What is Serotonin? How Does 5-HT Work?

Serotonin, also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter and neuromodulator that can be found in the Central Nervous System (CNS), in the blood platelets, and in the Gastrointestinal tract (GI) a.k.a. the stomach. Note that serotonin is manufactured by the body mainly in the GI tract. In fact, 90% of all of a human being’s total body serotonin is located in the GI tract to regulate the movements of the intestines. You should know that the intestines is composed of smooth muscles that deliver food from your stomach all the way to exit point.

Additionally, outside sources of serotonin have a hard time passing the blood brain barrier. That means most of the serotonin found in the brain is produced in the brain and that outside sources of serotonin, such as from the GI tract, does not effect the serotonin levels in the CNS.

Serotonin acts on serotonin (5-HT) receptors, of which there are many types and subtypes (e.g. 5-HT1A, 5-HT2C).

And when there is a problem with the amount of serotonin in the body or brain, it may lead to disorders such as ASPD (Anti-Social Personality Disorder), depression, anxiety, and fibromyalgia.

Serotonin has many functions throughout the brain and the body. Let’s start by first analyzing serotonin’s role in the brain.

Table of Contents

Serotonin & the CNS

orang white strips catty cat sleeping on a blanket peacefully white whiskers — Serotonin is required for the production of melatonin, the sleep hormone. This makes serotonin integral for good sleep.

Serotonin’s role in the CNS is to influence our cognition, mood, appetite, sleep, memory, sense perception, and sexual arousal. For our mood, high or sufficient levels of serotonin in the brain makes us feel happy and content. However, low levels of CNS serotonin may cause depression and insomnia, given that the brain needs serotonin as a precursor chemical for the production of melatonin in the body. Remember, we need melatonin in order to fall asleep.

An interesting effect that serotonin has is to reduce hunger. Such that high levels of serotonin reduces hunger, as seen with many different stimulants that increases the amount of monoamine neurotransmitters (serotonin is one of them) in the brain. Such as coffee, amphetamine, methamphetamine, modafinil, adrafinil, etc. Basically, any drug that raises the level of serotonin available in the CNS also reduces hunger.

On the other hand, a lack of serotonin causes us to become hungrier than usual. Note that serotonin is derived from the essential amino acid tryptophan that can only be acquired through diet. This is interesting because the hunger from low serotonin levels causes us to seek out food to replenished our serotonin levels, thereby acting as a sort of feedback loop.

And it is also interesting to consider that many people turn to food in times of stress, as a form of stress relief and anti-depressant. Perhaps food has a positive effect on our serotonin levels? Indeed, tryptophan that is commonly found in most foods has a mild anti-depressant effect, given that it bolsters the level of serotonin in the CNS.

Serotonin has an important role in our cognition. Specifically, serotonin helps us learn and form memories. You can tell the parts of the brain that serotonin is active in by noting which parts of the CNS has serotonin receptors. Specifically, serotonin receptors are found in the cortex (outer layer of the brain), amygdala, and the hippocampus. With sufficient serotonin, function in these parts are enhanced; however, learning and memory is hindered when CNS serotonin levels are lowered.^[1]

How Does Serotonin Affect our Mood?

scary eyes black paint streak down drip drop — Serotonin is believed to play a major role in mood and behavior, and that a lack of it in the brain may be a risk factor for depression.

In general, the presence of serotonin has a positive affect on our mood, and makes us more sociable. But a lack of serotonin makes a person more sensitive to stimuli in a negative way- in other words more irritable. That means that a lack of serotonin tends to make a person less sociable, and more introverted. I believe this goes to show that serotonin has an effect of blunting our (pain) sensitivity to stimuli. And that too little serotonin makes us more sensitive to stimuli in a negative way, thereby making a person introverted such as to avoid high-stimuli situations, like talking to other people, group events that tends to be noisy, etc.

This excerpt from a study observing the effect of lowering serotonin levels elaborates more on the role that serotonin has on mood:

Alterations in brain tryptophan levels cause changes in brain serotonin synthesis, and this has been used to study the implication of altered serotonin levels in humans. In the acute tryptophan depletion (ATD) technique, subjects ingest a mixture of amino acids devoid of tryptophan. This results in a transient decline in tissue tryptophan and in brain serotonin. ATD can result in lower mood and increase in irritability or aggressive responding. The magnitude of the effect varies greatly depending on the susceptibility of the subject to lowered mood or aggressivity. Unlike ATD, tryptophan can be given chronically. Tryptophan is an antidepressant in mild to moderate depression and a small body of data suggests that it can also decrease aggression. Preliminary data indicate that tryptophan also increases dominant behavior during social interactions. Overall, studies manipulating tryptophan levels support the idea that low serotonin can predispose subjects to mood and impulse control disorders. Higher levels of serotonin may help to promote more constructive social interactions by decreasing aggression and increasing dominance.^[2]

Serotonin & Blood Platelets

As for blood platelets, they actually store serotonin that is manufactured from the enterochromaffin cells of the GI tract. Specifically, the enterochromaffin cells reside on the surface of the digestive tract. So the question is, why is serotonin stored in the blood platelets? Because when blood platelets start to clot, they release the serotonin they carry to cause constriction of blood vessels (vasoconstriction). This is an important function that helps the body resist excessive bleeding when there is a cut.

The vasoconstriction due to blood platelet serotonin release also has a secondary function, which is to increase blood pressure. Narrower blood vessels requires almost the same amount of blood to travel through; so of course blood pressure is increased to compensate. I figure this is actually a good thing in the case of severe blood loss; the body can compensate for the lack of blood by decreasing the volume of blood required through vasoconstriction.

Serotonin and the Digestive System

Coffee is quite a fine antidepressant, don’t you agree? I believe one way coffee improves mood is by acting as a mild MAOI, and therefore boosting the amount of serotonin available in the brain.

As for the GI tract, serotonin is introduced into this body system through the enterochromaffin cells that line the surface of the digestive system. In the digestive system, serotonin has the function of speeding up the pace at which food transits from the mouth all the way to the “exit point”. In other words, you would become constipated if you were serotonin deficient. In fact, the amount of serotonin present in the digestive tract kind of also explains why coffee is such a good laxative. The MAOI inhibitors in the coffee bean prevent the breakdown of serotonin, thus increasing the amount of serotonin in the GI tract, and thereby the speed at which the digestive tract’s smooth muscles pulsate to push the food out.

Why would Serotonin Levels Become Low?

Well, you have to first consider how serotonin is introduced into the body. First of all, serotonin does not easily cross the blood brain barrier, such that it can be considered that the serotonin available in the brain is only produced by the brain itself- not other outside sources.

So how does the brain produce serotonin in the first place? Well, both the brain and the body produces serotonin from an organic chemical called tryptophan. Tryptophan isn’t made in the human body. Instead it is an essential amino acid that we need to acquire through diet.

That means a deficiency of tryptophan leads to a deficiency of serotonin. Ok, let’s take a look at what causes us to become deficient in tryptophan in order to understand what causes serotonin deficiency.

So one way Tryptophan deficiency can manifest is through a lack of tryptophan in the diet. This usually doesn’t happen, except perhaps for strict vegetarians with a bad diet. A lot of tryptophan can be found in animal products, like milk and cheese. Even cocoa has a significant amount of tryptophan.

Another way for tryptophan deficiency to develop is through the malabsorption of tryptophan in the digestive tract. Tryptophan malabsorption can happen in two non-inclusive ways:

Too many competing amino acids
fructose malabsorption

Tryptophan and Competing Amino Acids

To be brief, the amount of tryptophan that reaches the brain, that will later on become serotonin, has to compete for transport with other essential amino acids. And the type of diet can affect how well tryptophan is absorbed.

For example, you can actually improve the absorption of tryptophan by pairing it with carbohydrate ingestion. Carbohydrates improve the absorption of tryptophan by causing a huge amount of insulin to be released into the body. The insulin speeds up the rate at which essential amino acids such as valine, leucine, and isoleucine are removed. That means tryptophan has less competition for being transported into the brain past the blood brain barrier, to be eventually metabolized into serotonin. In other words, tryptophan paired with carbs raises the amount of serotonin that is present in the CNS.

On the other hand, high protein paired with tryptophan has the opposite effect. That is because most proteins (meaning it depends on the type of protein) have many amino acids, thereby providing more competition for tryptophan to be transported to the brain, and therefore reducing the amount of tryptophan that reaches the brain. And in turn, reducing the amount of brain tryptophan that gets turned into serotonin.

