serotonin

Biochemically, the indoleamine molecule derives from the amino acid tryptophan, via the (rate-limiting) hydroxylation of the 5 position on the ring (forming the intermediate 5-hydroxytryptophan), and then decarboxylation to produce serotonin.{{cite journal | vauthors = González-Flores D, Velardo B, Garrido M, et al. | year = 2011 | title = Ingestion of Japanese plums (Prunus salicina Lindl. cv. Crimson Globe) increases the urinary 6-sulfatoxymelatonin and total antioxidant capacity levels in young, middle-aged and elderly humans: Nutritional and functional characterization of their content | url = https://www.researchgate.net/publication/259983119 | journal = Journal of Food and Nutrition Research | volume = 50 | issue = 4| pages = 229–236 }} Preferable conformations are defined via ethylamine chain, resulting in six different conformations.{{Cite journal | vauthors = Rychkov DA, Hunter S, Kovalskii VY, Lomzov AA, Pulham CR, Boldyreva EV |date=July 2016 |title=Towards an understanding of crystallization from solution. DFT studies of multi-component serotonin crystals |journal=Computational and Theoretical Chemistry |language=en |volume=1088 |pages=52–61 |doi=10.1016/j.comptc.2016.04.027}}

Serotonin crystallizes in P2₁2₁2₁ chiral space group forming different hydrogen-bonding interactions between serotonin molecules via N-H...O and O-H...N intermolecular bonds.{{cite journal | vauthors = Naeem M, Chadeayne AR, Golen JA, Manke DR | title = Crystal structure of serotonin | journal = Acta Crystallographica Section E | volume = 78 | issue = Pt 4 | pages = 365–368 | date = April 2022 | pmid = 35492269 | pmc = 8983975 | doi = 10.1107/S2056989022002559 | bibcode = 2022AcCrE..78..365N }} Serotonin also forms several salts, including pharmaceutical formulation of serotonin adipate.{{cite journal | vauthors = Rychkov D, Boldyreva EV, Tumanov NA | title = A new structure of a serotonin salt: comparison and conformational analysis of all known serotonin complexes | journal = Acta Crystallographica Section C | volume = 69 | issue = Pt 9 | pages = 1055–1061 | date = September 2013 | pmid = 24005521 | doi = 10.1107/S0108270113019823 | bibcode = 2013AcCrC..69.1055R }}

Serotonin is involved in numerous physiological processes,{{cite journal | vauthors = Mohammad-Zadeh LF, Moses L, Gwaltney-Brant SM | title = Serotonin: a review | journal = Journal of Veterinary Pharmacology and Therapeutics | volume = 31 | issue = 3 | pages = 187–199 | date = June 2008 | pmid = 18471139 | doi = 10.1111/j.1365-2885.2008.00944.x | doi-access = free }} including sleep,{{cite journal | vauthors = Vaseghi S, Arjmandi-Rad S, Eskandari M, Ebrahimnejad M, Kholghi G, Zarrindast MR | title = Modulating role of serotonergic signaling in sleep and memory | journal = Pharmacological Reports | volume = 74 | issue = 1 | pages = 1–26 | date = February 2022 | pmid = 34743316 | doi = 10.1007/s43440-021-00339-8 }} thermoregulation, learning and memory, pain, (social) behavior, sexual activity, feeding, motor activity, neural development,{{cite journal | vauthors = Sinclair-Wilson A, Lawrence A, Ferezou I, Cartonnet H, Mailhes C, Garel S, Lokmane L | title = Plasticity of thalamocortical axons is regulated by serotonin levels modulated by preterm birth | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 120 | issue = 33 | pages = e2301644120 | date = August 2023 | pmid = 37549297 | pmc = 10438379 | doi = 10.1073/pnas.2301644120 | doi-access = free | bibcode = 2023PNAS..12001644S }} and biological rhythms.{{cite journal | vauthors = Zifa E, Fillion G | title = 5-Hydroxytryptamine receptors | journal = Pharmacological Reviews | volume = 44 | issue = 3 | pages = 401–458 | date = September 1992 | doi = 10.1016/S0031-6997(25)00462-4 | pmid = 1359584 | url = https://pubmed.ncbi.nlm.nih.gov/1359584 }} In less complex animals, such as some invertebrates, serotonin regulates feeding and other processes. In plants serotonin synthesis seems to be associated with stress signals.{{cite journal | vauthors = Ramakrishna A, Ravishankar GA | title = Influence of abiotic stress signals on secondary metabolites in plants | journal = Plant Signaling & Behavior | volume = 6 | issue = 11 | pages = 1720–1731 | date = November 2011 | pmid = 22041989 | pmc = 3329344 | doi = 10.4161/psb.6.11.17613 | publisher = Informa | doi-access = free | bibcode = 2011PlSiB...6.1720A }} Despite its longstanding prominence in pharmaceutical advertising, the claim that low serotonin levels cause depression is not supported by scientific evidence.{{cite book | vauthors = Whitaker R, Cosgrove L |title=Psychiatry Under the Influence: Institutional Corruption, Social Injury, and Prescriptions for Reform |year=2015 |publisher=Springer |isbn=978-1-137-51602-2 |pages=55–56 |url=https://books.google.com/books?id=fxPACQAAQBAJ&pg=PA55}}{{cite journal | vauthors = Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA | title = The serotonin theory of depression: a systematic umbrella review of the evidence | journal = Molecular Psychiatry | volume = 28 | issue = 8 | pages = 3243–3256 | date = August 2023 | pmid = 35854107 | pmc = 10618090 | doi = 10.1038/s41380-022-01661-0 | publisher = Nature Publishing Group | s2cid = 250646781 | doi-access = free }}{{Citation | vauthors = Ghaemi N | year=2022 | title=Has the Serotonin Hypothesis Been Debunked? | url=https://www.psychologytoday.com/us/blog/mood-swings/202210/has-the-serotonin-hypothesis-been-debunked | access-date=2 May 2023}}

Serotonin primarily acts through its receptors and its effects depend on which cells and tissues express these receptors.

Metabolism involves first oxidation by monoamine oxidase to 5-hydroxyindoleacetaldehyde (5-HIAL).{{cite book | vauthors = Bortolato M, Chen K, Shih JC | title=Handbook of Behavioral Neuroscience | chapter=The Degradation of Serotonin: Role of MAO | publisher=Elsevier | volume=21 | date=2010 | isbn=978-0-12-374634-4 | doi=10.1016/s1569-7339(10)70079-5 | pages=203–218}}{{cite journal | vauthors = Matthes S, Mosienko V, Bashammakh S, Alenina N, Bader M | title = Tryptophan hydroxylase as novel target for the treatment of depressive disorders | journal = Pharmacology | volume = 85 | issue = 2 | pages = 95–109 | date = 2010 | pmid = 20130443 | doi = 10.1159/000279322 | url = }} The rate-limiting step is hydride transfer from serotonin to the flavin cofactor.{{cite journal | vauthors = Prah A, Purg M, Stare J, Vianello R, Mavri J | title = How Monoamine Oxidase A Decomposes Serotonin: An Empirical Valence Bond Simulation of the Reactive Step | journal = The Journal of Physical Chemistry B | volume = 124 | issue = 38 | pages = 8259–8265 | date = September 2020 | pmid = 32845149 | pmc = 7520887 | doi = 10.1021/acs.jpcb.0c06502 }} There follows oxidation by aldehyde dehydrogenase (ALDH) to 5-hydroxyindoleacetic acid ({{nowrap|5-HIAA}}), the indole acetic-acid derivative. The latter is then excreted by the kidneys.

{{Main|Serotonin receptor}}

The serotonin receptors are located on the cell membrane of nerve cells and other cell types in animals, and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and psychedelic drugs. There are currently 14{{nbsp}}known serotonin receptors, including the serotonin 5-HT₁ (_1A, _1B, _1D, _1E, _1F), 5-HT₂ (_2A, _2B, _2C), 5-HT₃, 5-HT₄, 5-HT₅ (_5A, _5B), 5-HT₆, and 5-HT₇ receptors. Except for the serotonin 5-HT₃ receptor, a ligand-gated ion channel, all other 5-HT receptors are G-protein-coupled receptors (also called seven-transmembrane, or heptahelical receptors) that activate an intracellular second messenger cascade.{{cite journal | vauthors = Hannon J, Hoyer D | title = Molecular biology of 5-HT receptors | journal = Behavioural Brain Research | volume = 195 | issue = 1 | pages = 198–213 | date = December 2008 | pmid = 18571247 | doi = 10.1016/j.bbr.2008.03.020 | s2cid = 46043982 }} The 5-HT_5B receptor is present in rodents but not in humans.

In addition to the serotonin receptors, serotonin is an agonist of the trace amine-associated receptor 1 (TAAR1) in some species.{{cite journal | vauthors = Gainetdinov RR, Hoener MC, Berry MD | title = Trace Amines and Their Receptors | journal = Pharmacol Rev | volume = 70 | issue = 3 | pages = 549–620 | date = July 2018 | pmid = 29941461 | doi = 10.1124/pr.117.015305 | url = | doi-access = free }}{{cite journal | vauthors = Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME | title = In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1 | journal = J Pharmacol Exp Ther | volume = 357 | issue = 1 | pages = 134–144 | date = April 2016 | pmid = 26791601 | doi = 10.1124/jpet.115.229765 | url = https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA| archive-url = https://web.archive.org/web/20250509235235/https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA | archive-date = 9 May 2025 }} It is a weak TAAR1 partial agonist in rats, but is inactive at the TAAR1 in mice and humans.

The cryo-EM structures of the serotonin 5-HT_2A receptor with serotonin, as well as with various serotonergic psychedelics, have been solved and published by Bryan L. Roth and colleagues.{{cite journal | vauthors = Gumpper RH, Jain MK, Kim K, Sun R, Sun N, Xu Z, DiBerto JF, Krumm BE, Kapolka NJ, Kaniskan HÜ, Nichols DE, Jin J, Fay JF, Roth BL | title = The structural diversity of psychedelic drug actions revealed | journal = Nature Communications | volume = 16 | issue = 1 | pages = 2734 | date = March 2025 | pmid = 40108183 | doi = 10.1038/s41467-025-57956-7 | pmc = 11923220 | bibcode = 2025NatCo..16.2734G }}{{cite conference | vauthors = Gumpper RH, DiBerto J, Jain M, Kim K, Fay J, Roth BL | title = Structures of Hallucinogenic and Non-Hallucinogenic Analogues of the 5-HT2A Receptor Reveals Molecular Insights into Signaling Bias | conference = University of North Carolina at Chapel Hill Department of Pharmacology Research Retreat September 16th, 2022 – William and Ida Friday Center | date = September 2022 | url = https://www.med.unc.edu/pharm/wp-content/uploads/sites/930/2022/07/COMPLETE-PHARM-RETREAT-PROGRAM-2022-UPDATE.pdf#page=37}}

Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is accomplished through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake, including cocaine, dextromethorphan (an antitussive), tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). A 2006 study found that a significant portion of 5-HT's synaptic clearance is due to the selective activity of the plasma membrane monoamine transporter (PMAT) which actively transports the molecule across the membrane and back into the presynaptic cell.{{cite journal | vauthors = Zhou M, Engel K, Wang J | title = Evidence for significant contribution of a newly identified monoamine transporter (PMAT) to serotonin uptake in the human brain | journal = Biochemical Pharmacology | volume = 73 | issue = 1 | pages = 147–154 | date = January 2007 | pmid = 17046718 | pmc = 1828907 | doi = 10.1016/j.bcp.2006.09.008 }}

In contrast to the high affinity of SERT, the PMAT has been identified as a low-affinity transporter, with an apparent K_m of 114 micromoles/l for serotonin, which is approximately 230 times higher than that of SERT. However, the PMAT, despite its relatively low serotonergic affinity, has a considerably higher transport "capacity" than SERT, "resulting in roughly comparable uptake efficiencies to SERT ... in heterologous expression systems." The study also suggests that the administration of SSRIs such as fluoxetine and sertraline may be associated with an inhibitory effect on PMAT activity when used at higher than normal dosages (IC₅₀ test values used in trials were 3–4 fold higher than typical prescriptive dosage).

{{Main|Serotonylation}}

Serotonin can also signal through a nonreceptor mechanism called serotonylation, in which serotonin modifies proteins. This process underlies serotonin's effects upon platelet-forming cells (thrombocytes) in which it links to the modification of signaling enzymes called GTPases that then trigger the release of vesicle contents by exocytosis.{{cite journal | vauthors = Walther DJ, Peter JU, Winter S, Höltje M, Paulmann N, Grohmann M, Vowinckel J, Alamo-Bethencourt V, Wilhelm CS, Ahnert-Hilger G, Bader M | title = Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release | journal = Cell | volume = 115 | issue = 7 | pages = 851–862 | date = December 2003 | pmid = 14697203 | doi = 10.1016/S0092-8674(03)01014-6 | s2cid = 16847296 | doi-access = free }} A similar process underlies the pancreatic release of insulin.

The effects of serotonin upon vascular smooth muscle tone{{snd}}the biological function after which serotonin was originally named{{snd}}depend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells.{{cite journal | vauthors = Watts SW, Priestley JR, Thompson JM | title = Serotonylation of vascular proteins important to contraction | journal = PLOS ONE | volume = 4 | issue = 5 | pages = e5682 | date = May 2009 | pmid = 19479059 | pmc = 2682564 | doi = 10.1371/journal.pone.0005682 | doi-access = free | bibcode = 2009PLoSO...4.5682W }}

File:Pubmed equitativa hormonal.pngs upwards to the whole cerebrum, and one collection next to the cerebellum that sends axons downward to the spinal cord. Slightly forward the upper serotonergic neurons is the ventral tegmental area (VTA), which contains dopaminergic neurons. These neurons' axons then connect to the nucleus accumbens, hippocampus, and the frontal cortex. Over the VTA is another collection of dopaminergic cells, the substansia nigra, which send axons to the striatum. |Serotonin system, contrasted with the dopamine system]]

The neurons of the raphe nuclei are the principal source of 5-HT release in the brain.{{cite book | vauthors = Frazer A, Hensler JG | veditors = Siegel GJ, Agranoff, Bernard W, Fisher SK, Albers RW, Uhler MD |title = Basic Neurochemistry | url = https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm|edition = Sixth|year = 1999|publisher = Lippincott Williams & Wilkins|isbn = 978-0-397-51820-3|chapter = Understanding the neuroanatomical organization of serotonergic cells in the brain provides insight into the functions of this neurotransmitter|chapter-url = https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=raphe+AND+serotonin+release+AND+bnchm%5Bbook%5D+AND+160428%5Buid%5D&rid=bnchm.section.946#949|quote = In 1964, Dahlstrom and Fuxe (discussed in [2]), using the Falck-Hillarp technique of histofluorescence, observed that the majority of serotonergic soma are found in cell body groups, which previously had been designated as the Raphe nuclei.|editor-link1 = George J. Siegel}} There are nine raphe nuclei, designated B1–B9, which contain the majority of serotonin-containing neurons (some scientists chose to group the nuclei raphes lineares into one nucleus), all of which are located along the midline of the brainstem, and centered on the reticular formation.{{cite book| vauthors = Binder MD, Hirokawa N |title=encyclopedia of neuroscience|date=2009|publisher=Springer|location=Berlin|isbn=978-3-540-23735-8|page=705}}The raphe nuclei group of neurons are located along the brain stem from the labels 'Mid Brain' to 'Oblongata', centered on the pons. (See relevant image.) Axons from the neurons of the raphe nuclei form a neurotransmitter system reaching almost every part of the central nervous system. Axons of neurons in the lower raphe nuclei terminate in the cerebellum and spinal cord, while the axons of the higher nuclei spread out in the entire brain.

