Serotonin

When people think about serotonin, they typically envision the neurotransmitter within the brain. You may be surprised to learn that the serotonin (5-HT) made in the brain comprises only 10% of the 5-HT found within the body.

Serotonin made within the brain is synthesized by the raphe nuclei of the midbrain. It is prevented from leaving the brain by the blood-brain barrier. This specialty organ is comprised of cells called astrocytes, which prevent certain chemicals from entering and exiting the brain.

The rest of our serotonin is synthesized by the enterochromaffin cells of the intestine and are stored within the platelets of our blood.

Neurotransmitter: 5-HT influences a wide range of biological functions. In the CNS, it serves as a neurotransmitter that is responsible for influencing numerous behavioral traits. It helps regulate sleep/wakefulness, appetite, nociception, mood, stress, and maternal or sexual behavior. Interestingly enough, serotonin is used as a precursor by the pineal gland to create melatonin, the neurotransmitter used to help us fall asleep.  Additionally, during early brain development, serotonin is believed to be involved with neuronal proliferation, migration, and differentiation. Poorly regulated 5-HT has been found to cause personality disorders, such as impulsive aggression, manic depressive illness, anxiety, alcoholism, and neurological conditions, such as migraine. [2]

Blood Platelets (thrombocytes): Within the gastrointestinal tract, 5-HT is released by enterochromaffin cells. They are then picked up by blood platelets from within the bloodstream. When platelets are activated (by collagen, thrombin, or ADP) they release serotonin. When this mechanism is activated the serotonin binds to 5-HT2A receptors (a type of serotonin receptor [5]) on the surface of the platelet. As a result the platelet becomes more sticky and reactive, boosting their ability to aggregate and form a clot. In effect the vasoconstricting abilities of serotonin turns up the volume on the blood clotting response. Additionally, serotonin may be released to encourage platelets to clump together to create a plug at an injury site, which allows it to become more stable, so the bleeding stops faster. Another benefit of serotonin it can cause vessels to narrow (constrict), reducing blood flow to the site of injury. Less blood flow means less pressure on the forming clot, giving the platelets a higher likelihood of sealing the breach. 5-HT can also help tweak the aggressiveness of platelets, so they may adjust to react appropriately to the severity of an injury. This helps maintain a balanced hemostatic response, which prevents over- or under-clotting.

In most instances general platelets will get the job done to stop the flow of blood, and lay the foundation of what will eventually become a scab. However, when severe trauma has occurred it requires the assistance of the big boys. This is where COAT-platelets come into play. COAT-platelets (collagen and thrombin activated) are a specialized type of platelet, enriched with membrane-bound, procoagulant proteins like fibrinogen. In this instance 5-HT serves as a loudspeaker in a factory—it boosts worker morale and calls in extra hands—but it doesn’t place the order or decide what is produced. Instead, collagen and thrombin are foremen who decide when COAT-platelets are required. [4]

Serotonin causes vasoconstriction, which helps to inhibit blood loss from damaged vessels and promotes hemostasis (which is the process the body uses to stop bleeding after an injury). [1] In addition to helping with blood coagulation, 5-HT influences pressure and homeostasis. [1] Serotonin can initiate physiological responses within the gastrointestinal tract, such as nausea, intestinal secretion, and peristalsis. It has also been implicated in gastroenteric diseases, such as irritable bowel syndrome. [2]

Breathing: Serotonin is an important neuromodulator of breathing. 5-HT neurons located in close proximity to arteries entering the brainstem, may detect changes in arterial CO₂ and thus contribute to the adaptation of the central respiratory drive to environmental changes. [6] This suggests that serotonin-producing neurons near brainstem arteries might act like sensors. They could pick up on changes in blood CO2 levels caused by the environment and help tweak your breathing to keep everything in balance. For instance, if you’re in a stuffy room with more CO2 in the air, these neurons might notice the rise in arterial CO2 and tell your brain to breathe faster or deeper to compensate.

Additionally, serotonin plays a protective role in breathing regulation, particularly against opiate-induced respiratory depression. Research shows that serotonin 4(a) [5-HT4(a)] receptors are highly expressed in the Pre-Boetzinger complex (PBC), a brainstem region that generates breathing rhythm. Activating these receptors with a specific agonist in rats counteracted fentanyl’s suppression of breathing, restoring a stable rhythm without reducing pain relief. This suggests serotonin can safeguard respiratory function by stimulating PBC neurons, offering potential for targeted treatments to manage breathing disruptions. [8]

Heart: In a healthy heart, serotonin (5-HT) can play a supportive and protective role, particularly through its effects on blood vessels. Most 5-HT in the body is produced in the intestine, enters the bloodstream, and is stored in platelets. When platelets release 5-HT under normal conditions—such as during minor vessel repair—it travels a short distance to the endothelial cells lining the heart’s blood vessels. There, it binds to 5-HT receptors, typically triggering vasodilatation (widening of the blood vessels). This widening improves blood flow, reduces strain on the heart, and can be cardioprotective, helping maintain healthy circulation and oxygen delivery to the heart muscle. This process suggests that, in a balanced state, 5-HT helps regulate vascular tone and supports the heart’s normal function without causing disruption.

How is Serotonin Made?

The biosynthesis of 5-HT is catalyzed by tryptophan hydroxylase (TPH). Using the amino acid L-tryptophan, the TPH enzyme synthesizes serotonin. TPH enzyme is found in four locations: the pineal gland, the serotonergic neurons in the raphe nuclei, the enterochromaffin cells, and the myenteric neurons in the gut. [3]

Myenteric neurons are located within the myenteric plexus of the gastrointestinal tract and are responsible for bowel motility. Enterochromaffin-like (ECL) cells are a type of neuroendocrine cell found primarily in the stomach lining that secrete histamine, which play an important role in stimulating gastric acid secretion (stomach acid).