Tryptophan and Fructose Malabsorption

Now as for fructose malabsorption, a study gave 50g of fructose to adult test subjects that couldn’t digest fructose properly. The result was that the fructose remained in the intestinal tract, interfering with tryptophan absorption and also being consumed by intestinal bacteria, causing bloating, cramps, and diarrhea. Either the fructose directly interfered with the absorption of the tryptophan, or the resulting irritable bowel syndrome impeded tryptophan absorption. The later is not likely, given that lactose intolerance- which also causes irritable bowel syndrome, does not harm tryptophan absorption.^[3]

Tryptophan & Serotonin is Lowered by Inflammation & Infection

turmeric root uncut, cut into slices, and turmeric powder comparison picture — Keep in mind that turmeric is quite a potent anti-inflammatory. That means it may help prevent the destruction of tryptophan, and therefore increase levels of serotonin in the body

So one way tryptophan availability in the body can be lowered is through inflammation by an infection. This passage by Steven Fowkes elucidates what I am talking about:

For example, people with inflammation get far less efficacy from tryptophan. And from 5-hydroxytryptophan (5-HTP). This is because the human body is engineered to burn up tryptophan during an infection (it is one of four bacterial growth-limiting nutrients in the human blood stream), and the body cannot discriminate between infection-mediated inflammation and allergy-related inflammation. Any kind of inflammation induces indoleamine dioxygenase (IDO), an enzyme that catabolizes tryptophan and other indoleamines. So if this enzyme is active, any tryptophan you take will become substrate for IDO, and less will get across the blood-brain barrier to be converted into serotonin, for sleep enhancement. Furthermore, some of the catabolites of tryptophan are neurotoxic and excitotoxic. And I (we?) do not know what the catabolites of 5-HTP are.

There is a trick to getting past IDO. Curt Tigges (excellent post) mentions taking collagen for sleep for its glycine content, but there’s another amino-acid feature for collagen protein that is of relevance to sleep: low amounts of large neutral amino acids. This can be exploited by adding tryptophan to predigested collagen protein, which contains peptides that solublize tryptophan. So you get (1) pre-dissolved tryptophan, for fast absorption into the blood stream, and (2) decreased competition for tryptophan transport through the blood-brain barrier by other large neutral amino acids. It takes up to 30 minutes for tryptophan to dissolve in a solution of predigested (hydrolyzed) collagen, but once dissolved, the tryptophan absorbs exceedingly quickly when consumed on an empty stomach. This gives IDO less time to catabolize the supplemented tryptophan.^[4]

What is the Role of Serotonin in the Stomach?

Serotonin is a neurotransmitter that has a significant role in the digestive tract, made by the enterochromaffin cells lining the digestive tract, and has a function of controlling the gut smooth muscles contractions and gut sensations. Blocking the serotonin (5HT) receptors in the gut causes constipation. Too much blocking leads to vomiting or nausea. Whereas stimulating the 5HT receptors causes the contractions of GI tract smooth muscles, leading to bowel movements. Excess stimulation of 5HT receptors leads to diarrhea. You should note that blocking 5HT receptors in the stomach is akin to having low levels of the serotonin neurotransmitter in available in the stomach. And similarly, stimulating 5HT receptors is the stomach is like having sufficient to high levels of serotonin available to the stomach.

So to summarize, serotonin controls the speed at which food passes through our digestive system. More serotonin means faster transit, and less serotonin means slower transit.

To re-iterate, constipation can occur when not enough tryptophan is available to be made into serotonin. You can understand how serotonin levels become low in the passage above. Diarrhea can occur when there is too much serotonin in the GI tract. This can happen because of pathogenic bacteria or parasites that secrete serotonin into the infected host’s stomach. A prime example is the parasitic infection by entamoeba histolytica.^[5]

Interestingly, another way excess serotonin can end up in the stomach is due to monoamine oxidase inhibitors (MAOI), given that serotonin is a monoamine. A very well known example of a MAOI is coffee, which indeed causes symptoms of extra serotonin in the stomach, in the form of a bowel movement.

What are Supplements that Increase Serotonin Levels?

ginger root — Also, Ginger is another fine anti-inflammatory that may help prevent the destruction of tryptophan, and therefore may improve serotonin levels. Ginger is quite good for digestion too… Actually, I would go as far as to say that a healthy digestion is required for a healthy cognition.

Interestingly, there are two good ways you can choose supplements in order to boost serotonin levels inside the body and brain. Specifically, you can lower inflammation (and infection) given that the body destroys tryptophan when under inflammation. This is actually one reason why extremely heavy exercise can cause depression, due to the tryptophan being destroyed in the body from the inflammation. Our body’s need tryptophan in order to manufacture serotonin, and we need serotonin present in our brain in order to maintain a positive mood and stave depression.

Another interesting connection can be made with antibiotics and mood. Specifically, there exists anecdotes of people who become less depressed and have a uplift in mood from taking antibiotics for their illness. That’s for the same reason why lifting inflammation improves mood- less tryptophan as a result of the inflammation of the infection, and therefore more serotonin is manufactured in the brain to boost mood positively.

So you can focus on supplements that eliminate infection and/or inflammation. One that I personally use is ginger as my favored antibiotic/antiparasitic/anti-inflammatory. Another good anti-inflammatory is turmeric. No wonder I feel positively jovial after taking either herbal medicine.

Another way you can boost serotonin levels in the body is through tryptophan supplementation.

And finally you can artificially boost serotonin in the brain by taking a Selective Serotonin Re-uptake Inhibitor (SSRI), but I have doubts in its ethicacy. There are user reports that SSRIs can cause depression and suicidal tendencies. That’s not right, and rather a downright contradiction to what it is suppose to do, in my opinion. But I am no doctor, so you’ll have to consult a doctor about SSRIs.

Finally, some people advocate using 5 HTP supplements for increasing serotonin levels. Yes, 5 HTP may increases serotonin levels in the body peripherals. But NIH indicates that it may not actually increase serotonin levels in the CNS.

So according to a NIH paper^[6], 5HTP is immediately converted into serotonin. But the problem is that this serotonin doesn’t reach the brain.

Furthermore, it looks like 5 HTP supplements may actually “facilitates depletion of dopamine, norepinephrine, and epinephrine”, and “thereby worsening the disease and its underlying cause.”

The reviews on amazon for the 5 htp supplements indicates that 5 htp does work for some people. This could be the placebo effect in action.

I’ve listed all the supplements for boosting serotonin at the bottom of the article.

What Effect Does SSRIs have on Serotonin Levels?

According to one study, taking SSRIs actually decreased the amount of serotonin that the brain’s neurons released into the neuronal synapses. That makes sense. The brain tries to keep homeostasis, or a balance. So if there is already plenty of serotonin in the neuronal synapses, then the neurons decrease the amount of serotonin that they release.

But this change in serotonin output does not happen immediately. This is one reason why it is a bad idea to abruptly stop taking an SSRI; your brain has adapted and therefore developed a need for that SSRI to keep homeostasis, much like coffee drinkers need their caffeine everyday in order to maintain a baseline in their cognitive function.

What are the Metabolites for Serotonin? What is Serotonin Derived from?

Serotonin is derived from tryptophan, specifically the hydroxylation and decarboxylation of tryptophan.

You should know that hydroxylation refers to when a hydroxyl group (-OH) is added to an organic compound. And decarboxylation refers to when a carboxyl group (COOH) is removed from an organic compound.

Anyways, the fact that serotonin is derived from tryptophan is significant. That means we require tryptophan for the production of serotonin in the body. In fact, when tryptophan is malabsorbed or deficient in the diet, the person thereby may experience symptoms of serotonin deficiency.

Serotonin is part of a metabolic pathway, or basically a conversion chain of one substance turning into another substance. That chain is:

Tryptophan to Serotonin to Melatonin.

Serotonin Pathway

Serotonergic neurons are found in dense clumps called raphe nuclei, which project into the whole cortex, the striatum, the ventral tegmental area, the substantia nigra, amygdala, the thalamus, the cingulate cortex, the hypothalamus, and septum to name a few.

Cool Facts About Serotonin

Given the amount of research that I’ve had to do to understand the place that serotonin has in the function of the human body, I ended up digging up quite a few interesting facts that I didn’t want to disclude. So here they are:

LSD blocks the effects of serotonin in the brain. This is one reason for LSD’s psychedelic effects; serotonin kind of filters the amount of information that we perceive from out environment. LSD undoes that, giving the user a sensory overload “psychedelic” effect.

In the CNS, High serotonin levels usually produces harm avoidance and inhibited behavior. Whereas low serotonin paired with high dopamine produces a novelty seeking personality, a person who is driven to seek out stimulation and fun.