It is the dorsal part of the raphe nucleus that contains neurons projecting to the central nervous system. Serotonin-releasing neurons in this area receive input from a large number of areas, notably from prefrontal cortex, lateral habenula, preoptic area, substantia nigra and amygdala.{{cite journal | vauthors = Zhou L, Liu MZ, Li Q, Deng J, Mu D, Sun YG | title = Organization of Functional Long-Range Circuits Controlling the Activity of Serotonergic Neurons in the Dorsal Raphe Nucleus | journal = Cell Reports | volume = 18 | issue = 12 | pages = 3018–3032 | date = March 2017 | pmid = 28329692 | doi = 10.1016/j.celrep.2017.02.077 | doi-access = free }} These neurons are thought to communicate the expectation of rewards in the near future, a quantity called state value in reinforcement learning.{{cite journal | vauthors = Harkin EF, Grossman CD, Cohen JY, Béïque JC, Naud R | title = A prospective code for value in the serotonin system | journal = Nature | date = March 2025 | pmid = 40140568 | doi = 10.1038/s41586-025-08731-7 }}

The serotonin nuclei may also be divided into two main groups, the rostral and caudal containing three and four nuclei respectively. The rostral group consists of the caudal linear nuclei (B8), the dorsal raphe nuclei (B6 and B7) and the median raphe nuclei (B5, B8 and B9), that project into multiple cortical and subcortical structures. The caudal group consists of the nucleus raphe magnus (B3), raphe obscurus nucleus (B2), raphe pallidus nucleus (B1), and lateral medullary reticular formation, that project into the brainstem.{{cite book | veditors = Müller CP, Jacobs BL |title=Handbook of the behavioral neurobiology of serotonin |date=2009 |publisher= Academic |location=London |isbn=978-0-12-374634-4|pages=51–59|edition=1st}}

The serotonergic pathway is involved in sensorimotor function, with pathways projecting both into cortical (Dorsal and Median Raphe Nuclei), subcortical, and spinal areas involved in motor activity. Pharmacological manipulation suggests that serotonergic activity increases with motor activity while firing rates of serotonergic neurons increase with intense visual stimuli. Animal models suggest that kainate signaling negatively regulates serotonin actions in the retina, with possible implications for the control of the visual system.{{cite journal | vauthors = Passos AD, Herculano AM, Oliveira KR, de Lima SM, Rocha FA, Freitas HR, da Silva Sampaio L, Figueiredo DP, da Costa Calaza K, de Melo Reis RA, do Nascimento JL | title = Regulation of the Serotonergic System by Kainate in the Avian Retina | journal = Cellular and Molecular Neurobiology | volume = 39 | issue = 7 | pages = 1039–1049 | date = October 2019 | pmid = 31197744 | doi = 10.1007/s10571-019-00701-8 | s2cid = 189763144 | pmc = 11457822 }} The descending projections form a pathway that inhibits pain called the "descending inhibitory pathway" that may be relevant to a disorder such as fibromyalgia, migraine, and other pain disorders, and the efficacy of antidepressants in them.{{cite book | chapter = Serotonin in Pain and Pain Control | vauthors = Sommer C | veditors = Müller CP, Jacobs BL |title=Handbook of the behavioral neurobiology of serotonin|date=2009|publisher=Academic|location=London|isbn=978-0-12-374634-4|pages=457–460|edition=1st}}

Serotonergic projections from the caudal nuclei are involved in regulating mood and emotion, and hypo-{{cite book | chapter = Serotonin in Mode and Emotions | vauthors = Hensler JG | veditors = Müller CP, Jacobs BL | title=Handbook of the behavioral neurobiology of serotonin|date=2009|publisher=Academic|location=London|isbn=978-0-12-374634-4|pages=367–399|edition=1st}} or hyper-serotonergic{{cite journal | vauthors = Andrews PW, Bharwani A, Lee KR, Fox M, Thomson JA | title = Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response | journal = Neuroscience and Biobehavioral Reviews | volume = 51 | pages = 164–188 | date = April 2015 | pmid = 25625874 | doi = 10.1016/j.neubiorev.2015.01.018 | s2cid = 23980182 }} states may be involved in depression and sickness behavior.

Serotonin is released into the synapse, or space between neurons, and diffuses over a relatively wide gap (>20 nm) to activate 5-HT receptors located on the dendrites, cell bodies, and presynaptic terminals of adjacent neurons.

When humans smell food, dopamine is released to increase the appetite. But, unlike in worms, serotonin does not increase anticipatory behaviour in humans; instead, the serotonin released while consuming activates 5-HT2C receptors on dopamine-producing cells. This halts their dopamine release, and thereby serotonin decreases appetite. Drugs that block 5-HT_2C receptors make the body unable to recognize when it is no longer hungry or otherwise in need of nutrients, and are associated with weight gain,{{cite journal | vauthors = Stahl SM, Mignon L, Meyer JM | title = Which comes first: atypical antipsychotic treatment or cardiometabolic risk? | journal = Acta Psychiatrica Scandinavica | volume = 119 | issue = 3 | pages = 171–179 | date = March 2009 | pmid = 19178394 | doi = 10.1111/j.1600-0447.2008.01334.x | s2cid = 24035040 | doi-access = free }} especially in people with a low number of receptors.{{cite journal | vauthors = Buckland PR, Hoogendoorn B, Guy CA, Smith SK, Coleman SL, O'Donovan MC | title = Low gene expression conferred by association of an allele of the 5-HT2C receptor gene with antipsychotic-induced weight gain | journal = The American Journal of Psychiatry | volume = 162 | issue = 3 | pages = 613–615 | date = March 2005 | pmid = 15741483 | doi = 10.1176/appi.ajp.162.3.613 }} The expression of 5-HT_2C receptors in the hippocampus follows a diurnal rhythm,{{cite journal | vauthors = Holmes MC, French KL, Seckl JR | title = Dysregulation of diurnal rhythms of serotonin 5-HT2C and corticosteroid receptor gene expression in the hippocampus with food restriction and glucocorticoids | journal = The Journal of Neuroscience | volume = 17 | issue = 11 | pages = 4056–4065 | date = June 1997 | pmid = 9151722 | pmc = 6573558 | doi = 10.1523/JNEUROSCI.17-11-04056.1997 }} just as the serotonin release in the ventromedial nucleus, which is characterised by a peak at morning when the motivation to eat is strongest.{{cite journal | vauthors = Leibowitz SF | title = The role of serotonin in eating disorders | journal = Drugs | volume = 39 | issue = Suppl 3 | pages = 33–48 | year = 1990 | pmid = 2197074 | doi = 10.2165/00003495-199000393-00005 | s2cid = 8612545 }}

In macaques, alpha males have twice the level of serotonin in the brain as subordinate males and females (measured by the concentration of 5-HIAA in the cerebrospinal fluid (CSF)). Dominance status and CSF serotonin levels appear to be positively correlated. When dominant males were removed from such groups, subordinate males begin competing for dominance. Once new dominance hierarchies were established, serotonin levels of the new dominant individuals also increased to double those in subordinate males and females. The reason why serotonin levels are only high in dominant males, but not dominant females has not yet been established.McGuire, Michael (2013) "Believing, the neuroscience of fantasies, fears, and confictions" (Prometius Books)

In humans, levels of 5-HT_1A receptor inhibition in the brain show negative correlation with aggression,{{cite journal | vauthors = Caspi N, Modai I, Barak P, Waisbourd A, Zbarsky H, Hirschmann S, Ritsner M | title = Pindolol augmentation in aggressive schizophrenic patients: a double-blind crossover randomized study | journal = International Clinical Psychopharmacology | volume = 16 | issue = 2 | pages = 111–115 | date = March 2001 | pmid = 11236069 | doi = 10.1097/00004850-200103000-00006 | s2cid = 24822810 }} and a mutation in the gene that codes for the 5-HT_2A receptor may double the risk of suicide for those with that genotype.{{cite journal | vauthors = Ito Z, Aizawa I, Takeuchi M, Tabe M, Nakamura T | title = [Proceedings: Study of gastrointestinal motility using an extraluminal force transducer. 6. Observation of gastric and duodenal motility using synthetic motilin] | journal = Nihon Heikatsukin Gakkai Zasshi | volume = 11 | issue = 4 | pages = 244–246 | date = December 1975 | pmid = 1232434 }} Serotonin in the brain is not usually degraded after use, but is collected by serotonergic neurons by serotonin transporters on their cell surfaces. Studies have revealed nearly 10% of total variance in anxiety-related personality depends on variations in the description of where, when and how many serotonin transporters the neurons should deploy.{{cite journal | vauthors = Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Müller CR, Hamer DH, Murphy DL | title = Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region | journal = Science | volume = 274 | issue = 5292 | pages = 1527–1531 | date = November 1996 | pmid = 8929413 | doi = 10.1126/science.274.5292.1527 | s2cid = 35503987 | bibcode = 1996Sci...274.1527L }}

Serotonin regulates gastrointestinal (GI) function. The gut is surrounded by enterochromaffin cells, which release serotonin in response to food in the lumen. This makes the gut contract around the food. Platelets in the veins draining the gut collect excess serotonin. There are often serotonin abnormalities in gastrointestinal disorders such as constipation and irritable bowel syndrome.{{cite journal | vauthors = Beattie DT, Smith JA | title = Serotonin pharmacology in the gastrointestinal tract: a review | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 377 | issue = 3 | pages = 181–203 | date = May 2008 | pmid = 18398601 | doi = 10.1007/s00210-008-0276-9 | s2cid = 32820765 }}

If irritants are present in the food, the enterochromaffin cells release more serotonin to make the gut move faster, i.e., to cause diarrhea, so the gut is emptied of the noxious substance. If serotonin is released in the blood faster than the platelets can absorb it, the level of free serotonin in the blood is increased. This activates 5-HT3 receptors in the chemoreceptor trigger zone that stimulate vomiting.{{cite book | vauthors = Rang HP |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |page=187 |isbn=978-0-443-07145-4}} Thus, drugs and toxins stimulate serotonin release from enterochromaffin cells in the gut wall can induce emesis. The enterochromaffin cells not only react to bad food but are also very sensitive to irradiation and cancer chemotherapy. Drugs that block 5HT3 are very effective in controlling the nausea and vomiting produced by cancer treatment, and are considered the gold standard for this purpose.{{cite journal | vauthors = de Wit R, Aapro M, Blower PR | title = Is there a pharmacological basis for differences in 5-HT3-receptor antagonist efficacy in refractory patients? | journal = Cancer Chemotherapy and Pharmacology | volume = 56 | issue = 3 | pages = 231–238 | date = September 2005 | pmid = 15838653 | doi = 10.1007/s00280-005-1033-0 | s2cid = 27576150 }}

The lung,{{cite journal | vauthors = Lauweryns JM, Cokelaere J, Theunynck P | title = Serotonin producing neuroepithelial bodies in rabbit respiratory mucosa | journal = Science | volume = 180 | issue = 4084 | pages = 410–413 | date = April 1973 | pmid = 4121716 | doi = 10.1126/science.180.4084.410 | s2cid = 2809307 | bibcode = 1973Sci...180..410L }} including that of reptiles,{{cite journal | vauthors = Pastor LM, Ballesta J, Perez-Tomas R, Marin JA, Hernandez F, Madrid JF | title = Immunocytochemical localization of serotonin in the reptilian lung | journal = Cell and Tissue Research | volume = 248 | issue = 3 | pages = 713–715 | date = June 1987 | pmid = 3301000 | doi = 10.1007/bf00216504 | publisher = Springer Science and Business Media LLC | s2cid = 9871728 }} contains specialized epithelial cells that occur as solitary cells or as clusters called neuroepithelial bodies or bronchial Kulchitsky cells or alternatively K cells.{{cite journal | vauthors = Sonstegard KS, Mailman RB, Cheek JM, Tomlin TE, DiAugustine RP | title = Morphological and cytochemical characterization of neuroepithelial bodies in fetal rabbit lung. I. Studies of isolated neuroepithelial bodies | journal = Experimental Lung Research | volume = 3 | issue = 3–4 | pages = 349–377 | date = November 1982 | pmid = 6132813 | doi = 10.3109/01902148209069663 }} These are enterochromaffin cells that like those in the gut release serotonin. Their function is probably vasoconstriction during hypoxia.

Serotonin is also produced by Merkel cells which are part of the somatosensory system.{{cite journal | vauthors = Chang W, Kanda H, Ikeda R, Ling J, DeBerry JJ, Gu JG | title = Merkel disc is a serotonergic synapse in the epidermis for transmitting tactile signals in mammals | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 37 | pages = E5491–E5500 | date = September 2016 | pmid = 27573850 | pmc = 5027443 | doi = 10.1073/pnas.1610176113 | bibcode = 2016PNAS..113E5491C | doi-access = free }}

In mice and humans, alterations in serotonin levels and signalling have been shown to regulate bone mass.{{cite journal | vauthors = Frost M, Andersen TE, Yadav V, Brixen K, Karsenty G, Kassem M | title = Patients with high-bone-mass phenotype owing to Lrp5-T253I mutation have low plasma levels of serotonin | journal = Journal of Bone and Mineral Research | volume = 25 | issue = 3 | pages = 673–675 | date = March 2010 | pmid = 20200960 | doi = 10.1002/jbmr.44 | s2cid = 24280062 | doi-access = free }}{{cite journal | vauthors = Rosen CJ | title = Breaking into bone biology: serotonin's secrets | journal = Nature Medicine | volume = 15 | issue = 2 | pages = 145–146 | date = February 2009 | pmid = 19197289 | doi = 10.1038/nm0209-145 | s2cid = 5489589 }}{{cite journal | vauthors = Mödder UI, Achenbach SJ, Amin S, Riggs BL, Melton LJ, Khosla S | title = Relation of serum serotonin levels to bone density and structural parameters in women | journal = Journal of Bone and Mineral Research | volume = 25 | issue = 2 | pages = 415–422 | date = February 2010 | pmid = 19594297 | pmc = 3153390 | doi = 10.1359/jbmr.090721 }}{{cite journal | vauthors = Frost M, Andersen T, Gossiel F, Hansen S, Bollerslev J, van Hul W, Eastell R, Kassem M, Brixen K | title = Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high-bone-mass phenotype due to a mutation in Lrp5 | journal = Journal of Bone and Mineral Research | volume = 26 | issue = 8 | pages = 1721–1728 | date = August 2011 | pmid = 21351148 | doi = 10.1002/jbmr.376 | doi-access = free }} Mice that lack brain serotonin have osteopenia, while mice that lack gut serotonin have high bone density. In humans, increased blood serotonin levels have been shown to be a significant negative predictor of low bone density. Serotonin can also be synthesized, albeit at very low levels, in the bone cells. It mediates its actions on bone cells using three different receptors. Through 5-HT_1B receptors, it negatively regulates bone mass, while it does so positively through 5-HT_2B receptors and 5-HT_2C receptors. There is very delicate balance between physiological role of gut serotonin and its pathology. Increase in the extracellular content of serotonin results in a complex relay of signals in the osteoblasts culminating in FoxO1/ Creb and ATF4 dependent transcriptional events.{{cite journal | vauthors = Kode A, Mosialou I, Silva BC, Rached MT, Zhou B, Wang J, Townes TM, Hen R, DePinho RA, Guo XE, Kousteni S | title = FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin | journal = The Journal of Clinical Investigation | volume = 122 | issue = 10 | pages = 3490–3503 | date = October 2012 | pmid = 22945629 | pmc = 3461930 | doi = 10.1172/JCI64906 }} Following the 2008 findings that gut serotonin regulates bone mass, the mechanistic investigations into what regulates serotonin synthesis from the gut in the regulation of bone mass have started. Piezo1 has been shown to sense RNA in the gut and relay this information through serotonin synthesis to the bone by acting as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse Piezo1 profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels. Because of systemic 5-HT deficiency, conditional knockout of Piezo1 increased bone formation. Notably, fecal ssRNA was identified as a natural Piezo1 ligand, and ssRNA-stimulated 5-HT synthesis from the gut was evoked in a MyD88/TRIF-independent manner. Colonic infusion of RNase A suppressed gut motility and increased bone mass. These findings suggest gut ssRNA as a master determinant of systemic 5-HT levels, indicating the ssRNA-Piezo1 axis as a potential prophylactic target for treatment of bone and gut disorders. Studies in 2008, 2010 and 2019 have opened the potential for serotonin research to treat bone mass disorders.{{cite journal | vauthors = Yadav VK, Balaji S, Suresh PS, Liu XS, Lu X, Li Z, Guo XE, Mann JJ, Balapure AK, Gershon MD, Medhamurthy R, Vidal M, Karsenty G, Ducy P | title = Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis | journal = Nature Medicine | volume = 16 | issue = 3 | pages = 308–312 | date = March 2010 | pmid = 20139991 | pmc = 2836724 | doi = 10.1038/nm.2098 }}{{cite journal | vauthors = Sugisawa E, Takayama Y, Takemura N, Kondo T, Hatakeyama S, Kumagai Y, Sunagawa M, Tominaga M, Maruyama K | title = RNA Sensing by Gut Piezo1 Is Essential for Systemic Serotonin Synthesis | journal = Cell | volume = 182 | issue = 3 | pages = 609–624.e21 | date = August 2020 | pmid = 32640190 | doi = 10.1016/j.cell.2020.06.022 | doi-access = free }}

