Serotonin… a word that brings to mind commercials showing happy brain neurons bouncing serotonin between them.
There is a lot more to this molecule than most of us realize!
What does serotonin do?
About 90% of serotonin is made in the gut and regulates motility there.[ref] Serotonin also regulates other functions such as in bone mass, cardiovascular health, the endocrine system, and appetite.
In the brain, serotonin acts in several ways:
- as a neurotransmitter, sending a chemical message between neurons.
- as the precursor molecule for melatonin[ref]
- in sleep quality, including sleep hallucinations[ref] [ref]
Some researchers believe that imbalances in serotonin may play a role in depression or anxiety. Common anti-depressants include SSRI’s, which are thought to increase serotonin levels in the brain. Although, the method through which they work is still not completely understood.[ref]
Balance is key with serotonin. Too much serotonin is known as 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 break down. [ref]
Serotonin, also known as 5-hydroxytryptamine or 5-HT, is synthesized from the amino acid tryptophan using tryptophan hydroxylase (TPH1 and TPH2 gene).
It is transported by SLC6A4, which is also known as SERT or sodium-dependent serotonin transporter.
The serotonin signal is received by serotonin receptors on the cell membrane: HTR1A, HTR1B, and HTR2A.
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.
Below is a compilation of studies on genetic variants that affect serotonin. It is not an exhaustive list; instead, treat this as a starting point for you to find out more about your genes.
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.
A good overview of TPH2 can be found in the introduction of this study which also explains the link with GABA levels as well.
Several TPH2 genetic variants have been linked to psychiatric issues such as obsessive-compulsive disorder, depression, and bipolar disorder. These variants affect the rate at which serotonin is being produced in the brain.
Check your 23andMe results for rs4570625 (v4, v5):
- GG: most common form
- GT: decreased risk of depression[ref], less anxiety and aggression[ref][ref]
- TT: decreased risk of depression, less anxiety and aggression, more likely to be honest [ref]
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 GG and rs6265 TT 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 Transporter: 5-HTTLPR Short and Long
SLC6A4 is the gene that encodes the serotonin transporter. It is also called SERT or 5-HTT in some of the research. The 5-HTTLPR variant is a variable number tandem repeat. This just means that there is a short version of the gene and a long version – due to repeated parts of the gene.
Lots 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.
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 reults for 5-HTTLPR seems to be between those carrying the short/short version and risk of anxiety disorders.[ref][ref] [ref] Additional studies have shown that the short allele also increases the risk for major depressive disorder.[ref] The short form of this gene is associated with lower 5-HTT activity. [ref]
Studies show the long or short form may influence how well depression medications work for you:
- Escitalopram (Lexapro) was studied in a clinical trial of adults aged 60+ with generalized anxiety disorder. The study found that escitalopram had “no efficacy” for those with the low activity haplotype. [ref] (The short/short genotype is associated with lower activity.)
- In a study of citalopram for depression after TBI, 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 SSRI’s. 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 is also tied to an increased risk of gastrointestinal intolerance of metformin.[ref]
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 serotonin receptors is to moderate stress and anxiety through patience and coping.
The HTR1 receptors are thought 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 variant rs6295 is also known as C(-1019)G. In the plus (23andMe) orientation, C is the minor allele, but most studies use the minus orientation and will note G as the minor allele. Note that this is a very common variant with almost half of most populations carrying the minor allele.
Check your 23andMe results for rs6295 (v4, v5)
The HTR1B gene codes for another serotonin receptor. One well studied genetic variant is rs6296. Again, in the 23andMe orientation, G would be the risk allele, but when you read through the studies, it will refer to C as the minor allele.
Check your 23andMe results for rs6296 (v4, v5):
- GG: increased risk of depression, anxiety after stressful life events, increased risk of childhood aggressive behavior, ADHD[ref][ref]
- CG: somewhat increased risk of depression, anxiety after stressful life events, increased risk of childhood aggressive behavior, ADHD
- CC: normal (most common type)
The serotonin 2A receptor (HTR2A) also has several well-studied variants including rs6314, also known as C1354T. In the plus orientation (23andMe), A is the minor allele.
Check your 23andMe results for rs6314 (v4, v5):
- AA: reduced serotonin 2A receptors in the prefrontal cortex, increased risk of social withdrawal[ref][ref]
- AG: reduced serotonin 2A receptors in the prefrontal cortex, increased risk of social withdrawal
- GG: normal (most common)
Here are a few other studies on rs6314:
- In a study, paroxetine (Paxil) therapy response was tied to rs6314 polymorphism. Those with the minor allele (A) had a 7.5 times greater chance of response than those with GG. [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 rs6314 A allele and susceptibility towards food reinforcement. [ref]
- A study found that those with the minor allele may not improve as much on olanzapine (an antipsychotic). [ref]
Another HTR2A very common variant has also been well studied. The variant rs6311 (C allele) has been found to be associated with an increased risk of aggression in adults. [ref]
Check your 23andMe results for rs6311 (v4, v5):
- CC: more empathy for happiness, more speed-dating success for women[ref], increased risk of sexual dysfunction with SSRI[ref][ref]
- CT: more empathy for happiness,
- TT: normal
Below are evidence supported ways of affecting your serotonin levels. If you are needing psychiatric help, please be sure to contact a health care provider!
While your genes have an effect on serotonin levels in the body, there are also several environmental factors that also influence serotonin production. Exposure to bright light or sunlight is correlated to higher serotonin levels.[ref] Physical activity may also increase serotonin levels. Eating foods high in tryptophan may also increase serotonin levels, but it is hard to know how much of an effect it has on serotonin in the brain.[ref]
Don’t forget in all this talk about neurotransmitters that serotonin plays a big role in the gut. Here is a great research article on serotonin and the gut microbiome: Serotonin, tryptophan metabolism and the brain-gut-microbiome axis
There are quite a few studies (mostly animal studies) showing the effect of Lactobacillus species on serotonin production in the gut. This not only seems to have an effect on gut mobility and gut issues, but it also has an effect, perhaps through the gut-brain axis, on anxiety and depression.[ref][ref][ref][ref]
A good overview of the gut-brain axis and the recent research on the effect of gut microbes on mood and anxiety can be found in the March 2018 journal article “Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders“.
There are quite a few clinical trials showing that specific probiotics are effective for depression and anxiety (whether due to serotonin problems or other reasons). One clinical trial for postpartum depression found that Lactobacillus rhamnosus was effective. [ref] another clinical trial in IBS patients with depression found that Bifidobacterium longum reduced depression but not anxiety.[ref] A clinical trial using Lactobacillus casei, acidophilus, and Bifidobacterium bifidum found a significant decrease in depression scores. [ref] One probiotic that has worked well for me is the Renew Life Ultimate Flora that combines several strains of Lactobacillus and Bifidobacterium.
There is a supplemental form of the precursor to serotonin, 5-HTP that is readily available. There are many studies showing the effect of supplementing with 5-HTP, but I would say that caution is always advised when taking supplements that can affect your neurotransmitters. If you are under a doctor’s care or on other medications, be sure to check with your doctor. A case report shows that mixing MAOI prescription with over the counter 5-HTP supplement caused an adverse reaction (manic episode).[ref] [ref][ref]
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