Serotonin… a word that brings to mind a commercial that might show our happy brain neurons bouncing serotonin between them.
There is a lot more to serotonin than most of us realize! This article covers how the body makes and transports serotonin and the needed receptors to complete its pathway. I’ll explain the genetic variants that impact the serotonergic system and then go through the diet, supplement, and lifestyle changes that impact serotonin.
Members will see their genotype report below, plus additional solutions in the Lifehacks section. Join today.What does serotonin do?
In the brain, serotonin acts in several ways:
- as a neurotransmitter, sending a chemical message between neurons.
- as the precursor molecule for melatonin
- in sleep quality, including sleep hallucinations[ref][ref]
But there is more to serotonin than just its impact on the brain.
About 90% of serotonin is made in the gut and helps to regulate motility.[ref] Serotonin also regulates other functions such as; bone mass, cardiovascular health, the endocrine system, and appetite.
Serotonin is also important in energy metabolism, heart rate, cell growth, and immunity.[ref]
Depression:
Some researchers believe that imbalances in serotonin may play a role in depression or anxiety. Common antidepressants, including SSRIs (selective serotonin reuptake inhibitors), are thought to increase serotonin levels in the brain. However, the method through which they work is still not completely understood.[ref]
Another link between serotonin and depression is that serotonin modulates immune function.[ref] Increased inflammation is implicated in causing major depressive disorder for some.
Recent animal research shows that one reason that SSRIs may not work for everyone is due to increased inflammation. The study showed that in inflammatory situations, histamine is upregulated, and SSRIs act in off-target actions on histamine instead of increasing serotonin. In this study, decreasing histamine levels increased SSRI effectiveness.[ref] (Read more about histamine and check your histamine intolerance genes.)
Serotonin Synthesis and Transport:
Like most signaling molecules and neurotransmitters, serotonin first needs to be created (synthesized), then it needs to be transported, and finally, the signal needs to be received by a cellular receptor.
Synthesis:
Serotonin, also known as 5-hydroxytryptamine or 5-HT, is synthesized from the amino acid tryptophan using tryptophan hydroxylase. The TPH1 and TPH2 genes encode the tryptophan hydroxylase enzymes.
Transport:
Serotonin is transported by SLC6A4, which is also known as SERT or sodium-dependent serotonin transporter.
Receptors:
Serotonin receptors on the cell membrane, HTR1A, HTR1B, and HTR2A, receive the serotonin signal.
All of these work in concert: from the creation of serotonin from amino acids to the transport of serotonin to the receptors that are necessary to receive this chemical messenger.
Serotonin Syndrome: Too much serotonin
Ultimately, balance is the key to serotonin. Too much serotonin can result in serotonin syndrome. Symptoms include restlessness, confusion, shivering, diarrhea, and, potentially, death.[ref]
Serotonin syndrome is usually caused by drugs such as MAOIs or SSRIs that affect the rate of serotonin breakdown.[ref]
Serotonin Genotype Report:
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Below is a compilation of studies on genetic variants that affect serotonin synthesis, transport, and receptors. Please treat this as a starting point for learning more about your genes and serotonin. Talk with your doctor if you have any medical questions.
Serotonin Synthesis: Tryptophan Hydroxylase (TPH1 and TPH2)
Tryptophan hydroxylase is an enzyme that catalyzes the reaction that produces serotonin from the amino acid tryptophan. Iron is a co-factor, and BH4 is also used in the reaction.
There are two genes that code for tryptophan hydroxylase:
- TPH1 is found mainly in the gut, skin, and pineal gland.
- TPH2 works in the central nervous system.
(Learn more about tryptophan and how it converts to serotonin or kynurenine.)
Several TPH2 genetic variants have links to psychiatric issues such as obsessive-compulsive disorder, depression, and bipolar disorder. These variants affect the production rate of serotonin in the brain.
Check your genetic data for rs4570625 (23andMe v4, v5; AncestryDNA):
- G/G: typical
- G/T: decreased risk of depression[ref], less anxiety, and aggression[ref][ref]
- T/T: decreased risk of depression, less anxiety and aggression, more likely to be honest[ref]
Members: Your genotype for rs4570625 is —.
Interactions between different genetic variants can be important as well. There are a couple of interesting studies that look at the combination of carrying the rs4570625 genotypes with the BNDF Val66Met (rs6265) genotypes. Those with rs4570625 G/G and rs6265 T/T were more likely to have “impaired inhibition of negative emotional content”.[ref] (The next time you start yelling at someone, be sure to think about your “impaired inhibition of negative emotional content“!)
Serotonin Receptors: HTR1A, HTR1B, HTR2A
While there is still debate among researchers on this topic, one recent paper explains that the function of the brain’s serotonin receptors is to moderate stress and anxiety through patience and coping.
- The HTR1 receptors seem to mediate the ability to tolerate a source of stress, ‘passive coping’.
- The HTR2 receptors mediate the ability to actively cope and improve one’s ability to change due to adversity.
The HTR1A gene codes for a serotonin receptor.
Check your genetic data for rs6295 C1019G (23andMe v4, v5):
- C/C: higher impulsiveness, increased risk for depression[ref][ref]
- C/G: typical impulsiveness
- G/G: typical
*All alleles are given in the plus orientation to match 23andMe and AncestryDNA data
Members: Your genotype for rs6295 is —.