Since serotonin signals resource availability it is not surprising that it affects organ development. Many human and animal studies have shown that nutrition in early life can influence, in adulthood, such things as body fatness, blood lipids, blood pressure, atherosclerosis, behavior, learning, and longevity.{{cite journal | vauthors = Ozanne SE, Hales CN | title = Lifespan: catch-up growth and obesity in male mice | journal = Nature | volume = 427 | issue = 6973 | pages = 411–412 | date = January 2004 | pmid = 14749819 | doi = 10.1038/427411b | s2cid = 40256021 | bibcode = 2004Natur.427..411O }}{{cite journal | vauthors = Lewis DS, Bertrand HA, McMahan CA, McGill HC, Carey KD, Masoro EJ | title = Preweaning food intake influences the adiposity of young adult baboons | journal = The Journal of Clinical Investigation | volume = 78 | issue = 4 | pages = 899–905 | date = October 1986 | pmid = 3760191 | pmc = 423712 | doi = 10.1172/JCI112678 }}{{cite journal | vauthors = Hahn P | title = Effect of litter size on plasma cholesterol and insulin and some liver and adipose tissue enzymes in adult rodents | journal = The Journal of Nutrition | volume = 114 | issue = 7 | pages = 1231–1234 | date = July 1984 | pmid = 6376732 | doi = 10.1093/jn/114.7.1231 }} Rodent experiment shows that neonatal exposure to SSRIs makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes,{{cite journal | vauthors = Popa D, Léna C, Alexandre C, Adrien J | title = Lasting syndrome of depression produced by reduction in serotonin uptake during postnatal development: evidence from sleep, stress, and behavior | journal = The Journal of Neuroscience | volume = 28 | issue = 14 | pages = 3546–3554 | date = April 2008 | pmid = 18385313 | pmc = 6671102 | doi = 10.1523/JNEUROSCI.4006-07.2008 }}{{cite journal | vauthors = Maciag D, Simpson KL, Coppinger D, Lu Y, Wang Y, Lin RC, Paul IA | title = Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry | journal = Neuropsychopharmacology | volume = 31 | issue = 1 | pages = 47–57 | date = January 2006 | pmid = 16012532 | pmc = 3118509 | doi = 10.1038/sj.npp.1300823 }} which are reversed by treatment with antidepressants.{{cite journal | vauthors = Maciag D, Williams L, Coppinger D, Paul IA | title = Neonatal citalopram exposure produces lasting changes in behavior which are reversed by adult imipramine treatment | journal = European Journal of Pharmacology | volume = 532 | issue = 3 | pages = 265–269 | date = February 2006 | pmid = 16483567 | pmc = 2921633 | doi = 10.1016/j.ejphar.2005.12.081 }} By treating normal and knockout mice lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on active serotonin transporters during the neonatal period.{{cite journal | vauthors = Holden C | title = Neuroscience. Prozac treatment of newborn mice raises anxiety | journal = Science | volume = 306 | issue = 5697 | pages = 792 | date = October 2004 | pmid = 15514122 | doi = 10.1126/science.306.5697.792 | doi-access = free }}{{cite journal | vauthors = Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA | title = Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice | journal = Science | volume = 306 | issue = 5697 | pages = 879–881 | date = October 2004 | pmid = 15514160 | doi = 10.1126/science.1101678 | doi-access = free | bibcode = 2004Sci...306..879A }}

Human serotonin can also act as a growth factor directly. Liver damage increases cellular expression of 5-HT_2A and 5-HT_2B receptors, mediating liver compensatory regrowth (see {{section link|Liver|Regeneration and transplantation}}){{cite journal | vauthors = Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, Gachet C, Bader M, Clavien PA | title = Platelet-derived serotonin mediates liver regeneration | journal = Science | volume = 312 | issue = 5770 | pages = 104–107 | date = April 2006 | pmid = 16601191 | doi = 10.1126/science.1123842 | s2cid = 43189753 | bibcode = 2006Sci...312..104L }} Serotonin present in the blood then stimulates cellular growth to repair liver damage.{{cite journal | vauthors = Matondo RB, Punt C, Homberg J, Toussaint MJ, Kisjes R, Korporaal SJ, Akkerman JW, Cuppen E, de Bruin A | title = Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration | journal = American Journal of Physiology. Gastrointestinal and Liver Physiology | volume = 296 | issue = 4 | pages = G963–G968 | date = April 2009 | pmid = 19246633 | doi = 10.1152/ajpgi.90709.2008 | url = http://www.suaire.suanet.ac.tz:8080/xmlui/handle/123456789/2619 | access-date = 5 December 2019 | url-status = dead | archive-url = https://web.archive.org/web/20191228005416/http://www.suaire.suanet.ac.tz:8080/xmlui/handle/123456789/2619 | archive-date = 28 December 2019 | url-access = subscription }}

5-HT_2B receptors also activate osteocytes, which build up bone{{cite journal | vauthors = Collet C, Schiltz C, Geoffroy V, Maroteaux L, Launay JM, de Vernejoul MC | title = The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation | journal = FASEB Journal | volume = 22 | issue = 2 | pages = 418–427 | date = February 2008 | pmid = 17846081 | pmc = 5409955 | doi = 10.1096/fj.07-9209com | doi-access = free }} However, serotonin also inhibits osteoblasts, through 5-HT_1B receptors.{{cite journal | vauthors = Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G | title = Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum | journal = Cell | volume = 135 | issue = 5 | pages = 825–837 | date = November 2008 | pmid = 19041748 | pmc = 2614332 | doi = 10.1016/j.cell.2008.09.059 }}

• {{cite press release |date=December 1, 2008 |title=It Takes Guts To Build Bone, Scientists Discover |website=ScienceDaily |url=https://www.sciencedaily.com/releases/2008/11/081126122209.htm}}

{{Main|Cardiac fibrosis}}

Serotonin, in addition, evokes endothelial nitric oxide synthase activation and stimulates, through a 5-HT1B receptor-mediated mechanism, the phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures.{{clarify|incomprehensible to lay readers|date=December 2018}}{{cite journal | vauthors = McDuffie JE, Motley ED, Limbird LE, Maleque MA | title = 5-hydroxytryptamine stimulates phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures | journal = Journal of Cardiovascular Pharmacology | volume = 35 | issue = 3 | pages = 398–402 | date = March 2000 | pmid = 10710124 | doi = 10.1097/00005344-200003000-00008 | doi-access = free }} In blood, serotonin is collected from plasma by platelets, which store it. It is thus active wherever platelets bind in damaged tissue, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic (growth factor), to aid healing.{{cite journal | vauthors = Noguchi M, Furukawa KT, Morimoto M | title = Pulmonary neuroendocrine cells: physiology, tissue homeostasis and disease | journal = Disease Models & Mechanisms | volume = 13 | issue = 12 | pages = dmm046920 | date = December 2020 | pmid = 33355253 | pmc = 7774893 | doi = 10.1242/dmm.046920 }}

Serotonin also regulates white and brown adipose tissue function, and adipocytes are capable of producing 5-HT separately from the gut. Serotonin increases lipogenesis through HTR2A in white adipose tissue, and suppressed thermogenesis in brown adipose tissue via Htr3.{{cite journal | vauthors = Oh CM, Namkung J, Go Y, Shong KE, Kim K, Kim H, Park BY, Lee HW, Jeon YH, Song J, Shong M, Yadav VK, Karsenty G, Kajimura S, Lee IK, Park S, Kim H | title = Regulation of systemic energy homeostasis by serotonin in adipose tissues | journal = Nature Communications | volume = 6 | pages = 6794 | date = April 2015 | pmid = 25864946 | doi = 10.1038/ncomms7794 | pmc = 4403443 | bibcode = 2015NatCo...6.6794O }}

Several classes of drugs target the serotonin system, including some antidepressants, anxiolytics, antipsychotics, analgesics, antimigraine drugs, oxytocics, antiemetics, appetite suppressants, and anticonvulsants, as well as psychedelics and entactogens.

At rest, serotonin is stored within the vesicles of presynaptic neurons. When stimulated by nerve impulses, serotonin is released as a neurotransmitter into the synapse, reversibly binding to the postsynaptic receptor to induce a nerve impulse on the postsynaptic neuron. Serotonin can also bind to auto-receptors on the presynaptic neuron to regulate the synthesis and release of serotonin. Normally serotonin is taken back into the presynaptic neuron to stop its action, then reused or broken down by monoamine oxidase.{{cite journal | vauthors = Fuller RW | title = Pharmacology of central serotonin neurons | journal = Annual Review of Pharmacology and Toxicology | volume = 20 | pages = 111–127 | date = 1980 | pmid = 6992697 | doi = 10.1146/annurev.pa.20.040180.000551 }}

{{Main|Selective serotonin reuptake inhibitor|Monoamine oxidase inhibitor}}

Drugs that alter serotonin levels are used in treating depression, generalized anxiety disorder, and social phobia. Monoamine oxidase inhibitors (MAOIs) prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions, and patients are at risk of hypertensive emergency triggered by foods with high tyramine content, and certain drugs. Some drugs inhibit the re-uptake of serotonin, making it stay in the synaptic cleft longer. The tricyclic antidepressants (TCAs) inhibit the reuptake of both serotonin and norepinephrine. The newer selective serotonin reuptake inhibitors (SSRIs) have fewer side-effects and fewer interactions with other drugs.{{Cite book | vauthors = Goodman LS, Brunton LL, Chabner B, Knollmann BC | title = Goodman and Gilman's pharmacological basis of therapeutics | year = 2001 | publisher = McGraw-Hill | location = New York | isbn = 978-0-07-162442-8 | pages = 459–461 }}

Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases.{{cite journal | vauthors = Benmansour S, Cecchi M, Morilak DA, Gerhardt GA, Javors MA, Gould GG, Frazer A | title = Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level | journal = The Journal of Neuroscience | volume = 19 | issue = 23 | pages = 10494–10501 | date = December 1999 | pmid = 10575045 | pmc = 6782424 | doi = 10.1523/JNEUROSCI.19-23-10494.1999 }} The 5-HTTLPR gene codes for the number of serotonin transporters in the brain, with more serotonin transporters causing decreased duration and magnitude of serotonergic signaling.{{cite journal | vauthors = Beitchman JH, Baldassarra L, Mik H, De Luca V, King N, Bender D, Ehtesham S, Kennedy JL | title = Serotonin transporter polymorphisms and persistent, pervasive childhood aggression | journal = The American Journal of Psychiatry | volume = 163 | issue = 6 | pages = 1103–1105 | date = June 2006 | pmid = 16741214 | doi = 10.1176/appi.ajp.163.6.1103 }} The 5-HTTLPR polymorphism (l/l) causing more serotonin transporters to be formed is also found to be more resilient against depression and anxiety.{{cite journal | vauthors = Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR | title = 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression | journal = Nature Neuroscience | volume = 8 | issue = 6 | pages = 828–834 | date = June 2005 | pmid = 15880108 | doi = 10.1038/nn1463 | s2cid = 1864631 }}{{cite journal | vauthors = Schinka JA, Busch RM, Robichaux-Keene N | title = A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety | journal = Molecular Psychiatry | volume = 9 | issue = 2 | pages = 197–202 | date = February 2004 | pmid = 14966478 | doi = 10.1038/sj.mp.4001405 | doi-access = free }}

Besides their use in treating depression and anxiety, certain serotonergic antidepressants are also approved and used to treat fibromyalgia, neuropathic pain, and chronic fatigue syndrome.{{cite journal | vauthors = O'Malley PG, Jackson JL, Santoro J, Tomkins G, Balden E, Kroenke K | title = Antidepressant therapy for unexplained symptoms and symptom syndromes | journal = J Fam Pract | volume = 48 | issue = 12 | pages = 980–990 | date = December 1999 | pmid = 10628579 | doi = | url = }}{{cite journal | vauthors = Welsch P, Üçeyler N, Klose P, Walitt B, Häuser W | title = Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia | journal = Cochrane Database Syst Rev | volume = 2 | issue = 2 | pages = CD010292 | date = February 2018 | pmid = 29489029 | pmc = 5846183 | doi = 10.1002/14651858.CD010292.pub2 | url = }}

Azapirone anxiolytics like buspirone and tandospirone act as serotonin 5-HT_1A receptor agonists.{{cite journal | vauthors = Taylor DP, Moon SL | title = Buspirone and related compounds as alternative anxiolytics | journal = Neuropeptides | volume = 19 | issue = Suppl | pages = 15–19 | date = July 1991 | pmid = 1679210 | doi = 10.1016/0143-4179(91)90078-w | url = }}{{cite journal | vauthors = Kishi T, Meltzer HY, Matsuda Y, Iwata N | title = Azapirone 5-HT1A receptor partial agonist treatment for major depressive disorder: systematic review and meta-analysis | journal = Psychol Med | volume = 44 | issue = 11 | pages = 2255–2269 | date = August 2014 | pmid = 24262766 | doi = 10.1017/S0033291713002857 | url = }}

Many antipsychotics bind to and modulate serotonin receptors, including the serotonin 5-HT_1A, 5-HT_2A, 5-HT_2B, 5-HT_2C, 5-HT₆, and 5-HT₇ receptors, among others.{{cite journal | vauthors = Meltzer HY | title = The role of serotonin in antipsychotic drug action | journal = Neuropsychopharmacology | volume = 21 | issue = 2 Suppl | pages = 106S–115S | date = August 1999 | pmid = 10432496 | doi = 10.1016/S0893-133X(99)00046-9 | url = }}{{cite book | vauthors = Meltzer HY | chapter = Serotonergic Mechanisms as Targets for Existing and Novel Antipsychotics | title = Handb Exp Pharmacol | series = Handbook of Experimental Pharmacology | volume = 212| issue = 212 | pages = 87–124 | date = 2012 | pmid = 23129329 | doi = 10.1007/978-3-642-25761-2_4 | isbn = 978-3-642-25760-5 | chapter-url = }} Activation of serotonin 5-HT_1A receptors and blockade of serotonin 5-HT_2A receptors may contribute to the therapeutic antipsychotic effects of these agents, whereas antagonism of serotonin 5-HT_2C receptors has been especially implicated in side effects of antipsychotics.

Antimigraine agents such as the triptans like sumatriptan act as agonists of the serotonin 5-HT_1B, 5-HT_1D, and/or 5-HT_1F receptors.{{cite journal | vauthors = Tfelt-Hansen P, De Vries P, Saxena PR | title = Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy | journal = Drugs | volume = 60 | issue = 6 | pages = 1259–1287 | date = December 2000 | pmid = 11152011 | doi = 10.2165/00003495-200060060-00003 | url = }} Earlier antimigraine agents were the ergoline derivatives and ergot-related drugs such as ergotamine, dihydroergotamine, and methysergide, which act as non-selective serotonin receptor agonists.{{cite journal | vauthors = Ramírez Rosas MB, Labruijere S, Villalón CM, Maassen Vandenbrink A | title = Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs | journal = Expert Opin Pharmacother | volume = 14 | issue = 12 | pages = 1599–1610 | date = August 2013 | pmid = 23815106 | doi = 10.1517/14656566.2013.806487 | url = }}{{cite journal | vauthors = Saxena PR, Den Boer MO | title = Pharmacology of antimigraine drugs | journal = J Neurol | volume = 238 | issue = Suppl 1 | pages = S28–S35 | date = 1991 | pmid = 1646288 | doi = 10.1007/BF01642903 | url = }}{{cite book | vauthors = Whealy M, Becker WJ | chapter = The 5-HT1B and 5-HT1D agonists in acute migraine therapy: Ergotamine, dihydroergotamine, and the triptans | title = Handbook of Clinical Neurology | volume = 199 | pages = 17–42 | date = 2024 | pmid = 38307644 | doi = 10.1016/B978-0-12-823357-3.00008-2 | isbn = 978-0-12-823357-3 | url = }}

Certain lysergamides like ergometrine and methylergometrine are used clinically as oxytocic agents.{{cite journal | vauthors = Schiff PL | title = Ergot and its alkaloids | journal = American Journal of Pharmaceutical Education | volume = 70 | issue = 5 | pages = 98 | date = October 2006 | pmid = 17149427 | pmc = 1637017 | doi = 10.5688/aj700598 | doi-broken-date = 26 March 2025 | quote = Ergonovine is a selective and moderately potent tryptaminergic receptor antagonist in various smooth muscles, being only a partially agonistic or antagonistic at tryptaminergic receptors in the central nervous system. In blood vessels the alkaloid is only weakly antagonistic of dopaminergic receptors and partitally agonistic of α-adrenergic receptors. The most pronounced effect of ergonovine is one of direct stimulation of the uterine smooth musculature, resulting in increased muscular tone and an enhancement of the rate and force of rhythmical contractions. This stimulant effect seems to be most closely associated with agonist or partial agonist effects at 5-HT2 receptors. [...] LSD and related hallucinogens are known to interact with brain 5-HT receptors to produce agonist or partial antagonist effects on serotonin activity. }}{{cite journal | vauthors = Vallera C, Choi LO, Cha CM, Hong RW | title = Uterotonic Medications: Oxytocin, Methylergonovine, Carboprost, Misoprostol | journal = Anesthesiology Clinics | volume = 35 | issue = 2 | pages = 207–219 | date = June 2017 | pmid = 28526143 | doi = 10.1016/j.anclin.2017.01.007 | quote = Methylergonovine is a serotonergic receptor agonist in the smooth muscle. It is also a weak antagonist of dopaminergic receptors and partial agonist of α-adrenergic receptors.22 Methylergonovine causes uterine contractions and relaxation at low doses, but causes sustained contractions and increased basal tone at high doses.24 The mechanism of action for uterine contraction is not well defined. Uterine contraction is likely produced by methylergonovine agonist effects on the 5-HT2 receptor found in uterine smooth muscle.22 Alternatively, methylergonovine could cause uterine contraction through direct stimulation of the α-adrenergic receptors in the uterus, which has been postulated to lead to calcium mobilization.25 }} The oxytocic effects of these drugs are thought to most likely be mediated by agonism of serotonin 5-HT₂ receptors in uterine smooth muscle tissue.

Some serotonin 5-HT₃ receptor antagonists, such as ondansetron, granisetron, and tropisetron, are important antiemetic agents.{{cite journal | vauthors = Ho KY, Gan TJ | title = Pharmacology, pharmacogenetics, and clinical efficacy of 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting | journal = Curr Opin Anesthesiol | volume = 19 | issue = 6 | pages = 606–611 | date = December 2006 | pmid = 17093363 | doi = 10.1097/01.aco.0000247340.61815.38 | url = }}{{cite journal | vauthors = Seynaeve C, Verweij J, de Mulder PH | title = 5-HT3 receptor antagonists, a new approach in emesis: a review of ondansetron, granisetron and tropisetron | journal = Anticancer Drugs | volume = 2 | issue = 4 | pages = 343–355 | date = August 1991 | pmid = 1665723 | doi = 10.1097/00001813-199108000-00003 | url = }} They are particularly important in treating the nausea and vomiting that occur during anticancer chemotherapy using cytotoxic drugs. Another application is in the treatment of postoperative nausea and vomiting.

Some serotonin releasing agents, serotonin reuptake inhibitors, and/or serotonin 5-HT_2C receptor agonists, such as fenfluramine, dexfenfluramine, chlorphentermine, sibutramine, and lorcaserin, have been approved and used as appetite suppressants for purposes of weight loss in the treatment of overweightness or obesity.{{cite journal | vauthors = Halford JC, Harrold JA, Boyland EJ, Lawton CL, Blundell JE | title = Serotonergic drugs : effects on appetite expression and use for the treatment of obesity | journal = Drugs | volume = 67 | issue = 1 | pages = 27–55 | date = 2007 | pmid = 17209663 | doi = 10.2165/00003495-200767010-00004 | url = }}{{cite journal | vauthors = Hurren KM, Berlie HD | title = Lorcaserin: an investigational serotonin 2C agonist for weight loss | journal = Am J Health Syst Pharm | volume = 68 | issue = 21 | pages = 2029–2037 | date = November 2011 | pmid = 22011982 | doi = 10.2146/ajhp100638 | url = }}{{cite journal | vauthors = Halford JC, Boyland EJ, Lawton CL, Blundell JE, Harrold JA | title = Serotonergic anti-obesity agents: past experience and future prospects | journal = Drugs | volume = 71 | issue = 17 | pages = 2247–2255 | date = December 2011 | pmid = 22085383 | doi = 10.2165/11596680-000000000-00000 | url = }}{{cite book | vauthors = Halford JC, Harrold JA | chapter = 5-HT2C Receptor Agonists and the Control of Appetite | title = Handbook of Experimental Pharmacology | volume = 209| issue = 209 | pages = 349–356 | date = 2012 | pmid = 22249823 | doi = 10.1007/978-3-642-24716-3_16 | isbn = 978-3-642-24715-6 | chapter-url = }}{{cite journal | vauthors = Przegaliński E, Witek K, Wydra K, Kotlińska JH, Filip M | title = 5-HT2C Receptor Stimulation in Obesity Treatment: Orthosteric Agonists vs. Allosteric Modulators | journal = Nutrients | volume = 15 | issue = 6 | date = March 2023 | page = 1449 | pmid = 36986191 | pmc = 10058696 | doi = 10.3390/nu15061449 | doi-access = free | url = }} Several of the preceding agents have been withdrawn from the market due to toxicity, such as cardiac fibrosis or pulmonary hypertension.

Although it was previously withdrawn from the market as an appetite suppressant, fenfluramine was reintroduced as an anticonvulsant for treatment of seizures in certain rare forms of epilepsy like Dravet syndrome and Lennox–Gastaut syndrome.{{cite journal | vauthors = Dini G, Di Cara G, Ferrara P, Striano P, Verrotti A | title = Reintroducing Fenfluramine as a Treatment for Seizures: Current Knowledge, Recommendations and Gaps in Understanding | journal = Neuropsychiatr Dis Treat | volume = 19 | issue = | pages = 2013–2025 | date = 2023 | pmid = 37790801 | pmc = 10543412 | doi = 10.2147/NDT.S417676 | doi-access = free | url = }} Selective serotonin 5-HT_2C receptor agonists, like lorcaserin, bexicaserin, and BMB-101, are also being developed for this use.{{cite journal | vauthors = Bialer M, Perucca E | title = Lorcaserin for Dravet Syndrome: A Potential Advance Over Fenfluramine? | journal = CNS Drugs | volume = 36 | issue = 2 | pages = 113–122 | date = February 2022 | pmid = 35094259 | doi = 10.1007/s40263-022-00896-3 | url = }}{{cite journal | vauthors = Dell'isola GB, Verrotti A, Sciaccaluga M, Roberti R, Parnetti L, Russo E, Costa C | title = Evaluating bexicaserin for the treatment of developmental epileptic encephalopathies | journal = Expert Opin Pharmacother | volume = 25 | issue = 9 | pages = 1121–1130 | date = June 2024 | pmid = 38916481 | doi = 10.1080/14656566.2024.2373350 | url = }}{{cite web | title=BMB 101 | website=AdisInsight | date=23 October 2024 | url=https://adisinsight.springer.com/drugs/800065004 | access-date=30 October 2024}}

{{See also|Psychedelic drug#Mechanism of action}}

Serotonergic psychedelics, including drugs like psilocybin (found in psilocybin mushrooms), dimethyltryptamine (DMT) (found in ayahuasca), lysergic acid diethylamide (LSD), mescaline (found in peyote cactus), and 5-MeO-DMT (found in Anadenanthera trees and the Bufo alvarius toad), are non-selective agonists of the serotonin receptors and mediate their hallucinogenic effects specifically by activation of the serotonin 5-HT_2A receptor.{{cite journal | vauthors = Slocum ST, DiBerto JF, Roth BL | title = Molecular insights into psychedelic drug action | journal = J Neurochem | volume = 162 | issue = 1 | pages = 24–38 | date = July 2022 | pmid = 34797943 | doi = 10.1111/jnc.15540 | url = }}{{cite journal | vauthors = Duan W, Cao D, Wang S, Cheng J | title = Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants | journal = Chem Rev | volume = 124 | issue = 1 | pages = 124–163 | date = January 2024 | pmid = 38033123 | doi = 10.1021/acs.chemrev.3c00375 | url = }}{{cite book | vauthors = Nichols DE | title = Chemistry and Structure-Activity Relationships of Psychedelics | series = Current Topics in Behavioral Neurosciences | volume = 36 | pages = 1–43 | date = 2018 | pmid = 28401524 | doi = 10.1007/7854_2017_475 | isbn = 978-3-662-55878-2 | url = }} This is evidenced by the fact that serotonin 5-HT_2A receptor antagonists and so-called "trip killers" like ketanserin block the hallucinogenic effects of serotonergic psychedelics in humans, among many other findings.{{Cite journal |vauthors=Halman A, Kong G, Sarris J, Perkins D |date=January 2024 |title=Drug-drug interactions involving classic psychedelics: A systematic review |journal=J Psychopharmacol |volume=38 |issue=1 |pages=3–18 |doi=10.1177/02698811231211219 |pmc=10851641 |pmid=37982394}} Some serotonergic psychedelics, like psilocin, DMT, and 5-MeO-DMT, are substituted tryptamines and are very similar in chemical structure to serotonin.

Serotonin itself, despite acting as a serotonin 5-HT_2A receptor agonist, is thought to be non-hallucinogenic. The hallucinogenic effects of serotonergic psychedelics appear to be mediated by activation of serotonin 5-HT_2A receptors expressed in a population of cortical neurons in the medial prefrontal cortex (mPFC).{{cite journal | vauthors = Sapienza J | title=The Key Role of Intracellular 5-HT2A Receptors: A Turning Point in Psychedelic Research? | journal=Psychoactives | volume=2 | issue=4 | date=13 October 2023 | issn=2813-1851 | doi=10.3390/psychoactives2040018 | doi-access=free | pages=287–293}}{{cite journal | vauthors = Vargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, Cameron LP, Patel SD, Hennessey JJ, Saeger HN, McCorvy JD, Gray JA, Tian L, Olson DE | title = Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors | journal = Science | volume = 379 | issue = 6633 | pages = 700–706 | date = February 2023 | pmid = 36795823 | pmc = 10108900 | doi = 10.1126/science.adf0435 | bibcode = 2023Sci...379..700V | url = | quote = In addition to promoting psychedelic-induced structural neuroplasticity, the intracellular population of 5-HT2ARs might also contribute to the hallucinogenic effects of psychedelics. When we administered a serotonin-releasing agent to wild type mice, we did not observe a HTR. However, the same drug was able to induce a HTR in mice expressing SERT on cortical neurons of the mPFC—a brain region known to be essential for the HTR (49). Thus, activation of intracellular cortical 5-HT2ARs may play a role in the subjective effects of psychedelics. This hypothesis is further supported by previous work demonstrating that a high dose of the serotonin precursor 5-hydroxytryptophan (5-HTP) induces a HTR in WT mice, which can be blocked by an N-methyltransferase inhibitor that prevents the metabolism of 5-HTP to N-methyltryptamines (50). Inhibition of N-methyltransferase failed to block the HTR induced by 5-MeO-DMT (50). Taken together, this work emphasizes that accessing intracellular 5-HT2ARs is important for 5-HT2AR agonists to produce a HTR.}} These serotonin 5-HT_2A receptors, unlike most serotonin and related receptors, are expressed intracellularly. In addition, the neurons containing them lack expression of the serotonin transporter (SERT), which normally transports serotonin from the extracellular space to the intracellular space within neurons. Serotonin itself is too hydrophilic to enter serotonergic neurons without the SERT, and hence these serotonin 5-HT_2A receptors are inaccessible to serotonin. Conversely, serotonergic psychedelics are more lipophilic than serotonin and readily enter these neurons. In addition to explaining why serotonin does not show psychedelic effects, these findings may explain why drugs that increase serotonin levels, like selective serotonin reuptake inhibitors (SSRIs) and various other types of serotonergic agents, do not produce psychedelic effects. Artificial expression of the SERT in these medial prefrontal cortex neurons resulted in the serotonin releasing agent para-chloroamphetamine (PCA), which does not normally show psychedelic-like effects, being able to produce psychedelic-like effects in animals.

Although serotonin itself is non-hallucinogenic, administration of very high doses of a serotonin precursor, like tryptophan or 5-hydroxytryptophan (5-HTP), or intracerebroventricular injection of high doses of serotonin directly into the brain, can produce psychedelic-like effects in animals.{{cite book | vauthors = Schmid CL, Bohn LM | title=5-HT2A Receptors in the Central Nervous System | chapter=βArrestins: Ligand-Directed Regulators of 5-HT2A Receptor Trafficking and Signaling Events | publisher=Springer International Publishing | publication-place=Cham | date=2018 | isbn=978-3-319-70472-2 | doi=10.1007/978-3-319-70474-6_2 | pages=31–55}}{{cite book | vauthors = Kozlenkov A, González-Maeso J | title=The Neuroscience of Hallucinations | chapter=Animal Models and Hallucinogenic Drugs | publisher=Springer New York | publication-place=New York, NY | date=2013 | isbn=978-1-4614-4120-5 | doi=10.1007/978-1-4614-4121-2_14 | pages=253–277}}{{cite journal | vauthors = Schmid CL, Bohn LM | title = Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a β-arrestin2/Src/Akt signaling complex in vivo | journal = J Neurosci | volume = 30 | issue = 40 | pages = 13513–24 | date = October 2010 | pmid = 20926677 | pmc = 3001293 | doi = 10.1523/JNEUROSCI.1665-10.2010 | url = }} These psychedelic-like effects can be abolished by indolethylamine N-methyltransferase (INMT) inhibitors, which block conversion of serotonin and other endogenous tryptamines into N-methylated tryptamines, including N-methylserotonin (NMS; norbufotenin), bufotenin (5-hydroxy-N,N-dimethyltryptamine; 5-HO-DMT), N-methyltryptamine (NMT), and N,N-dimethyltryptamine (DMT).{{cite book | vauthors = Halberstadt AL, Geyer MA | title = Behavioral Neurobiology of Psychedelic Drugs | chapter = Effect of Hallucinogens on Unconditioned Behavior | series = Current Topics in Behavioral Neurosciences | volume = 36 | pages = 159–199 | date = 2018 | pmid = 28224459 | pmc = 5787039 | doi = 10.1007/7854_2016_466 | isbn = 978-3-662-55878-2 | chapter-url = }} These N-methyltryptamines are much more lipophilic than serotonin and, in contrast, are able to diffuse into serotonergic neurons and activate intracellular serotonin 5-HT_2A receptors. Another possible metabolite of serotonin with psychedelic-like effects in animals is 5-methoxytryptamine (5-MT).{{cite journal | vauthors = Pévet P | title = Is 5-methoxytryptamine a pineal hormone? | journal = Psychoneuroendocrinology | volume = 8 | issue = 1 | pages = 61–73 | date = 1983 | pmid = 6136058 | doi = 10.1016/0306-4530(83)90041-0 | url = }}{{cite journal | vauthors = Tan DX, Hardeland R, Back K, Manchester LC, Alatorre-Jimenez MA, Reiter RJ | title = On the significance of an alternate pathway of melatonin synthesis via 5-methoxytryptamine: comparisons across species | journal = J Pineal Res | volume = 61 | issue = 1 | pages = 27–40 | date = August 2016 | pmid = 27112772 | doi = 10.1111/jpi.12336 | url = }}{{cite journal | vauthors = Przegaliński E, Zebrowska-Lupina I, Wójcik A, Kleinrok Z | title = 5-Methoxytryptamine-induced head twitches in rats | journal = Pol J Pharmacol Pharm | volume = 29 | issue = 3 | pages = 253–261 | date = 1977 | pmid = 267911 | doi = | url = }}

DMT is a naturally occurring endogenous compound in the body.{{cite journal | vauthors = Jiménez JH, Bouso JC | title = Significance of mammalian N, N-dimethyltryptamine (DMT): A 60-year-old debate | journal = J Psychopharmacol | volume = 36 | issue = 8 | pages = 905–919 | date = August 2022 | pmid = 35695604 | doi = 10.1177/02698811221104054 | url = }}{{cite journal | vauthors = Barker SA | title = N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function | journal = Front Neurosci | volume = 12 | issue = | pages = 536 | date = 2018 | pmid = 30127713 | pmc = 6088236 | doi = 10.3389/fnins.2018.00536 | doi-access = free | url = }}{{cite journal | vauthors = Cameron LP, Olson DE | title = Dark Classics in Chemical Neuroscience: N, N-Dimethyltryptamine (DMT) | journal = ACS Chem Neurosci | volume = 9 | issue = 10 | pages = 2344–2357 | date = October 2018 | pmid = 30036036 | doi = 10.1021/acschemneuro.8b00101 | url = }} In relation to the fact that serotonin itself is unable to activate intracellular serotonin 5-HT_2A receptors, it is possible that DMT might be the endogenous ligand of these receptors rather than serotonin.

{{See also|Entactogen#Mechanism of action}}

The entactogen MDMA is a serotonin releasing agent and, while it also possesses other actions such as concomitant release of norepinephrine and dopamine and weak direct agonism of the serotonin 5-HT₂ receptors, its serotonin release plays a key role in its unique entactogenic effects.{{cite journal | vauthors = Dunlap LE, Andrews AM, Olson DE | title = Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine | journal = ACS Chem Neurosci | volume = 9 | issue = 10 | pages = 2408–2427 | date = October 2018 | pmid = 30001118 | pmc = 6197894 | doi = 10.1021/acschemneuro.8b00155 | url = }} Entactogens like MDMA should be distinguished from other drugs such as stimulants like amphetamine and psychedelics like LSD, although MDMA itself also has some characteristics of both of these types of agents.{{cite journal | vauthors = Nichols DE | title = Entactogens: How the Name for a Novel Class of Psychoactive Agents Originated | journal = Front Psychiatry | volume = 13 | issue = | pages = 863088 | date = 2022 | pmid = 35401275 | pmc = 8990025 | doi = 10.3389/fpsyt.2022.863088 | doi-access = free | url = }} Coadministration of selective serotonin reuptake inhibitors (SSRIs), which block the serotonin transporter (SERT) and prevent MDMA from inducing serotonin release, markedly reduce the subjective effects of MDMA, demonstrating the key role of serotonin in the effects of the drug.{{cite journal | vauthors = Sarparast A, Thomas K, Malcolm B, Stauffer CS | title = Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review | journal = Psychopharmacology (Berl) | volume = 239 | issue = 6 | pages = 1945–1976 | date = June 2022 | pmid = 35253070 | pmc = 9177763 | doi = 10.1007/s00213-022-06083-y | url = }} Serotonin releasing agents like MDMA achieve much greater increases in serotonin levels than SSRIs and have far more robust of subjective effects.{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Curr Top Med Chem | volume = 6 | issue = 17 | pages = 1845–1859 | date = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 | url = }}{{cite journal |vauthors=Scorza C, Silveira R, Nichols DE, Reyes-Parada M | title = Effects of 5-HT-releasing agents on the extracellullar hippocampal 5-HT of rats. Implications for the development of novel antidepressants with a short onset of action | journal = Neuropharmacology | volume = 38 | issue = 7 | pages = 1055–1061 |date=July 1999 | pmid = 10428424 | doi = 10.1016/S0028-3908(99)00023-4| s2cid = 13714807 }}{{cite journal | vauthors = Marona-Lewicka D, Nichols DE | title = The Effect of Selective Serotonin Releasing Agents in the Chronic Mild Stress Model of Depression in Rats | journal = Stress | volume = 2 | issue = 2 | pages = 91–100 | date = December 1997 | pmid = 9787258 | doi = 10.3109/10253899709014740 | url = }}{{cite journal | vauthors = Marona-Lewicka D, Nichols DE | title = Drug discrimination studies of the interoceptive cues produced by selective serotonin uptake inhibitors and selective serotonin releasing agents | journal = Psychopharmacology (Berl) | volume = 138 | issue = 1 | pages = 67–75 | date = July 1998 | pmid = 9694528 | doi = 10.1007/s002130050646 | url = }} Besides MDMA, many other entactogens also exist and are known.{{cite journal | vauthors = Simmler LD, Liechti ME | title = Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances | journal = Handb Exp Pharmacol | series = Handbook of Experimental Pharmacology | volume = 252 | issue = | pages = 143–164 | date = 2018 | pmid = 29633178 | doi = 10.1007/164_2018_113 | isbn = 978-3-030-10560-0 | url = }}{{cite journal | vauthors = Oeri HE | title = Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy | journal = J Psychopharmacol | volume = 35 | issue = 5 | pages = 512–536 | date = May 2021 | pmid = 32909493 | pmc = 8155739 | doi = 10.1177/0269881120920420 | url = }}

{{Main|Serotonin syndrome}}

Extremely high levels of serotonin or activation of certain serotonin receptors can cause a condition known as serotonin syndrome, with toxic and potentially fatal effects. In practice, such toxic levels are essentially impossible to reach through an overdose of a single antidepressant drug, but require a combination of serotonergic agents, such as an SSRI with a MAOI, which may occur in therapeutic doses.{{cite journal | vauthors = New AM, Nelson S, Leung JG | title = Psychiatric Emergencies in the Intensive Care Unit | journal = AACN Advanced Critical Care | volume = 26 | issue = 4 | pages = 285–293; quiz 294–295 | date = 2015-10-01 | pmid = 26484986 | doi = 10.4037/NCI.0000000000000104 | veditors = Alexander E, Susla GM }}{{cite journal | vauthors = Isbister GK, Bowe SJ, Dawson A, Whyte IM | title = Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose | journal = Journal of Toxicology. Clinical Toxicology | volume = 42 | issue = 3 | pages = 277–285 | year = 2004 | pmid = 15362595 | doi = 10.1081/CLT-120037428 | s2cid = 43121327 }} However, serotonin syndrome can occur with overdose of certain serotonin receptor agonists, like the NBOMe series of serotonergic psychedelics.{{cite journal | vauthors = Scotton WJ, Hill LJ, Williams AC, Barnes NM | title = Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions | journal = Int J Tryptophan Res | volume = 12 | issue = | pages = 1178646919873925 | date = 2019 | pmid = 31523132 | pmc = 6734608 | doi = 10.1177/1178646919873925 | url = }}{{cite journal | vauthors = Ordak M, Zmysłowska A, Bielski M, Rybak D, Tomaszewska M, Wyszomierska K, Kmiec A, Garlicka N, Zalewska M, Zalewski M, Nasierowski T, Muszynska E, Bujalska-Zadrozny M | title = Pharmacotherapy of Patients Taking New Psychoactive Substances: A Systematic Review and Analysis of Case Reports | journal = Front Psychiatry | volume = 12 | issue = | pages = 669921 | date = 2021 | pmid = 33967865 | pmc = 8102790 | doi = 10.3389/fpsyt.2021.669921 | doi-access = free | url = }}{{cite journal | vauthors = Jacobs ET, Akers KG, Vohra V, King AM | title=Cyproheptadine for Serotonin Toxicity: an Updated Systematic Review and Grading of Evidence | journal=Current Emergency and Hospital Medicine Reports | publisher=Springer Science and Business Media LLC | volume=8 | issue=4 | date=10 October 2020 | issn=2167-4884 | doi=10.1007/s40138-020-00222-5 | pages=151–159}}

The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at nontoxic levels.{{cite journal | vauthors = Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM | title = The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity | journal = QJM | volume = 96 | issue = 9 | pages = 635–642 | date = September 2003 | pmid = 12925718 | doi = 10.1093/qjmed/hcg109 | doi-access = free }} It is estimated that 14% of patients experiencing serotonin syndrome overdose on SSRIs; meanwhile the fatality rate is between 2% and 12%.{{cite journal | vauthors = Frank C | title = Recognition and treatment of serotonin syndrome | journal = Canadian Family Physician | volume = 54 | issue = 7 | pages = 988–992 | date = July 2008 | pmid = 18625822 | pmc = 2464814 | doi = }}{{cite journal | vauthors = Boyer EW, Shannon M | title = The serotonin syndrome | journal = The New England Journal of Medicine | volume = 352 | issue = 11 | pages = 1112–1120 | date = March 2005 | pmid = 15784664 | doi = 10.1056/NEJMra041867 }}

Some serotonergic agonist drugs cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis, as well as cardiac valve fibrosis.{{cite book | vauthors = Baskin SI|title = Principles of cardiac toxicology|publisher = CRC Press|location = Boca Raton|year = 1991|isbn = 978-0-8493-8809-5|url = https://books.google.com/books?id=AW7M6jBixj4C&pg=PA626|access-date = 3 February 2010}}

In the past, three groups of serotonergic drugs have been epidemiologically linked with these syndromes. These are the serotonergic vasoconstrictive antimigraine drugs (ergotamine and methysergide), the serotonergic appetite suppressant drugs (fenfluramine, chlorphentermine, and aminorex), and certain anti-Parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT_2B receptors. These include pergolide and cabergoline, but not the more dopamine-specific lisuride.{{cite web|url = http://userpage.fu-berlin.de/~hpertz/Presentation001.pdf|title = Pergolide and Cabergoline But not Lisuride Exhibit Agonist Efficacy at Serotonin 5-HT_2B Receptors| vauthors = Jähnichen S, Horowski R, Pertz H |access-date = 3 February 2010}}

As with fenfluramine, some of these drugs have been withdrawn from the market after groups taking them showed a statistical increase of one or more of the side effects described. An example is pergolide. The drug was declining in use since it was reported in 2003 to be associated with cardiac fibrosis.{{cite journal |year=2004 |title=Cardiac valvulopathy with pergolide |journal=Aust Adv Drug React Bull |volume=23 |issue=4 | author = Adverse Drug Reactions Advisory Committee, Australia |url=http://www.tga.gov.au/adr/aadrb/aadr0408.htm | url-status = dead | archive-url = https://web.archive.org/web/20120627200919/http://www.tga.gov.au/adr/aadrb/aadr0408.htm |archive-date=27 June 2012 }}

Two independent studies published in The New England Journal of Medicine in January 2007 implicated pergolide, along with cabergoline, in causing valvular heart disease.{{cite journal | vauthors = Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E | title = Dopamine agonists and the risk of cardiac-valve regurgitation | journal = The New England Journal of Medicine | volume = 356 | issue = 1 | pages = 29–38 | date = January 2007 | pmid = 17202453 | doi = 10.1056/NEJMoa062222 | doi-access = free }}{{cite journal | vauthors = Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G | title = Valvular heart disease and the use of dopamine agonists for Parkinson's disease | journal = The New England Journal of Medicine | volume = 356 | issue = 1 | pages = 39–46 | date = January 2007 | pmid = 17202454 | doi = 10.1056/NEJMoa054830 | doi-access = free }} As a result of this, the FDA removed pergolide from the United States market in March 2007.{{cite web |url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm152695.htm |title=Food and Drug Administration Public Health Advisory |website=Food and Drug Administration |date=29 March 2007 |access-date=7 February 2010}}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}} (Since cabergoline is not approved in the United States for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. Treatment for hyperprolactinemia requires lower doses than that for Parkinson's Disease, diminishing the risk of valvular heart disease).{{cite web|url = https://www.fda.gov/medwatch/safety/2007/safety07.htm#Pergolide|title = MedWatch – 2007 Safety Information Alerts. Permax (pergolide) and generic equivalents|publisher = United States Food and Drug Administration|date = 29 March 2007|access-date = 30 March 2007}}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}}

Serotonin is used by a variety of single-cell organisms for various purposes. SSRIs have been found to be toxic to algae.{{cite journal | vauthors = Johnson DJ, Sanderson H, Brain RA, Wilson CJ, Solomon KR | title = Toxicity and hazard of selective serotonin reuptake inhibitor antidepressants fluoxetine, fluvoxamine, and sertraline to algae | journal = Ecotoxicology and Environmental Safety | volume = 67 | issue = 1 | pages = 128–139 | date = May 2007 | pmid = 16753215 | doi = 10.1016/j.ecoenv.2006.03.016 | bibcode = 2007EcoES..67..128J }} The gastrointestinal parasite Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some people.{{cite journal | vauthors = McGowan K, Kane A, Asarkof N, Wicks J, Guerina V, Kellum J, Baron S, Gintzler AR, Donowitz M | title = Entamoeba histolytica causes intestinal secretion: role of serotonin | journal = Science | volume = 221 | issue = 4612 | pages = 762–764 | date = August 1983 | pmid = 6308760 | doi = 10.1126/science.6308760 | bibcode = 1983Sci...221..762M }}{{cite book | vauthors = McGowan K, Guerina V, Wicks J, Donowitz M | chapter = Secretory Hormones of Entamoeba histolytica | title = Ciba Foundation Symposium | volume = 112 | pages = 139–154 | year = 1985 | pmid = 2861068 | doi = 10.1002/9780470720936.ch8 | series = Novartis Foundation Symposia | isbn = 978-0-470-72093-6 }} Patients infected with E. histolytica have been found to have highly elevated serum serotonin levels, which returned to normal following resolution of the infection.{{cite journal | vauthors = Banu N, Zaidi KR, Mehdi G, Mansoor T | title = Neurohumoral alterations and their role in amoebiasis | journal = Indian Journal of Clinical Biochemistry | volume = 20 | issue = 2 | pages = 142–145 | date = July 2005 | pmid = 23105547 | pmc = 3453840 | doi = 10.1007/BF02867414 }} E. histolytica also responds to the presence of serotonin by becoming more virulent.{{cite journal | vauthors = Acharya DP, Sen MR, Sen PC | title = Effect of exogenous 5-hydroxytryptamine on pathogenicity of Entamoeba histolytica in experimental animals | journal = Indian Journal of Experimental Biology | volume = 27 | issue = 8 | pages = 718–720 | date = August 1989 | pmid = 2561282 }} This means serotonin secretion not only serves to increase the spread of entamoebas by giving the host diarrhea but also serves to coordinate their behaviour according to their population density, a phenomenon known as quorum sensing. Outside the gut of a host, there is nothing that the entamoebas provoke to release serotonin, hence the serotonin concentration is very low. Low serotonin signals to the entamoebas they are outside a host and they become less virulent to conserve energy. When they enter a new host, they multiply in the gut, and become more virulent as the enterochromaffine cells get provoked by them and the serotonin concentration increases.

{{anchor|Plants|Mushrooms}}

In drying seeds, serotonin production is a way to get rid of the buildup of poisonous ammonia. The ammonia is collected and placed in the indole part of L-tryptophan, which is then decarboxylated by tryptophan decarboxylase to give tryptamine, which is then hydroxylated by a cytochrome P450 monooxygenase, yielding serotonin.{{cite book | vauthors = Schröder P, Abele C, Gohr P, Stuhlfauth-Roisch U, Grosse W | chapter = Latest on Enzymology of Serotonin Biosynthesis in Walnut Seeds | volume = 467 | pages = 637–644 | year = 1999 | pmid = 10721112 | doi = 10.1007/978-1-4615-4709-9_81 | isbn = 978-0-306-46204-7 | series = Advances in Experimental Medicine and Biology | title = Tryptophan, Serotonin, and Melatonin }}

However, since serotonin is a major gastrointestinal tract modulator, it may be produced in the fruits of plants as a way of speeding the passage of seeds through the digestive tract, in the same way as many well-known seed and fruit associated laxatives. Serotonin is found in mushrooms, fruits, and vegetables. The highest values of 25–400 mg/kg have been found in nuts of the walnut (Juglans) and hickory (Carya) genera. Serotonin concentrations of 3–30 mg/kg have been found in plantains, pineapples, banana, kiwifruit, plums, and tomatoes. Moderate levels from 0.1–3 mg/kg have been found in a wide range of tested vegetables.{{cite journal | vauthors = Feldman JM, Lee EM | title = Serotonin content of foods: effect on urinary excretion of 5-hydroxyindoleacetic acid | journal = The American Journal of Clinical Nutrition | volume = 42 | issue = 4 | pages = 639–643 | date = October 1985 | pmid = 2413754 | doi = 10.1093/ajcn/42.4.639 | doi-access = free }}

Serotonin is one compound of the poison contained in stinging nettles (Urtica dioica), where it causes pain on injection in the same manner as its presence in insect venoms. It is also naturally found in Paramuricea clavata, or the Red Sea Fan.{{cite journal | vauthors = Pénez N, Culioli G, Pérez T, Briand JF, Thomas OP, Blache Y | title = Antifouling properties of simple indole and purine alkaloids from the Mediterranean gorgonian Paramuricea clavata | journal = Journal of Natural Products | volume = 74 | issue = 10 | pages = 2304–2308 | date = October 2011 | pmid = 21939218 | doi = 10.1021/np200537v | bibcode = 2011JNAtP..74.2304P }}

Serotonin and tryptophan have been found in chocolate with varying cocoa contents. The highest serotonin content (2.93 μg/g) was found in chocolate with 85% cocoa, and the highest tryptophan content (13.27–13.34 μg/g) was found in 70–85% cocoa. The intermediate in the synthesis from tryptophan to serotonin, 5-hydroxytryptophan, was not found.{{cite journal | vauthors = Guillén-Casla V, Rosales-Conrado N, León-González ME, Pérez-Arribas LV, Polo-Díez LM | title = Determination of serotonin and its precursors in chocolate samples by capillary liquid chromatography with mass spectrometry detection | journal = Journal of Chromatography A | volume = 1232 | pages = 158–165 | date = April 2012 | pmid = 22186492 | doi = 10.1016/j.chroma.2011.11.037 }}

Root development in Arabidopsis thaliana is stimulated and modulated by serotonin – in various ways at various concentrations.{{cite journal | vauthors = Pelagio-Flores R, Ortíz-Castro R, Méndez-Bravo A, Macías-Rodríguez L, López-Bucio J | title = Serotonin, a tryptophan-derived signal conserved in plants and animals, regulates root system architecture probably acting as a natural auxin inhibitor in Arabidopsis thaliana | journal = Plant & Cell Physiology | volume = 52 | issue = 3 | pages = 490–508 | date = March 2011 | pmid = 21252298 | doi = 10.1093/pcp/pcr006 | publisher = Oxford University Press (OUP) | doi-access = free }}

Serotonin serves as a plant defense chemical against fungi. When infected with Fusarium crown rot (Fusarium pseudograminearum), wheat (Triticum aestivum) greatly increases its production of tryptophan to synthesize new serotonin.{{cite journal | vauthors = Powell JJ, Carere J, Fitzgerald TL, Stiller J, Covarelli L, Xu Q, Gubler F, Colgrave ML, Gardiner DM, Manners JM, Henry RJ, Kazan K | title = The Fusarium crown rot pathogen Fusarium pseudograminearum triggers a suite of transcriptional and metabolic changes in bread wheat (Triticum aestivum L.) | journal = Annals of Botany | volume = 119 | issue = 5 | pages = 853–867 | date = March 2017 | pmid = 27941094 | pmc = 5604588 | doi = 10.1093/aob/mcw207 | publisher = Oxford University Press (OUP) | s2cid = 3823345 | doi-access = free }} The function of this is poorly understood but wheat also produces serotonin when infected by Stagonospora nodorum – in that case to retard spore production.{{cite journal | vauthors = Du Fall LA, Solomon PS | title = The necrotrophic effector SnToxA induces the synthesis of a novel phytoalexin in wheat | journal = The New Phytologist | volume = 200 | issue = 1 | pages = 185–200 | date = October 2013 | pmid = 23782173 | doi = 10.1111/nph.12356 | publisher = Wiley | doi-access = free | bibcode = 2013NewPh.200..185D }} The model cereal Brachypodium distachyon – used as a research substitute for wheat and other production cereals – also produces serotonin, coumaroyl-serotonin, and feruloyl-serotonin in response to F. graminearum. This produces a slight antimicrobial effect. B. distachyon produces more serotonin (and conjugates) in response to deoxynivalenol (DON)-producing F. graminearum than non-DON-producing.{{cite journal | vauthors = Pasquet JC, Chaouch S, Macadré C, Balzergue S, Huguet S, Martin-Magniette ML, Bellvert F, Deguercy X, Thareau V, Heintz D, Saindrenan P, Dufresne M | title = Differential gene expression and metabolomic analyses of Brachypodium distachyon infected by deoxynivalenol producing and non-producing strains of Fusarium graminearum | journal = BMC Genomics | volume = 15 | issue = 1 | pages = 629 | date = July 2014 | pmid = 25063396 | pmc = 4124148 | doi = 10.1186/1471-2164-15-629 | publisher = BioMed Central | doi-access = free }} Solanum lycopersicum produces many AA conjugates – including several of serotonin – in its leaves, stems, and roots in response to Ralstonia solanacearum infection.{{cite journal | vauthors = Zeiss DR, Piater LA, Dubery IA | title = Hydroxycinnamate Amides: Intriguing Conjugates of Plant Protective Metabolites | journal = Trends in Plant Science | volume = 26 | issue = 2 | pages = 184–195 | date = February 2021 | pmid = 33036915 | doi = 10.1016/j.tplants.2020.09.011 | publisher = Cell Press | bibcode = 2021TPS....26..184Z | s2cid = 222256660 }}

Serotonin occurs in several hallucinogenic mushrooms of the genus Panaeolus.{{cite journal | vauthors = Tyler VE | title = Occurrence of serotonin in a hallucinogenic mushroom | journal = Science | volume = 128 | issue = 3326 | pages = 718 | date = September 1958 | pmid = 13580242 | doi = 10.1126/science.128.3326.718 | bibcode = 1958Sci...128..718T }}

Serotonin functions as a neurotransmitter in the nervous systems of most animals.

For example, in the roundworm Caenorhabditis elegans, which feeds on bacteria, serotonin is released as a signal in response to positive events, such as finding a new source of food or in male animals finding a female with which to mate.{{cite journal | vauthors = Jonz MG, EkateriniMercier A, JoffrePotter JW | year = 2001 | title = Effects Of 5-HT (Serotonin) On Reproductive Behaviour In Heterodera Schachtii (Nematoda) | journal = Canadian Journal of Zoology | volume = 79 | issue = 9| page = 1727 | doi = 10.1139/z01-135 | bibcode = 2001CaJZ...79.1727J }} When a well-fed worm feels bacteria on its cuticle, dopamine is released, which slows it down; if it is starved, serotonin also is released, which slows the animal down further. This mechanism increases the amount of time animals spend in the presence of food.{{cite journal | vauthors = Sawin ER, Ranganathan R, Horvitz HR | title = C. elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway | journal = Neuron | volume = 26 | issue = 3 | pages = 619–631 | date = June 2000 | pmid = 10896158 | doi = 10.1016/S0896-6273(00)81199-X | s2cid = 9247380 | doi-access = free }} The released serotonin activates the muscles used for feeding, while octopamine suppresses them.{{cite journal | vauthors = Niacaris T, Avery L | title = Serotonin regulates repolarization of the C. elegans pharyngeal muscle | journal = The Journal of Experimental Biology | volume = 206 | issue = Pt 2 | pages = 223–231 | date = January 2003 | pmid = 12477893 | pmc = 4441752 | doi = 10.1242/jeb.00101 | bibcode = 2003JExpB.206..223N }}{{cite journal | vauthors = Rosso MN, Jones JT, Abad P | title = RNAi and functional genomics in plant parasitic nematodes | journal = Annual Review of Phytopathology | volume = 47 | issue = 1 | pages = 207–232 | year = 2009 | pmid = 19400649 | doi = 10.1146/annurev.phyto.112408.132605 | publisher = Annual Reviews | bibcode = 2009AnRvP..47..207R | quote-page = 218 | quote = Octopamine and serotonin regulates the activity of the M3 neurons that direct contraction of the pharynx during C. elegans feeding... Soaking Meloidogyne J2 in dsRNA in the presence of ... resorcinol plus serotonin resulted in uptake of solutions and silencing of genes expressed in the intestine and esophageal glands. }} Serotonin diffuses to serotonin-sensitive neurons, which control the animal's perception of nutrient availability.

If lobsters are injected with serotonin, they behave like dominant individuals whereas octopamine causes subordinate behavior.{{cite journal | vauthors = Kravitz EA | title = Hormonal control of behavior: amines and the biasing of behavioral output in lobsters | journal = Science | volume = 241 | issue = 4874 | pages = 1775–1781 | date = September 1988 | pmid = 2902685 | doi = 10.1126/science.2902685 | bibcode = 1988Sci...241.1775K }} A crayfish that is frightened may flip its tail to flee, and the effect of serotonin on this behavior depends largely on the animal's social status. Serotonin inhibits the fleeing reaction in subordinates, but enhances it in socially dominant or isolated individuals. The reason for this is social experience alters the proportion between serotonin receptors (5-HT receptors) that have opposing effects on the fight-or-flight response.{{Clarify|date=January 2012}} The effect of 5-HT₁ receptors predominates in subordinate animals, while 5-HT₂ receptors predominates in dominants.{{cite journal | vauthors = Yeh SR, Fricke RA, Edwards DH | title = The effect of social experience on serotonergic modulation of the escape circuit of crayfish | journal = Science | volume = 271 | issue = 5247 | pages = 366–369 | date = January 1996 | pmid = 8553075 | doi = 10.1126/science.271.5247.366 | s2cid = 1575533 | citeseerx = 10.1.1.470.6528 | bibcode = 1996Sci...271..366Y }}

{{anchor|Invertebrate venom|Invertebrate venoms|In venom}}

Serotonin is a common component of invertebrate venoms, salivary glands, nervous tissues, and various other tissues, across molluscs, insects, crustaceans, scorpions, various kinds of worms, and jellyfish. Adult Rhodnius prolixus – hematophagous on vertebrates – secrete lipocalins into the wound during feeding. In 2003 these lipocalins were demonstrated to sequester serotonin to prevent vasoconstriction (and possibly coagulation) in the host.{{cite journal | vauthors = Fry BG, Roelants K, Champagne DE, Scheib H, Tyndall JD, King GF, Nevalainen TJ, Norman JA, Lewis RJ, Norton RS, Renjifo C, de la Vega RC | title = The toxicogenomic multiverse: convergent recruitment of proteins into animal venoms | journal = Annual Review of Genomics and Human Genetics | volume = 10 | issue = 1 | pages = 483–511 | year = 2009 | pmid = 19640225 | doi = 10.1146/annurev.genom.9.081307.164356 | publisher = Annual Reviews | doi-access = free }}

Serotonin is evolutionarily conserved and appears across the animal kingdom. It is seen in insect processes in roles similar to in the human central nervous system, such as memory, appetite, sleep, and behavior.{{cite journal |doi=10.14800/nt.314 |title=Serotonin, serotonin receptors and their actions in insects |journal=Neurotransmitter |year=2015 |volume=2 |pages=1–14 |doi-access=free }} Some circuits in mushroom bodies are serotonergic.{{cite journal | vauthors = Schoofs L, De Loof A, Van Hiel MB | title = Neuropeptides as Regulators of Behavior in Insects | journal = Annual Review of Entomology | volume = 62 | issue = 1 | pages = 35–52 | date = January 2017 | pmid = 27813667 | doi = 10.1146/annurev-ento-031616-035500 | publisher = Annual Reviews | doi-access = free }} (See specific Drosophila example below, §Dipterans.)

Locust swarming is initiated but not maintained by serotonin,{{cite journal | vauthors = Wang X, Kang L | title = Molecular mechanisms of phase change in locusts | journal = Annual Review of Entomology | volume = 59 | issue = 1 | pages = 225–244 | date = 2014-01-07 | pmid = 24160426 | doi = 10.1146/annurev-ento-011613-162019 | publisher = Annual Reviews | quote =
p.{{spaces}}231,
The change in the number of several potential neurotransmitters ... such as serotonin... may play an important role in remodeling the CNS during phase change (26, 56, 80).
p.{{spaces}}233,
In the locust S. gregaria, the amount of serotonin in the thoracic ganglia was positively correlated with the extent of gregarious behavior induced by different periods of crowding. A series of pharmacological and behavioral experiments demonstrated that serotonin plays a key role in inducing initial behavioral gregarization (2, 80). However, serotonin is not responsible for maintaining gregarious behavior because its amount in long-term gregarious locusts is less than half that in long-term solitarious locusts (80). In L. migratoria, the injection of serotonin can also slightly initiate gregarious behavior, but serotonin when accompanying crowding treatment induced more solitarious-like behavior than did serotonin injection alone (48). Significant differences in serotonin levels were not found in brain tissues between the two phases of L. migratoria. A recent report by Tanaka & Nishide (97) measured attraction/avoidance behavior in S. gregaria after single and multiple injections of serotonin at different concentrations. Serotonin had only a short-term effect on the level of some locomotor activities and was not involved in the control of gregarious behavior (97). In addition, it is not clear how the neurotransmitter influences this unique behavior, because a binary logistic regression model used in these studies for the behavioral assay focused mostly on only one behavioral parameter representing an overall phase state. Obviously, behavioral phase change might involve alternative regulatory mechanisms in different locust species. Therefore, these studies demonstrate that CNS regulatory mechanisms governing initiation and maintenance of phase change are species specific and involve the interactions between these neurotransmitters.
Given the key roles of aminergic signaling, what are the downstream pathways involved in the establishment of long-term memory? Ott et al. (63) investigated the role of [] protein kinase[] in the phase change in S. gregaria: ... cAMP-dependent protein kinase A (PKA). Through use of pharmacological and RNAi intervention, these authors have demonstrated that PKA... has a critical role in modulating the propensity of locusts to acquire and express gregarious behavior. ... Unfortunately, although a correlation between serotonin and PKA was hypothesized, direct evidence was not provided. | doi-access = free }} with release being triggered by tactile contact between individuals.{{cite journal | vauthors = Zhang L, Lecoq M, Latchininsky A, Hunter D | title = Locust and Grasshopper Management | journal = Annual Review of Entomology | volume = 64 | issue = 1 | pages = 15–34 | date = January 2019 | pmid = 30256665 | doi = 10.1146/annurev-ento-011118-112500 | publisher = Annual Reviews | quote-page = 20 | s2cid = 52843907 | doi-access = free | quote = ...gregarization is evoked by... tactile stimulation... Tactile stimuli trigger the increase of biogenic amines, particularly serotonin, in the locust nervous system (1, 116); these amines play critical roles in the neurophysiology of locust behavioral phase change. }} This transforms social preference from aversion to a gregarious state that enables coherent groups.{{cite journal | vauthors = Anstey ML, Rogers SM, Ott SR, Burrows M, Simpson SJ | title = Serotonin mediates behavioral gregarization underlying swarm formation in desert locusts | journal = Science | volume = 323 | issue = 5914 | pages = 627–630 | date = January 2009 | pmid = 19179529 | doi = 10.1126/science.1165939 | s2cid = 5448884 | bibcode = 2009Sci...323..627A }}

• {{cite news | vauthors = Morgan J |date=29 January 2009 |title=Locust swarms 'high' on serotonin |work=BBC News |url=http://news.bbc.co.uk/2/hi/science/nature/7858996.stm}} Learning in flies and honeybees is affected by the presence of serotonin.{{cite journal | vauthors = Sitaraman D, LaFerriere H, Birman S, Zars T | title = Serotonin is critical for rewarded olfactory short-term memory in Drosophila | journal = Journal of Neurogenetics | volume = 26 | issue = 2 | pages = 238–244 | date = June 2012 | pmid = 22436011 | doi = 10.3109/01677063.2012.666298 | s2cid = 23639918 }}{{cite journal | vauthors = Bicker G, Menzel R | title = Chemical codes for the control of behaviour in arthropods | journal = Nature | volume = 337 | issue = 6202 | pages = 33–39 | date = January 1989 | pmid = 2562906 | doi = 10.1038/337033a0 | s2cid = 223750 | bibcode = 1989Natur.337...33B }}

{{anchor|Insecticide|Insecticides}}

Insect 5-HT receptors have similar sequences to the vertebrate versions, but pharmacological differences have been seen. Invertebrate drug response has been far less characterized than mammalian pharmacology and the potential for species selective insecticides has been discussed.{{cite journal | vauthors = Cai M, Li Z, Fan F, Huang Q, Shao X, Song G | title = Design and synthesis of novel insecticides based on the serotonergic ligand 1-[(4-aminophenyl)ethyl]-4-[3-(trifluoromethyl)phenyl]piperazine (PAPP) | journal = Journal of Agricultural and Food Chemistry | volume = 58 | issue = 5 | pages = 2624–2629 | date = March 2010 | pmid = 20000410 | doi = 10.1021/jf902640u | bibcode = 2010JAFC...58.2624C }}

{{anchor|Hymenoptera}}

Wasps and hornets have serotonin in their venom,{{cite book | vauthors = Manahan SE |title=Toxicological Chemistry and Biochemistry |edition=3rd |publisher=CRC Press |year=2002 |isbn=978-1-4200-3212-3 |page=393 }} which causes pain and inflammation{{cite journal | vauthors = Chen J, Lariviere WR | title = The nociceptive and anti-nociceptive effects of bee venom injection and therapy: a double-edged sword | journal = Progress in Neurobiology | volume = 92 | issue = 2 | pages = 151–183 | date = October 2010 | pmid = 20558236 | pmc = 2946189 | doi = 10.1016/j.pneurobio.2010.06.006 }} as do scorpions.{{cite book | vauthors = Postma TL |chapter=Neurotoxic Animal Poisons and Venoms |chapter-url=http://www.sciencedirect.com/science/article/pii/B9780323052603500496 |pages=463–489 | veditors = Dobbs MR |year=2009 |title=Clinical Neurotoxicology |publisher=W.B. Saunders |doi=10.1016/B978-032305260-3.50049-6 |isbn=978-0-323-05260-3 }} Pheidole dentata takes on more and more tasks in the colony as it gets older, which requires it to respond to more and more olfactory cues in the course of performing them. This olfactory response broadening was demonstrated to go along with increased serotonin and dopamine, but not octopamine in 2006.{{cite journal | vauthors = Gadenne C, Barrozo RB, Anton S | title = Plasticity in Insect Olfaction: To Smell or Not to Smell? | journal = Annual Review of Entomology | volume = 61 | issue = 1 | pages = 317–333 | date = 2016-03-11 | pmid = 26982441 | doi = 10.1146/annurev-ento-010715-023523 | publisher = Annual Reviews | hdl-access = free | s2cid = 207568844 | hdl = 11336/19586 }}

If flies are fed serotonin, they are more aggressive; flies depleted of serotonin still exhibit aggression, but they do so much less frequently.{{cite journal | vauthors = Dierick HA, Greenspan RJ | title = Serotonin and neuropeptide F have opposite modulatory effects on fly aggression | journal = Nature Genetics | volume = 39 | issue = 5 | pages = 678–682 | date = May 2007 | pmid = 17450142 | doi = 10.1038/ng2029 | s2cid = 33768246 }} In their crops it plays a vital role in digestive motility produced by contraction. Serotonin that acts on the crop is exogenous to the crop itself and 2012 research suggested that it probably originated in the serotonin neural plexus in the thoracic-abdominal synganglion.{{cite journal | vauthors = Stoffolano JG, Haselton AT | title = The adult Dipteran crop: a unique and overlooked organ | journal = Annual Review of Entomology | volume = 58 | issue = 1 | pages = 205–225 | date = 2013-01-07 | pmid = 23317042 | doi = 10.1146/annurev-ento-120811-153653 | publisher = Annual Reviews | author-link = John Stoffolano }} In 2011 a Drosophila serotonergic mushroom body was found to work in concert with Amnesiac to form memories. In 2007 serotonin was found to promote aggression in Diptera, which was counteracted by neuropeptide F – a surprising find given that they both promote courtship, which is usually similar to aggression in most respects.

Serotonin, also referred to as 5-hydroxytryptamine (5-HT), is a neurotransmitter most known for its involvement in mood disorders in humans. It is also a widely present neuromodulator among vertebrates and invertebrates.{{cite journal | vauthors = Bacqué-Cazenave J, Bharatiya R, Barrière G, Delbecque JP, Bouguiyoud N, Di Giovanni G, Cattaert D, De Deurwaerdère P | title = Serotonin in Animal Cognition and Behavior | journal = International Journal of Molecular Sciences | volume = 21 | issue = 5 | pages = 1649 | date = February 2020 | pmid = 32121267 | pmc = 7084567 | doi = 10.3390/ijms21051649 | doi-access = free }} Serotonin has been found having associations with many physiological systems such as cardiovascular, thermoregulation, and behavioral functions, including: circadian rhythm, appetite, aggressive and sexual behavior, sensorimotor reactivity and learning, and pain sensitivity.{{cite journal | vauthors = Lucki I | title = The spectrum of behaviors influenced by serotonin | journal = Biological Psychiatry | volume = 44 | issue = 3 | pages = 151–162 | date = August 1998 | pmid = 9693387 | doi = 10.1016/s0006-3223(98)00139-5 | s2cid = 3001666 | doi-access = free }} Serotonin's function in neurological systems along with specific behaviors among vertebrates found to be strongly associated with serotonin will be further discussed. Two relevant case studies are also mentioned regarding serotonin development involving teleost fish and mice.

In mammals, 5-HT is highly concentrated in the substantia nigra, ventral tegmental area and raphe nuclei. Lesser concentrated areas include other brain regions and the spinal cord. 5-HT neurons are also shown to be highly branched, indicating that they are structurally prominent for influencing multiple areas of the CNS at the same time, although this trend is exclusive solely to mammals.

Vertebrates are multicellular organisms in the phylum Chordata that possess a backbone and a nervous system. This includes mammals, fish, reptiles, birds, etc. In humans, the nervous system is composed of the central and peripheral nervous system, with little known about the specific mechanisms of neurotransmitters in most other vertebrates. However, it is known that while serotonin is involved in stress and behavioral responses, it is also important in cognitive functions. Brain organization in most vertebrates includes 5-HT cells in the hindbrain. In addition to this, 5-HT is often found in other sections of the brain in non-placental vertebrates, including the basal forebrain and pretectum.{{cite journal | vauthors = Backström T, Winberg S | title = Serotonin Coordinates Responses to Social Stress-What We Can Learn from Fish | journal = Frontiers in Neuroscience | volume = 11 | pages = 595 | date = 2017-10-25 | pmid = 29163002 | pmc = 5669303 | doi = 10.3389/fnins.2017.00595 | doi-access = free }} Since location of serotonin receptors contribute to behavioral responses, this suggests serotonin is part of specific pathways in non-placental vertebrates that are not present in amniotic organisms.{{cite journal | vauthors = Berger M, Gray JA, Roth BL | title = The expanded biology of serotonin | journal = Annual Review of Medicine | volume = 60 | issue = 1 | pages = 355–366 | date = 2009-02-01 | pmid = 19630576 | pmc = 5864293 | doi = 10.1146/annurev.med.60.042307.110802 }} Teleost fish and mice are organisms most often used to study the connection between serotonin and vertebrate behavior. Both organisms show similarities in the effect of serotonin on behavior, but differ in the mechanism in which the responses occur.

There are few studies of serotonin in dogs. One study reported serotonin values were higher at dawn than at dusk.{{cite journal | vauthors = Alberghina D, Piccione G, Pumilia G, Gioè M, Rizzo M, Raffo P, Panzera M | title = Daily fluctuation of urine serotonin and cortisol in healthy shelter dogs and influence of intraspecific social exposure | journal = Physiology & Behavior | volume = 206 | pages = 1–6 | date = July 2019 | pmid = 30898540 | doi = 10.1016/j.physbeh.2019.03.016 | s2cid = 81965422 }} In another study, serum 5-HT levels did not seem to be associated with dogs' behavioural response to a stressful situation.{{cite journal | vauthors = Riggio G, Mariti C, Sergi V, Diverio S, Gazzano A | title = Serotonin and Tryptophan Serum Concentrations in Shelter Dogs Showing Different Behavioural Responses to a Potentially Stressful Procedure | journal = Veterinary Sciences | volume = 8 | issue = 1 | pages = 1 | date = December 2020 | pmid = 33374183 | pmc = 7824451 | doi = 10.3390/vetsci8010001 | doi-access = free }} Urinary serotonin/creatinine ratio in bitches tended to be higher 4 weeks after surgery. In addition, serotonin was positively correlated with both cortisol and progesterone but not with testosterone after ovariohysterectomy.{{cite journal | vauthors = Hydbring-Sandberg E, Larsson E, Madej A, Höglund OV | title = Short-term effect of ovariohysterectomy on urine serotonin, cortisol, testosterone and progesterone in bitches | journal = BMC Research Notes | volume = 14 | issue = 1 | pages = 265 | date = July 2021 | pmid = 34246304 | pmc = 8272283 | doi = 10.1186/s13104-021-05680-y | doi-access = free }}

Like non-placental vertebrates, teleost fish also possess 5-HT cells in other sections of the brain, including the basal forebrain. Danio rerio (zebra fish) are a species of teleost fish often used for studying serotonin within the brain. Despite much being unknown about serotonergic systems in vertebrates, the importance in moderating stress and social interaction is known.{{cite journal | vauthors = Winberg S, Thörnqvist PO | title = Role of brain serotonin in modulating fish behavior | journal = Current Zoology | volume = 62 | issue = 3 | pages = 317–323 | date = June 2016 | pmid = 29491919 | pmc = 5804243 | doi = 10.1093/cz/zow037 }} It is hypothesized that AVT and CRF cooperate with serotonin in the [https://link.springer.com/referenceworkentry/10.1007%2F978-1-4419-1005-9_460 hypothalamic-pituitary-interrenal axis]. These neuropeptides influence the plasticity of the teleost, affecting its ability to change and respond to its environment. Subordinate fish in social settings show a drastic increase in 5-HT concentrations. High levels of 5-HT long term influence the inhibition of aggression in subordinate fish.

Researchers at the Department of Pharmacology and Medical Chemistry used serotonergic drugs on male mice to study the effects of selected drugs on their behavior.{{cite journal | vauthors = Olivier B, Mos J, van der Heyden J, Hartog J | title = Serotonergic modulation of social interactions in isolated male mice | journal = Psychopharmacology | volume = 97 | issue = 2 | pages = 154–156 | date = 1989-02-01 | pmid = 2498921 | doi = 10.1007/BF00442239 | s2cid = 37170174 }} Mice in isolation exhibit increased levels of agonistic behavior towards one another. Results found that serotonergic drugs reduce aggression in isolated mice while simultaneously increasing social interaction. Each of the treatments use a different mechanism for targeting aggression, but ultimately all have the same outcome. While the study shows that serotonergic drugs successfully target serotonin receptors, it does not show specifics of the mechanisms that affect behavior, as all types of drugs tended to reduce aggression in isolated male mice. Aggressive mice kept out of isolation may respond differently to changes in serotonin reuptake.

Like in humans, serotonin is involved in regulating behavior in most other vertebrates. This includes not only response and social behaviors, but also influencing mood. Defects in serotonin pathways can lead to intense variations in mood, as well as symptoms of mood disorders, which can be present in more than just humans.

One of the most researched aspects of social interaction in which serotonin is involved is aggression. Aggression is regulated by the 5-HT system, as serotonin levels can both induce or inhibit aggressive behaviors, as seen in mice (see section on Mice) and crabs. While this is widely accepted, it is unknown if serotonin interacts directly or indirectly with parts of the brain influencing aggression and other behaviors. Studies of serotonin levels show that they drastically increase and decrease during social interactions, and they generally correlate with inhibiting or inciting aggressive behavior.{{cite journal | vauthors = Huber R, Smith K, Delago A, Isaksson K, Kravitz EA | title = Serotonin and aggressive motivation in crustaceans: altering the decision to retreat | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 11 | pages = 5939–5942 | date = May 1997 | pmid = 9159179 | pmc = 20885 | doi = 10.1073/pnas.94.11.5939 | doi-access = free | bibcode = 1997PNAS...94.5939H }} The exact mechanism of serotonin influencing social behaviors is unknown, as pathways in the 5-HT system in various vertebrates can differ greatly.

Serotonin is important in environmental response pathways, along with other neurotransmitters.{{cite journal | vauthors = Sanchez CL, Biskup CS, Herpertz S, Gaber TJ, Kuhn CM, Hood SH, Zepf FD | title = The Role of Serotonin (5-HT) in Behavioral Control: Findings from Animal Research and Clinical Implications | journal = The International Journal of Neuropsychopharmacology | volume = 18 | issue = 10 | pages = pyv050 | date = May 2015 | pmid = 25991656 | pmc = 4648158 | doi = 10.1093/ijnp/pyv050 }} Specifically, it has been found to be involved in auditory processing in social settings, as primary sensory systems are connected to social interactions.{{cite journal | vauthors = Petersen CL, Hurley LM | title = Putting it in Context: Linking Auditory Processing with Social Behavior Circuits in the Vertebrate Brain | journal = Integrative and Comparative Biology | volume = 57 | issue = 4 | pages = 865–877 | date = October 2017 | pmid = 28985384 | pmc = 6251620 | doi = 10.1093/icb/icx055 }} Serotonin is found in the IC structure of the midbrain, which processes specie specific and non-specific social interactions and vocalizations. It also receives acoustic projections that convey signals to auditory processing regions. Research has proposed that serotonin shapes the auditory information being received by the IC and therefore is influential in the responses to auditory stimuli. This can influence how an organism responds to the sounds of predatory or other impactful species in their environment, as serotonin uptake can influence aggression or social interaction.

We can describe mood not as specific to an emotional status, but as associated with a relatively long-lasting emotional state. Serotonin's association with mood is most known for various forms of depression and bipolar disorders in humans. Disorders caused by serotonergic activity potentially contribute to the many symptoms of major depression, such as overall mood, activity, suicidal thoughts and sexual and cognitive dysfunction. Selective serotonin reuptake inhibitors (SSRI's) are a class of drugs demonstrated to be an effective treatment in major depressive disorder and are the most prescribed class of antidepressants. SSRI's function is to block the reuptake of serotonin, making more serotonin available to absorb by the receiving neuron. Animals have been studied for decades in order to understand depressive behavior among species. One of the most familiar studies, the forced swimming test (FST), was performed to measure potential antidepressant activity. Rats were placed in an inescapable container of water, at which point time spent immobile and number of active behaviors (such as splashing or climbing) were compared before and after a panel of anti-depressant drugs were administered. Antidepressants that selectively inhibit NE reuptake were shown to reduce immobility and selectively increase climbing without affecting swimming. However, results of the SSRI's also show reduced immobility but increased swimming without affecting climbing. This study demonstrated the importance of behavioral tests for antidepressants, as they can detect drugs with an effect on core behavior along with behavioral components of species.

In the nematode C. elegans, artificial depletion of serotonin or the increase of octopamine cues behavior typical of a low-food environment: C. elegans becomes more active, and mating and egg-laying are suppressed, while the opposite occurs if serotonin is increased or octopamine is decreased in this animal.{{cite journal | vauthors = Srinivasan S, Sadegh L, Elle IC, Christensen AG, Faergeman NJ, Ashrafi K | title = Serotonin regulates C. elegans fat and feeding through independent molecular mechanisms | journal = Cell Metabolism | volume = 7 | issue = 6 | pages = 533–544 | date = June 2008 | pmid = 18522834 | pmc = 2495008 | doi = 10.1016/j.cmet.2008.04.012 }} Serotonin is necessary for normal nematode male mating behavior,{{cite journal | vauthors = Loer CM, Kenyon CJ | title = Serotonin-deficient mutants and male mating behavior in the nematode Caenorhabditis elegans | journal = The Journal of Neuroscience | volume = 13 | issue = 12 | pages = 5407–5417 | date = December 1993 | pmid = 8254383 | pmc = 6576401 | doi = 10.1523/JNEUROSCI.13-12-05407.1993 }} and the inclination to leave food to search for a mate.{{cite journal | vauthors = Lipton J, Kleemann G, Ghosh R, Lints R, Emmons SW | title = Mate searching in Caenorhabditis elegans: a genetic model for sex drive in a simple invertebrate | journal = The Journal of Neuroscience | volume = 24 | issue = 34 | pages = 7427–7434 | date = August 2004 | pmid = 15329389 | pmc = 6729642 | doi = 10.1523/JNEUROSCI.1746-04.2004 }} The serotonergic signaling used to adapt the worm's behaviour to fast changes in the environment affects insulin-like signaling and the TGF beta signaling pathway,{{cite journal | vauthors = Murakami H, Murakami S | title = Serotonin receptors antagonistically modulate Caenorhabditis elegans longevity | journal = Aging Cell | volume = 6 | issue = 4 | pages = 483–488 | date = August 2007 | pmid = 17559503 | doi = 10.1111/j.1474-9726.2007.00303.x | s2cid = 8345654 | doi-access = free }} which control long-term adaption.

In the fruit fly insulin both regulates blood sugar as well as acting as a growth factor. Thus, in the fruit fly, serotonergic neurons regulate the adult body size by affecting insulin secretion.{{cite journal | vauthors = Kaplan DD, Zimmermann G, Suyama K, Meyer T, Scott MP | title = A nucleostemin family GTPase, NS3, acts in serotonergic neurons to regulate insulin signaling and control body size | journal = Genes & Development | volume = 22 | issue = 14 | pages = 1877–1893 | date = July 2008 | pmid = 18628395 | pmc = 2492735 | doi = 10.1101/gad.1670508 }}{{cite journal | vauthors = Ruaud AF, Thummel CS | title = Serotonin and insulin signaling team up to control growth in Drosophila | journal = Genes & Development | volume = 22 | issue = 14 | pages = 1851–1855 | date = July 2008 | pmid = 18628391 | pmc = 2735276 | doi = 10.1101/gad.1700708 }} Serotonin has also been identified as the trigger for swarm behavior in locusts. In humans, though insulin regulates blood sugar and IGF regulates growth, serotonin controls the release of both hormones, modulating insulin release from the beta cells in the pancreas through serotonylation of GTPase signaling proteins.{{cite journal | vauthors = Paulmann N, Grohmann M, Voigt JP, Bert B, Vowinckel J, Bader M, Skelin M, Jevsek M, Fink H, Rupnik M, Walther DJ | title = Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation | journal = PLOS Biology | volume = 7 | issue = 10 | pages = e1000229 | date = October 2009 | pmid = 19859528 | pmc = 2760755 | doi = 10.1371/journal.pbio.1000229 | veditors = O'Rahilly S | doi-access = free }} Exposure to SSRIs during pregnancy reduces fetal growth.{{cite journal | vauthors = Davidson S, Prokonov D, Taler M, Maayan R, Harell D, Gil-Ad I, Weizman A | title = Effect of exposure to selective serotonin reuptake inhibitors in utero on fetal growth: potential role for the IGF-I and HPA axes | journal = Pediatric Research | volume = 65 | issue = 2 | pages = 236–241 | date = February 2009 | pmid = 19262294 | doi = 10.1203/PDR.0b013e318193594a | doi-access = free }}

Genetically altered C. elegans worms that lack serotonin have an increased reproductive lifespan, may become obese, and sometimes present with arrested development at a dormant larval state.{{cite journal | vauthors = Ben Arous J, Laffont S, Chatenay D | title = Molecular and sensory basis of a food related two-state behavior in C. elegans | journal = PLOS ONE | volume = 4 | issue = 10 | pages = e7584 | date = October 2009 | pmid = 19851507 | pmc = 2762077 | doi = 10.1371/journal.pone.0007584 | veditors = Brezina V | doi-access = free | bibcode = 2009PLoSO...4.7584B }}{{cite journal | vauthors = Sze JY, Victor M, Loer C, Shi Y, Ruvkun G | title = Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant | journal = Nature | volume = 403 | issue = 6769 | pages = 560–564 | date = February 2000 | pmid = 10676966 | doi = 10.1038/35000609 | s2cid = 4394553 | bibcode = 2000Natur.403..560S }}

{{See also|Aging brain#Serotonin}}

Serotonin is known to regulate aging, learning, and memory. The first evidence comes from the study of longevity in C. elegans. During early phase of aging{{vague|date=September 2017}}, the level of serotonin increases, which alters locomotory behaviors and associative memory.{{cite journal | vauthors = Murakami H, Bessinger K, Hellmann J, Murakami S | title = Manipulation of serotonin signal suppresses early phase of behavioral aging in Caenorhabditis elegans | journal = Neurobiology of Aging | volume = 29 | issue = 7 | pages = 1093–1100 | date = July 2008 | pmid = 17336425 | doi = 10.1016/j.neurobiolaging.2007.01.013 | s2cid = 37671716 }} The effect is restored by mutations and drugs (including mianserin and methiothepin) that inhibit serotonin receptors. The observation does not contradict with the notion that the serotonin level goes down in mammals and humans, which is typically seen in late but not early{{vague|date=September 2017}} phase of aging.

File:Serotonin biosynthesis.svg catalyses this reaction with help of O₂ and tetrahydrobiopterin, which becomes water and dihydrobiopterin. From the 5-HTP molecule goes an arrow down to a serotonin molecule. Aromatic L-amino acid decarboxylase or 5-Hydroxytryptophan decarboxylase catalyses this reaction with help of pyridoxal phosphate. From the serotonin molecule goes an arrow to a 5-HIAA molecule at the bottom of the image. Monoamine oxidase catalyses this reaction, in the process O₂ and water is consumed, and ammonia and hydrogen peroxide is produced.|The pathway for the synthesis of serotonin from tryptophan]]

In animals and humans, serotonin is synthesized from the amino acid L-tryptophan by a short metabolic pathway consisting of two enzymes, tryptophan hydroxylase (TPH) and aromatic amino acid decarboxylase (DDC), and the coenzyme pyridoxal phosphate. The TPH-mediated reaction is the rate-limiting step in the pathway.

TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a neuron-specific isoform.{{cite journal | vauthors = Côté F, Thévenot E, Fligny C, Fromes Y, Darmon M, Ripoche MA, Bayard E, Hanoun N, Saurini F, Lechat P, Dandolo L, Hamon M, Mallet J, Vodjdani G | title = Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 23 | pages = 13525–13530 | date = November 2003 | pmid = 14597720 | pmc = 263847 | doi = 10.1073/pnas.2233056100 | first14 = G | doi-access = free | bibcode = 2003PNAS..10013525C }}

Serotonin can be synthesized from tryptophan in the lab using Aspergillus niger and Psilocybe coprophila as catalysts. The first phase to 5-hydroxytryptophan would require letting tryptophan sit in ethanol and water for 7 days, then mixing in enough HCl (or other acid) to bring the pH to 3, and then adding NaOH to make a pH of 13 for 1 hour. Aspergillus niger would be the catalyst for this first phase. The second phase to synthesizing tryptophan itself from the 5-hydroxytryptophan intermediate would require adding ethanol and water, and letting sit for 30 days this time. The next two steps would be the same as the first phase: adding HCl to make the pH = 3, and then adding NaOH to make the pH very basic at 13 for 1 hour. This phase uses the Psilocybe coprophila as the catalyst for the reaction.{{cite journal | vauthors = Alarcón J, Cid E, Lillo L, Céspedesa C, Aguila S, Alderete JB | title = Biotransformation of indole derivatives by mycelial cultures | journal = Zeitschrift für Naturforschung C | volume = 63 | issue = 1–2 | pages = 82–84 | year = 2008 | pmid = 18386493 | doi = 10.1515/znc-2008-1-215 | s2cid = 29472174 | doi-access = free }}

File:Biosynthesis and breakdown of serotonin and the catecholamines, and the metabolic block in AADC deficiency.png

Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system, because it does not cross the blood–brain barrier. However, tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is synthesized, do cross the blood–brain barrier. These agents are available as dietary supplements and in various foods, and may be effective serotonergic agents.

One product of serotonin breakdown is 5-hydroxyindoleacetic acid (5-HIAA), which is excreted in the urine. Serotonin and 5-HIAA are sometimes produced in excess amounts by certain tumors or cancers, and levels of these substances may be measured in the urine to test for these tumors.

Indium tin oxide is recommended for the electrode material in electrochemical investigation of concentrations produced, detected, or consumed by microbes.{{cite journal | vauthors = Sismaet HJ, Goluch ED | title = Electrochemical Probes of Microbial Community Behavior | journal = Annual Review of Analytical Chemistry | volume = 11 | issue = 1 | pages = 441–461 | date = June 2018 | pmid = 29490192 | doi = 10.1146/annurev-anchem-061417-125627 | publisher = Annual Reviews | quote-page = 449 | s2cid = 3632265 | doi-access = free | bibcode = 2018ARAC...11..441S | quote = Table 1{{spaces|5}}The respective potential peaks for various electroactive biomolecules that are produced or consumed by microbes reported in the literature{{sup|a}} ... Serotonin {{!}} Indium tin oxide {{!}} +0.67 {{!}} 66 }} A mass spectrometry technique was developed in 1994 to measure the molecular weight of both natural and synthetic serotonins.{{cite journal | vauthors = Henson JM, Butler MJ, Day AW | title = THE DARK SIDE OF THE MYCELIUM: Melanins of Phytopathogenic Fungi | journal = Annual Review of Phytopathology | volume = 37 | issue = 1 | pages = 447–471 | year = 1999 | pmid = 11701831 | doi = 10.1146/annurev.phyto.37.1.447 | publisher = Annual Reviews | bibcode = 1999AnRvP..37..447H }}

It had been known to physiologists for over a century that a vasoconstrictor material appears in serum when blood was allowed to clot.{{cite journal | vauthors = Anthony M | title = Serotonin antagonists | journal = Australian and New Zealand Journal of Medicine | volume = 14 | issue = 6 | pages = 888–895 | date = December 1984 | pmid = 6398056 | doi = 10.1111/j.1445-5994.1984.tb03802.x | s2cid = 28327178 }} In 1935, Italian Vittorio Erspamer, working in Pavia, showed an extract from enterochromaffin cells made intestines contract. Some believed it contained adrenaline, but two years later, Erspamer was able to show it was a previously unknown amine, which he named "enteramine".{{cite journal | vauthors = Erspamer V | title = Pharmacology of indole-alkylamines | journal = Pharmacological Reviews | volume = 6 | issue = 4 | pages = 425–487 | date = December 1954 | doi = 10.1016/S0031-6997(25)07372-7 | pmid = 13236482 }}{{cite journal | vauthors = Negri L | title = [Vittorio Erspamer (1909-1999)] | journal = Medicina Nei Secoli | volume = 18 | issue = 1 | pages = 97–113 | year = 2006 | pmid = 17526278 | url = https://www.medicinaneisecoli.it/index.php/MedSecoli/article/view/491 }} In 1948, Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic discovered a vasoconstrictor substance in blood serum, and since it was a serum agent affecting vascular tone, they named it serotonin.{{cite journal | vauthors = Rapport MM, Green AA, Page IH | title = Serum vasoconstrictor, serotonin; isolation and characterization | journal = The Journal of Biological Chemistry | volume = 176 | issue = 3 | pages = 1243–1251 | date = December 1948 | pmid = 18100415 | doi = 10.1016/S0021-9258(18)57137-4 | doi-access = free }}

In 1952, enteramine was shown to be the same substance as serotonin, and as the broad range of physiological roles was elucidated, the abbreviation 5-HT of the proper chemical name 5-hydroxytryptamine became the preferred name in the pharmacological field.{{cite journal | vauthors = Feldberg W, Toh CC | title = Distribution of 5-hydroxytryptamine (serotonin, enteramine) in the wall of the digestive tract | journal = The Journal of Physiology | volume = 119 | issue = 2–3 | pages = 352–362 | date = February 1953 | pmid = 13035756 | pmc = 1392800 | doi = 10.1113/jphysiol.1953.sp004850 }} Synonyms of serotonin include: 5-hydroxytriptamine, enteramine, substance DS, and 3-(β-aminoethyl)-5-hydroxyindole.SciFinder – Serotonin Substance Detail. Accessed (4 November 2012).{{full citation needed|date=October 2017}} In 1953, Betty Twarog and Page discovered serotonin in the central nervous system.{{cite journal | vauthors = Twarog BM, Page IH | title = Serotonin content of some mammalian tissues and urine and a method for its determination | journal = The American Journal of Physiology | volume = 175 | issue = 1 | pages = 157–161 | date = October 1953 | pmid = 13114371 | doi = 10.1152/ajplegacy.1953.175.1.157 | doi-access = free }} Page regarded Erspamer's work on Octopus vulgaris, Discoglossus pictus, Hexaplex trunculus, Bolinus brandaris, Sepia, Mytilus, and Ostrea as valid and fundamental to understanding this newly identified substance, but regarded his earlier results in various models – especially those from rat blood – to be too confounded by the presence of other bioactive chemicals, including some other vasoactives.{{cite journal | vauthors = Page IH | title = Serotonin (5-hydroxytryptamine) | journal = Physiological Reviews | volume = 34 | issue = 3 | pages = 563–588 | date = July 1954 | pmid = 13185755 | doi = 10.1152/physrev.1954.34.3.563 | publisher = American Physiological Society | author-link = Irvine Page }}

Serotonin, given orally at a dose of 100{{nbsp}}mg, produced effects in humans including blood pressure changes, abdominal cramps, muscle aches, and a feeling of sedation.{{cite journal | vauthors = McKenna DJ, Towers GH | title = Biochemistry and pharmacology of tryptamines and beta-carbolines. A minireview | journal = J Psychoactive Drugs | volume = 16 | issue = 4 | pages = 347–358 | date = 1984 | pmid = 6394730 | doi = 10.1080/02791072.1984.10472305 | url = https://bitnest.netfirms.com/external/10.1080/02791072.1984.10472305 | quote = Table III: Orally and Parenterally Active Psychotropic Tryptamine Derivatives* [...] Name of Compound: Serotonin [...] Dosage (mg): 100#. Route: Oral. [...] # Cardiovascular and autonomic symptoms; little central activity.| url-access = subscription }}{{cite journal | vauthors = Kantor RE, Dudlettes SD, Shulgin AT | title = 5-Methoxy-α-Methyltryptamine (α,O-Dimethylserotonin), A Hallucinogenic Homolog of Serotonin | journal = Biol Psychiatry | volume = 15 | issue = 2 | pages = 349–352 | date = April 1980 | pmid = 7417623 | doi = | url = https://bitnest.netfirms.com/external/Biol.Psychiatry/15.2.349 | quote = Table I. Human Potency of the Hallucinogenic Tryptamines [...] Name: Serotonin. Dosage: 100^c. Route: Oral. Reference: Murphree et al., 1960. [...] ^c Largely cardiovascular and autonomic distress.}}{{cite journal | vauthors = Murphree HB, Jenney EH, Pfeiffer CC | title = Comparison of the Effects of Congeners of Lysergic Acid Diethylamide and Tryptophane in Normal Volunteers | journal = Pharmacologist | volume = 2 | issue = 2 | pages = 64 | url = https://bibliography.maps.org/resources/download/9620 | archive-url = https://web.archive.org/web/20250407090049/https://bibliography.maps.org/resources/download/9620 | archive-date = 7 April 2025 | quote = [...] Comparison was made in normal human volunteers of the effects of [...] 5-hydroxytryptamine [...] with [LSD]. The subjects were highly trained to recognize the effects of [LSD] and other hallucinogens. All compounds were given orally. [...] 5-hydroxytryptamine in a dose of 100 mg produced a fall in systolic and a rise in diastolic blood pressures together with a feeling of sedation, abdominal cramping, and muscle aching similar to those of [LSD]. