As the science of our brains slowly becomes more widely known, the neurotransmitter Serotonin has become a relatively commonplace phrase among laymen. Pop science media frequently has dubbed the compound "the happiness chemical" and equates lowered levels with depression. This all sounds good, but the question is, is it even true?

Is Serotonin Really the Happiness Chemical?

Serotonin, or 5-hydroxytryptamine (5ht) is one of the basic monoamine neurotransmitters, and while it has a massive impact on our mood, the real story is far more fascinating.

An Overloaded Neurotransmitter

Although mood regulation is one of Serotonin's major duties, the compound actually has a wide range of functions throughout the body ranging from thermoregulation, nausea control, gut motility, regulation of the production of other neurotransmitters, regulation of orgasm, regulation of the production of hormones, aggression control, anxiety, appetite, cognitive abilities, sleep, memory, neuroplasticity, and many more.

Far from being simply a mood chemical, serotonin is an integral part of your body and has one of the most wide ranging duties out of all your bodily chemicals. It was also one of the earlier neurotransmitters to evolve, with it shared across numerous species in a wide array of absurdly disconnected functions.

A Fun Fact About Grasshoppers

Grasshoppers have special sensors on their legs that detect physical contact. These sensors are connected to serotonergic neurons that release serotonin into the synapse when they fire. In normal life, physical contact occurs sparingly, and the serotonin spikes never reach a high enough level to effect much change. This all becomes a whole different picture when the population of grasshoppers starts reaching too high of a density. As the grasshopper colony gets overcrowded, grasshoppers start rubbing on each others legs more and more often, leading to massively increased serotonin releases. Once enough has been released, a series of metamorphosis begins in the body of the grasshopper, transforming it both physically and behaviorally into the aggressive swarming locust. Eventually the whole colony converts one by one, and the entire horde swarms out, devastating everything their wake.

Chemistry

Serotonin is a relatively simple compound in the tryptamine class. A tryptamine molecule is an indole (a fused benzene and pyrrole ring) joined with an ethyl amine group and forms the basis of a vast array of psychedelics such as Psilocin, DMT, and LSD. Serotonin is the 5-hydroxy version of Tryptamine, meaning there is the addition of an hydroxy group (an oxygen bonded to a hydrogen) on the 5th position on the indole structure.

The similarity of serotonin to numerous psychedelics is a big part of these psychedelics are able to bind to the 5-ht2a (serotonin receptor subset best known for psychedelic effects) receptor. As for why serotonin itself does not cause these effects, that will have to wait on a future section on biased agonism / functional selectivity.

Some of Serotonin's Effects on Humans

There are way too many effects to really discuss comprehensively in one article, but here we dive into a few interesting highlights.

Mood Regulation

Serotonin's relationship with mood is highly complicated and involves numerous positive and negative self feedback loops and implicates numerous other neurotransmitter systems. Our previous understanding of "serotonin go up, mood go up" has been proven to be vastly oversimplified, and indeed even high serotonin can lead to dysphoria and distressing mood. Irritability and heightened aggression and anxiety is a common symptom of serotonin syndrome (a toxic excess of serotonin), disproving the notion that serotonin is strictly a "happy chemical".

However, within reasonable ranges, an acute increase in global serotonin levels does generally correlate to a series of predictable and consistent subjective impacts on mood:

1) A sense of calm, quiet, serenity. The noises and worries of the world almost seem hushed and dimmed.

2) An increase in emotionality, particularly around trust and love of those you deem in your ingroup. This is primarily associated with release of oxytocin mediated via activity at the 5-HT1A in neurons of the hypothalamus. Oxytocin is the molecule most that induces heightened trust and love of ingroup and heightened distrust of outgroup (love your friends more hate your enemies more) depending on how and where it is released. Oxytocin acts upon different regions of the amygdala regions of the brain to effect these changes. This is most likely the primary cause of the entactogenic (pro-love) effects of MDMA, MDA, 5-MAPB, 4-MMC, and other drugs in the class.

