can have detrimental effects. An overdose of serotonin can cause serotonin syndrome, which causes high body temperature, headache, diarrhea, tremor, sweating, increased heart rate, and seizures. The body temperature can reach 106 °F, which is life-threatening.

What causes serotonin syndrome? Usually, it is the interaction between serotonergic drugs, such as MAOIs and SSRIs. Drugs such as fentanyl, tramadol, MDMA, and LSD may also interact to cause serotonin syndrome.  Some supplements, such as St. John’s Wort, Panax ginseng, and Yohimbe are also implicated.[ref]  Most cases of serotonin syndrome are caused by combining MAOIs and SSRIs.[ref]

It is theoretically possible to supplement with enough 5-HTP (serotonin precursor)  to cause serotonin syndrome (animal studies show it), but there aren’t human studies showing that supplemental doses of 5-HTP cause serotonin syndrome.[ref] Nonetheless, if you are on an SSRI or MAOI, talk with your doctor before adding in more serotonin precursors.[ref]

Tryptophan for sleep:

For sleep, tryptophan has some pretty good studies showing that it increases melatonin.

One study showed that tryptophan (476 mg) at breakfast increased melatonin production. This was enhanced by adding bright light exposure during the day. [ref]

Another study found that eating foods high in tryptophan in the morning (bananas, fermented soybeans) along with decreasing blue-light exposure in the evening worked to increase melatonin production. Note that they didn’t actually block all blue light in the evening, just switch the overhead lights to incandescent (warm color) bulbs.[ref]

Finally, a one-week-long study of 1000 mg tryptophan/day found that it only improved sleep quality in people with the 5-HTTLPR short/short genotype.[ref]

If you decide to supplement with tryptophan, taking it with some carbs and without other protein sources should help it cross the blood-brain barrier. You can get it as a supplement either in capsules or as a powder.

Tryptophan for weight loss?

A study in lean men (why do they always study lean men?) found that 2 or 3 g doses of tryptophan 45 minutes before eating decreased food consumption at a buffet. It also decreased both hunger and alertness.[ref]

Another study found that tryptophan reduced stress eating only in people with the 5-HTTLPR short/short genotype.[ref]

Decreasing tryptophan conversion to serotonin: 

In mice, withaferin A (ashwagandha) downregulates TPH2.[ref]

Related article: Ashwagandha research studies and side effects


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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.