History of Serotonin

Italian pharmacologist Vitorio Erspamer developed a fascination with amine substances in the 1930’s. While studying enterochromaffin cells of the gut, Erspamer discover an indole, naming it enteramine, which would later be discovered to have the same structure of 5-Hydroxytryptamine (5-HT). Eventually enteramine would no longer be associated with 5-HT.

Serotonin was named by Irvine H. Page at Cleveland Clinic (Cleveland Ohio) while searching for the cause of hypertension in patients. His team analyzed blood collected from hypertension patients to see if chemical compounds present were in smaller amounts of people with normal blood pressure. Using this strategy, they identified 5-HT, a compound they called serotonin in the extracts was higher in those with hypertension. [7] It wasn’t till 1963 when Wooley demonstrated the importance of 5-HT to the CNS in relation to brain development, function and mental illness. [6]

My Interest in Serotonin

My interest in serotonin started after I was diagnosed with neuroendocrine cancer (NET cancer). Sometimes called carcinoids, neuroendocrine cancer is a large family of malignancies that can affect several different organs. It is a rare, but increasingly common diagnosis. People like Steve Job, Aretha Franklin and Dave Thomas of Wendy’s are all celebrities who have died of neuroendocrine cancer. Specifically I have Stage 3, Grade 2 Pulmonary Neuroendocrine cancer. I experience mild symptoms, which means my tumors are functional. NET cancer is fascinating because it can have what are called functional tumors, this means they can synthesize and secrete hormones. The hormones my tumors make are serotonin and histamines. Thankfully my symptoms are mild, but people who have more intense symptoms have to make drastic alterations to their lifestyle to account for the physiological effects the disease places on their body.

My cancer cells synthesize serotonin and histamines, which I find particularly fascinating since both serotonin and histamines are found within the myenteric neurons of the gut. 

Neuroendocrine Cancer

Neuroendocrine cancer is a fascinating disease and as a survivor who has lived with this disease it has been quite the wild ride. I often say getting cancer was the third greatest blessing of my life. If you would like to read more about my journey through cancer and bright and beautiful lessons I have learned check out the link below.

Why are people with Neuroendocrine cancer tested for these hormones? In NETs, serotonin tests (especially 5-HIAA) are standard for midgut tumors causing carcinoid syndrome (flushing, diarrhea, heart valve issues). Histamine tests are more relevant for foregut NETs with atypical symptoms (e.g., histamine-driven flushing from gastric or lung tumors).

Doctors often pair these with chromogranin A (CgA) blood tests—a general NET marker—and imaging (CT, MRI, or somatostatin receptor scans) to locate tumors. Biopsies may also check tissue for serotonin or histamine production via immunohistochemistry.

Elevated levels alone don’t confirm NETs—symptoms, imaging, and histology are key. False positives (e.g., from diet or meds) or negatives (e.g., non-secreting tumors) mean results must be contextualized.

Citations

[1] Wittlinger, H., Wittlinger, D., Wittlinger, A., & Wittlinger, M. (2018). Dr. Vodder’s manual lymph drainage: A practical guide. Thieme.

[2] Mercado, C. P., & Kilic, F. (2010). Molecular mechanisms of SERT in platelets: Regulation of plasma serotonin levels. Molecular Interventions, 10(4), 231–241. https://pmc.ncbi.nlm.nih.gov/articles/PMC2965611/

[3] Côté, F., Thévenot, E., Fligny, C., Fromes, Y., Darmon, M., Ripoche, M.-A., Bayard, E., Hanoun, N., Saurini, F., Lechat, P., Dandolo, L., Hamon, M., Mallet, J., & Vodjdani, G. (2003). Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proceedings of the National Academy of Sciences of the United States of America, 100(23), 13525–13530. https://doi.org/10.1073/pnas.2233056100

[4] Szasz, R., & Dale, G. L. (2002). Thrombospondin and fibrinogen bind serotonin-derivatized proteins on COAT-platelets. Blood, 100(8), 2827–2831. https://doi.org/10.1182/blood-2002-02-0354

[5]  Farias, C. P., Leite, A. K. O., Schmidt, B. E., Myskiw, J. C., & Wyse, A. T. S. (2024). The 5-HT2A, 5-HT5A, and 5-HT6 serotonergic receptors in the medial prefrontal cortex behave differently in extinction learning: Does social support play a role? Behavioural Brain Research, 463, Article 114922. https://doi.org/10.1016/j.bbr.2024.114922

[6] Hilaire, G., Voituron, N., Menuet, C., Ichiyama, R. M., Subramanian, H. H., & Dutschmann, M. (2010). The role of serotonin in respiratory function and dysfunction. Respiratory Physiology & Neurobiology, 174(1-2), 76–88. https://doi.org/10.1016/j.resp.2010.08.017

[7] Neumann, J., Hofmann, B., Dhein, S., & Gergs, U. (2023). Cardiac roles of serotonin (5-HT) and 5-HT-receptors in health and disease. International Journal of Molecular Sciences, 24(5), Article 4765. https://doi.org/10.3390/ijms24054765

[8] Manzke, T., Guenther, U., Ponimaskin, E. G., Haller, M., Dutschmann, M., Schwarzacher, S., & Richter, D. W. (2003). 5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia. Science, 301(5630), 226–229. https://doi.org/10.1126/science.1084674