Serotonin, also known as 5-hydroxytryptamine (5-HT), is a neurotransmitter playing an essential role in transmitting signals between the nerve cells (neurons). In the brain, serotonin is believed to be a key factor in memory building and mood regulation, for which it is widely known as the happy hormone. It is noteworthy that a major proportion of the body’s serotonin (about 90%) is found in the gut and not in the brain. The intestines are responsible for most of the body’s serotonin production, where serotonin is necessary for healthy digestion. Elsewhere in the body, serotonin also regulates sleep, sexual function, bone health, and blood clotting. It is produced by the serotonergic neurons and is responsible for transmitting signals from one nerve cell to another. This subsequently activates a secondary intracellular messenger cascade producing an excitatory or inhibitory response, relaxing the brain.4,5
Serotonin in the brain
Only 1-2% of the body’s natural production of serotonin (happy hormone) occurs in the brain. The serotonergic neurons found clustered in the middle of the brain are a unique source of serotonin forming the serotonergic system. Once produced, serotonin commonly gets stored in the presynaptic vesicles of the serotonergic neurons. Upon activation of the neuron by nerve impulses, serotonin gets released into the synaptic cleft (the space separating two neurons), subsequently binding to postsynaptic receptors. These postsynaptic receptors can be G-couple protein receptors or ligand-gated ion channels, leading to activation of another intracellular messenger cascade producing different types of excitatory or inhibitory responses in the brain.
The production of these responses results in a relaxing effect in the brain, proving serotonin as the body’s natural “feel-good” chemical. It is important to note that serotonin cannot cross the blood-brain barrier, making it essential for the brain to produce its own serotonin. The latter makes it impossible to measure brain serotonin levels as they are totally independent of blood serotonin levels. Hence, mental health interventions do not supply serotonin directly but aid an increase in serotonin levels indirectly through triggering related chemical reactions.10
Several studies investigated the effect of brain serotonin levels on mood through a technique called acute tryptophan depletion (ATD). It is believed that once in the central nervous system, tryptophan gets hydroxylated to 5-hydroxytryptophan, which subsequently gets decarboxylated into serotonin (5-hydroxytryptamine, 5-HT).11 Hence, lowering tryptophan levels in the diet would lower serotonin production in the brain allowing the ATD technique to reveal behavioral effects of brain serotonin levels.
Clinical studies have shown that healthy and never-depressed volunteers with an established familial history of depression. showed clear mood abnormalities upon depletion of dietary tryptophan.12,13 Moreover, the temporary lowering of dietary tryptophan in remitted depressed patients resulted in a relapse of acute depression.14-16 Interestingly, dietary tryptophan depletion in never-depressed healthy volunteers without familial history of depression showed little to no effect on mood.17,18 Moreover, healthy women showed more susceptibility to mood-lowering upon tryptophan depletion than healthy men.19 These findings reveal that people with pre-existing vulnerabilities in the serotonergic system were more vulnerable tryptophan challenge, making it evident that lower tryptophan and serotonin levels contribute towards lowered mood states.
Poor sleep and sexual activity, serotonin at play?
Apart from lowering the mood, low serotonin levels are also linked with poor sleep and sexual activity. The same ATD technique was used to investigate the impact of lower brain serotonin levels on sleep quality. Various studies on mice models and zebrafish showed that increased brain serotonin levels increased the body’s homeostatic sleep pressure, resulting in improved sleep compared to lower brain serotonin levels.20 Interestingly, high levels of serotonin in the brain downregulate human sexual activity.
The inhibitory role of the body’s naturally produced chemical 5-HT (serotonin) and the anti-depressants that increase brain serotonin levels on human sexual activity is well-evident from different studies performed in rat and mice models as well as in humans. 5-HT is found to elevate the lateral hypothalamic area (LHA) and decrease extracellular dopamine (a feel-good hormone) during sexual activity hence downregulating it. Together these findings are of great clinical value for depressed patients regularly utilizing anti-depressants and experiencing behavioral side-effects. 21
Serotonin in the Guts
It is estimated that 90% of the serotonin in the human body is stored in the Enterochromaffin (EC) cells located in gut epithelia. EC cells storing the largest 5-HT (serotonin) pool release it into the gut lumen in response to various stimuli.22 For example, nutrients such as fatty acids, glucose, and some acids and bases have been evidenced to induce the release of 5-HT (serotonin) from EC cells.23 Upon being secreted, the serotonin gets absorbed by the circulating platelets, subsequently causing intestinal contractions. The excess serotonin enters the bloodstream interacting with blood platelets, where the platelets absorb and store until the clots form. Upon clot formation, the serotonin gets re-released into the bloodstream hence regulating homeostasis and blood clotting.24 The mentioned findings highlight the essential role played by serotonin in regulating normal body functions.
Where else is the happy hormone found outside the body?
The happy hormone lies right there in tryptophan-rich protein-based foods, including meats such as salmon, and turkey which are rich tryptophan sources. It is also evident that dairy products such as eggs are boosters of blood plasma tryptophan levels. Cheese is also a great source of tryptophan. Fruits such as bananas and pineapples are also serotonin boosters. Most interestingly, all sorts of nuts and seeds are also vibrant sources of tryptophan, a raw product for serotonin production.25 Hence, apart from the body’s natural serotonin production, tryptophan intake through the mentioned foods would essentially increase serotonin levels. This would subsequently improve the body’s normal functioning and improve one’s mental health naturally without taking anti-depressants that possess various side effects when used in the long term.
- Frazer A, Hensler JG. Serotonin involvement in physiological function and behavior. In: Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular, and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.
- Lv J, Liu F. The role of serotonin beyond the central nervous system during embryogenesis. Front Cell Neurosci. 2017;11. doi:10.3389/fncel.2017.00074
- Yano JM, Yu K, Donaldson GP, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161(2):264-276. doi:10.1016/j.cell.2015.02.047
- David DJ, Gardier AM, [The pharmacological basis of the serotonin system: Application to antidepressant response]. L’Encephale. 2016 Jun; [PubMed PMID: 27112704]
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- Kling A (2013). 5-HT2A: a serotonin receptor with a possible role in joint diseases (PDF) (Thesis). Umeå Universitet. ISBN 978-91-7459-549-9.
- Cao L, Hu R, Xu T, Zhang Z, Li W, Lu J. Characterization of Induced Pluripotent Stem Cell-derived Human Serotonergic Neurons. Frontiers in Cellular Neuroscience. 2017;11.
- Jenkins TA, Nguyen JC, Polglaze KE, Bertrand PP. Influence of tryptophan and serotonin on mood and cognition with a possible role of the gut-brain axis. Nutrients. 2016;8(1):56. doi:10.3390/nu8010056
- Serotonin: Function, uses, SSRIs, and sources [Internet]. Medicalnewstoday.com. 2021 [cited 25 April 2021]. Available from: https://www.medicalnewstoday.com/articles/232248
- Fernstrom J.D., Fernstrom M.H. Exercise, serum-free tryptophan, and central fatigue. J. Nutr. 2006;136:553S–559S
- Feder, A.; Skipper, J.; Blair, J.R.; Buchholz, K.; Mathew, S.J.; Schwarz, M.; Doucette, J.T.; Alonso, A.; Collins, K.A.; Neumeister, A.; et al. Tryptophan depletion and emotional processing in healthy volunteers at high risk for depression. Biol. Psychiatry 2011, 69, 804–807. [Google Scholar] [CrossRef] [PubMed]
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