The HTR1B gene codes for another serotonin receptor.
Check your genetic data for rs6296 (23andMe v4, v5; AncestryDNA):
- G/G: increased risk of depression, anxiety after stressful life events, increased risk of childhood aggressive behavior, ADHD[ref][ref]
- C/G: somewhat increased risk of depression, anxiety after stressful life events, increased risk of childhood aggressive behavior, ADHD
- C/C: typical
*All alleles are given in the plus orientation to match 23andMe and AncestryDNA data
Members: Your genotype for rs6296 is —.
HTR2A gene: The serotonin 2A receptor (HTR2A) also has several well-studied variants, including rs6314, also known as C1354T.
Check your genetic data for rs6314 C1354T(23andMe v4, v5; AncestryDNA):
- A/A: reduced serotonin 2A receptors in the prefrontal cortex, increased risk of social withdrawal[ref][ref]
- A/G: reduced serotonin 2A receptors in the prefrontal cortex, increased risk of social withdrawal
- G/G: typical
Members: Your genotype for rs6314 is —.
Other studies on rs6314 show:
- In a study, paroxetine therapy response has ties to rs6314 polymorphism. Those with the minor allele (A) had a 7.5 times greater chance of response than those with G/G.[ref]
- Note that this variant is not linked to response to all SSRIs. For example, one study found that rs6314 was not linked to response to citalopram.[ref]
- An interesting 2013 study looked at serotonin receptor polymorphisms in association with a food reward. The study found that there was an association between the rs6314 A allele and susceptibility toward food reinforcement.[ref]
- A study found that those with the minor allele may not improve as much on olanzapine (an antipsychotic).[ref]
Serotonin Transporter: 5-HTTLPR Short and Long
SLC6A4 is the gene that encodes the serotonin transporter. You will find it as SERT or 5-HTT in some of the research. The 5-HTTLPR variant is a variable number tandem repeat. This just means there is a short version of the gene and a long version – due to repeated parts of the gene.
A lot of researchers have studied the 5-HTTLPR short/short and long/long forms. Initial studies in the ’90s and early 2000s found that those with the short version of the gene were more prone to depression due to stressful events. Here is a nice article summarizing the research that has been done on this gene: Controversial Gene-Depression Link Confirmed in New Study.
Variable number tandem repeats are not included in 23andMe or AncestryDNA data, but there are SNPs that usually go along with the serotonin transporter repeats. So you can get a pretty good idea of whether you carry the long or short version. A couple of studies have found that two SNPs predict the long or short version of 5-HTTLPR fairly well – around 95+% of the time.[ref][ref][ref] These are found in both v.4 and v.5 for 23andMe data.
| 5HTTLPR | rs2129785 (23andMe v4, v5; AncestryDNA) |
rs11867581 (23andMe v4, v5; AncestryDNA) |
|---|---|---|
| Long | T | G |
| Long | C | A |
| Short | T | A |
Your genotype for rs2129785 is —.
Your genotype for rs11867581 is —.
Examples:
- If your rs2129785 genotype is T/T and your rs11867581 genotype is G/G, you likely have two copies of the long version.
- If your rs2129785 genotype is T/T and your rs11867581 genotype is A/G, you have one copy of the 5-HTTLPR short and one copy of the long version.
- If your rs2129785 genotype is T/T and your rs11867581 genotype is A/A, you have two copies of the 5-HTTLPR short.
- rs2129785 genotype is C/T and your rs11867581 genotype is A/A, you likely have one copy of the 5-HTTLPR short and one of the long.
- If your rs2129785 genotype is C/C and your rs11867581 genotype is A/G, you likely have two copies of the 5-HTTLPR long.
Studies on personality traits and genes tend to show all kinds of different results — with the results of one study often contradicting other studies. So take the following with a grain of salt:
- The most replicated results for 5-HTTLPR show a link between carrying the short/short version and an increased risk of anxiety disorders.[ref][ref][ref]
- The short form of this gene has associations to lower 5-HTT activity.[ref]
A recent study may explain some of the contradictory results from previous studies.[ref] The researchers found that people who carried two copies of the long allele were more affected by environmental influences on mood (e.g., good or bad life events). Thus, people who carried the long/long genotype were more likely to have a positive mood in a positive environment, but they were also more negative when bad things happened.
Studies show the long or short form may influence how well depression medications work for you:
- Escitalopram was studied in a clinical trial of adults aged 60+ with a generalized anxiety disorder. The study found that escitalopram had “no efficacy” for those with low-activity haplotypes.[ref] (The short/short genotype is associated with lower activity.)
- In a study of citalopram for depression after TBI (traumatic brain injury), the results showed that those patients carrying the short/short genotype were more likely to have adverse events. (But honestly, with 84% of patients having adverse events, it doesn’t look like genotype plays a huge role here.)[ref]
- In an analysis of studies on Caucasian populations, those with the long/long genotype had a better response rate to SSRIs. This didn’t hold true for Asian populations, though.[ref]
Serotonin plays a major role in the gut, and IBS patients with a short allele had worse symptoms than those with a long/long version of this gene.[ref]
The short/short genotype also has ties to an increased risk of gastrointestinal intolerance of metformin.[ref]
Lifehacks for Serotonin:
Below you will find research-supported ways of affecting your serotonin levels. If you need psychiatric help, please be sure to contact a healthcare provider!
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