Serotonin (also known as 5-hydroxytryptamine or 5-HT) is often referred to as the “feel-good” neurotransmitter, but it also has diverse roles throughout the central and peripheral systems of the body [1-4].
It carries signals between nerve cells in the brain but also affects mood, appetite, digestion, sleep, bone health, blood clotting, and sexual activity. Evolutionarily, it is one of the oldest central neurotransmitters . For an in-depth guide on serotonin, read here.
In today’s article, we are going to examine how and where serotonin is produced so that we can better understand its impact on mental and physical health and well-being.
Serotonin is synthesized through a series of enzymatic reactions, beginning with the essential amino acid tryptophan. Essential amino acids cannot be produced by the body, hence the name, and must therefore be consumed through the food we eat. As a serotonin precursor, the dietary intake of tryptophan is closely related to the suppression of depressed and anxious moods . Different protein diets have been found to alter specific gut microbes, and ultimately affect the levels of serotonin found in the blood serum .
The first, and rate-limiting, step in the metabolic pathway leading to serotonin production involves tryptophan hydroxylase (TPH) . This enzyme converts tryptophan into 5-hydroxytryptophan (5-HTP) within the central nervous system and gastrointestinal tract. Even minor changes in TPH activity can cause drastic changes in serotonin content and serotonergic functions .
In mammals, there are two isoforms of TPH. TPH1 is mainly expressed by specialized gut endocrine cells called enterochromaffin cells  as well as by other non-neuronal cells such as adipocytes or fat cells . TPH2 is primarily expressed in neurons of the raphe nuclei in the brainstem and a subset of neurons in the enteric nervous system .
After the conversion of tryptophan to 5-HTP has taken place, aromatic L-amino acid decarboxylase (AAAD) brings about the decarboxylation of 5-HTP to form 5-HT or serotonin [11,13].
This process predominantly occurs in serotonergic neurons located in the raphe nuclei of the brainstem  and enterochromaffin cells in the gastrointestinal tract. Somewhat surprisingly, the overwhelming majority (over 90%) of the serotonin produced by the body is synthesized in the gut, as opposed to the brain .
Regulators of Serotonin Production
The key determinants of serotonin production include dietary tryptophan, given its importance as a serotonin precursor. Secondly, the activity of tryptophan hydroxylase is highly important, and is regulated by numerous hormones and neurotransmitters. The release and reuptake of serotonin also influences the duration and strength of serotonin signaling . Lastly, the body employs feedback mechanisms to regulate serotonin production. For example, when serotonin levels are high, feedback signals can reduce its synthesis to prevent excessive activity.
Serotonin and Mental Health
The role of serotonin in mood and emotional regulation has led to extensive research on its connection to mental health disorders [16-18]. Although most of the serotonin in the body is distributed outside the central nervous system, the 2% that is within said system plays a pivotal role in mental health.
Imbalances in serotonin levels are associated with conditions such as depression, anxiety, addiction, schizophrenia, and bipolar disorder, to name a few. Functional neuroimaging studies using positron-emission tomography (PET) and single photon emission computed tomography (SPECT) have demonstrated persuasive evidence of the role of serotonin in such conditions .
Selective serotonin reuptake inhibitors (SSRIs), a class of antidepressant medications, work by increasing the availability of serotonin in the brain, and were the first class of psychotropic medications to be rationally designed . They are among the most commonly prescribed medications and some of the first-line in treating chronic psychiatric conditions such as major depressive disorder .
An understanding of the production and regulation of serotonin is crucial for developing effective treatments for psychological disorders. By targeting the serotonergic system, the symptoms of these conditions can be treated.
Recently, the so-called serotonergic theory of depression has been questioned. A major review of research conducted by University College London found that there was no clear evidence to suggest that serotonin levels or activity are responsible for depression . These findings cast doubt on the “chemical imbalance” supposition that has taken hold over previous decades.
How Do Psychedelics Affect Serotonin Production?
Serotonergic or “classic” psychedelic compounds include psilocybin, dimethyltryptamine (DMT), and lysergic acid diethylamide (LSD). The psychoactive effect of these substances is brought about by their agonism of the 5-HT2A serotonin receptor (5-HT2AR). The agonism of this receptor increases serotonin release. That is to say, these substances stimulate serotonin receptors in the brain just like serotonin does. Take psilocybin for example: its intake leads to occupancy of the 5-HT2AR in the brain, which is linked to the intensity of the experience 
Other receptors are involved in the antidepressant effect of psychedelics as well. In the case of LSD, a partial agonist of 5-HT2AR, the 5-HT1AR receptor is primarily responsible [23,24].
In this article, we have explained how serotonin, a monoamine neurotransmitter with diverse physiological functions and roles, is produced through the conversion of tryptophan in both the central nervous system and the gastrointestinal tract.
In the brain, serotonergic neurons in the raphe nuclei play a critical role in mood regulation, whereas in the gut, enterochromaffin cells contribute to the regulation of intestinal functions. The synthesis and regulation of serotonin are both governed by dietary factors, enzyme activity, and feedback mechanisms, making it a complex system to study and comprehend.
We have also looked at the role of psychedelics and their impact on serotonin and its associated receptors in the brain.
As research in this area continues to evolve and expand, our knowledge of the role of serotonin in mental health and overall well-being will likely improve as well, leading to more targeted therapies and treatments for a wide range of conditions.
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