3) An alteration of anxiety levels. Serotonin's relationship with anxiety is highly complex and a subject of ongoing scientific study. Drastically altered serotonin levels can have either an increasing (anxiogenic) or decreasing (anxiolytic) impact on anxiety levels depending on a complex variety of factors including other neurotransmitter levels, genetic differences, and more.

Nausea Regulation

As mentioned earlier, serotonin is used for every function under the sun. Tons of harmful microbes, obviously, also use it extensively as part of their metabolic process. Over the eons of our evolutionary history, we have evolved a high concentration of 5-ht3 serotonin receptors in the gut, aimed specifically at detecting excess serotonin in our gi tract (In fact, over 80% of our serotonin activity are in the gut!). Since serotonin is excreted as part of harmful microbe's metabolic process, this is a great proxy for detecting food poisoning. Our body has evolved a nausea and emesis (vomit) response to activity from these 5ht3 receptors.

This is the primary reason why serotonergic substances (either releasers such as MDMA or agonists such as psychedelics) so frequently cause nausea and stomach upset.

The primary treatment for serotonin induced nausea is the application of 5ht3 antagonists. There are two main category of compounds that are in this class:

1) The Setrons: A family of pharmaceutical drugs that all tend to end in the suffix -setron. Examples include ondansetron, dolasetron, etc. These are typically prescribed for nausea, especially as a part of chemo treatments. They competitively block the 5ht3 receptor, making it harder for serotonin to bind to it. However, sufficient amounts of serotonin or serotonin agonists could overwhelm this effect.

2) Ginger: Ginger contains gingerole and various derivations of gingerole. Gingerole is a noncompetitive antagonist of the 5ht3 receptor. The noncompetitive means that it doesn't even bother playing musical chairs for the receptor, it instead, picks a chair, sits down, and then burns the whole building down so no one else can even think about sitting on a chair again. Noncompetitive antagonists bind to a separate site on the receptor (known as an allosteric site), which then completely and permanently disables the receptor. This isn't dangerous as your brain is constantly making and recycling receptors, so after a short period of time it will go back to normal again. The benefit of this, though, is that ginger cannot be overcome by excess serotonin and in theory is more effective than the -setrons. However, clinical research suggests best results are achieved with co-administration of both ginger and ondansetron [https://pubmed.ncbi.nlm.nih.gov/24497743/]

The primary negative of ginger is a short duration of effect (your brain quickly replenishes those lost receptors and ginger itself only has very short half lifes [sauce], potentially owing to other lackluster when taken with less frequent dosing schedules: https://pubmed.ncbi.nlm.nih.gov/27714530/

A Note on SSRIs and Depression

Another frequent reason why serotonin is associated with good mood is due to the efficacy of Selective Serotonin Reuptake Inhibitors (SSRIs) in treating depression. Since SSRIs raise serotonin levels in the brain, we assumed at the time that serotonin must have a direct relationship with depression. We've since learned that this is an oversimplification at best.

What is an SSRI?

SSRIs are drugs that have good binding affinity for the Serotonin Transporter (SERT), which is a protein primarily responsible for transporting serotonin back out of the synaptic cleft after it has done its job. This process of removing serotonin is known as serotonin reuptake, and SSRIs inhibit SERT's ability to do its job. With SERT inhibited, synapses tend to accumulate higher levels of serotonin than usual, allowing them to bind to more receptors or for longer before eventually being reuptaken.

So Why do They (Sometimes) Work?

The latest hypothesis on SSRIs is that they also boost neuroplasticity, which is a measure of the brains ability to strengthen existing synaptic connections (in a process known as long term potentiation which we will cover in the future) and grow new synaptic connections. Depression is highly correlated with lowered neuroplasticity, reducing the brain's ability to form positive mental habits and recover from psychological trauma. Drugs that tend to boost neuroplasticity such as Ketamine (through a paradoxic glutamate increase), psychedelics (perhaps through increasing BDNF or by suppressing the Default Mode Network) tend to all have a beneficial effect in the treatment of depression, and the primary common pathway they share with SSRIs is the increased neuroplasticity.

Of course, even this is a vast oversimplification of both depression and neuroplasticity, we'll get to more details in future articles.

Serotonin, is it Really the Happiness Chemical?