Tryptophan: Building serotonin and melatonin

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:

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 the effects from shunting tryptophan towards this path. For the most part, I will focus on the effects of these metabolites in the brain.

Quinolinic acid:
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 that 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:
Quinolinic acid is converted by the body into NAD+ (nicotinamide adenine dinucleotide), which is used in the mitochondria in the production of ATP. Magnesium is a co-factor in this conversion. (We also get niacin through our diet.)

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.

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

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 protein, it often doesn’t reach the brain. That transport across the blood-brain barrier also needs insulin.

Depression, serotonin, and quinolinic acid:

While it is often thought that decreased serotonin in the brain causes depression, the science is not exactly cut-and-dried here. It turns out that 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 show that this decreased TPH2 activity causes mice to be susceptible to psychosocial stress.[ref]  Decreased serotonin synthesis in adult mice also causes circadian diruption 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 the 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]

Don’t forget the gut microbiome…

The nice graphic up above that I made about the various ways the body can convert tryptophan leaves out one potentially 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 also. This makes my nifty flow chart all messy. [ref]

Dietary sources of tryptophan:

Estimated recommended daily intake for adults is between 250- 425 mg/day of tryptophan — so not a whole lot!  Most individuals get a lot more than this amount.  Common sources of tryptophan in the diet include oatmeal, bananas, milk, tuna, chicken, turkey, peanuts, chocolate, and cheese. [ref]

A study of 29,000 people found that even higher 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 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 through the kynurenine pathway into niacin. Pellagra was a problem in the southern US after the Civil War due to nutritional deficiency of niacin and eating a lot of corn.  Corn doesn’t have tryptophan in it, and the niacin is bound up in such a way that it needs to be nixtamalized before eating it. This is why the native populations in Mexico soaked the corn with limewater (or another alkaline solution) before making tortillas.

Not only does corn lack tryptophan or bioavailable niacin, but it also contains a lot of leucine, which is a branched-chain amino acid (BCAA).  Leucine (and other BCAA) competes 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:

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: normal IDO1
  • G/G: normal IDO1
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: normal IDO1

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

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

  • C/C: normal 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]

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: (most common genotype for most populations), 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]
Check your genetic data for rs11178997 (23andMe v4; AncestryDNA):

  • T/T: (most common genotype)
  • A/T: somewhat increased risk of depression
  • A/A: increased risk of depression and suicide [ref][ref]

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

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

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

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

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

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

 

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 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:

Before we go any further, let’s talk about 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. Not something you want to experience!

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 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]

Should you take tryptophan? or 5-HTP?
If you have variants above that impact your tryptophan pathway, you may be wondering about supplementing with either tryptophan or 5-HTP. Both are readily available as supplements.

You may want to use a whole lot of caution with adding in tryptophan or 5-HTP in the following situations:

  • For people with depression, the studies on adding in tryptophan in an effort to boost serotonin show mixed results. This could be because inflammation is pushing the tryptophan down the kynurenine pathway and increasing quinolinic acid at the same time as increasing serotonin. [ref]
  • If you are under a doctors care for depression, you could talk to your doc about whether adding in 5-HTP would be a benefit. This isn’t something to mess around with if you are already on an anti-depressant, especially without talking to your doctor.
  • Increasing serotonin in the gut may increase motility, which could be good or bad, depending on your situation.  Some people with IBS-D have higher serotonin levels in the gut, and blocking the serotonin receptor helps there.[ref] I don’t know for certain that supplementing with higher doses of tryptophan or 5-HTP would be detrimental with IBS-D, but it seems like that would be a distinct possibility.

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]

Increasing tryptophan conversion to serotonin:
In addition to responding to inflammation or stress, the body also shunts more tryptophan towards the kynurenine pathway when niacin is low. [ref] Thus, ensuring that you get enough niacin may help to increase the conversion of tryptophan to serotonin (assuming no stress or inflammation). Foods that are rich in niacin include liver, chicken, pork, turkey, fish, soy, and pumpkin seeds.

Probiotics:
Taking lactobacillus Plantarum 299v may alter the amount of kynurenine produced. In a study of people with depression who were taking an SSRI, 8-weeks of taking the probiotic decreased kynurenine concentrations compared to a placebo group. It also improved cognitive function compared with placebo and baseline. [ref]  Lactobacillus Plantarum 299v is available on Amazon.

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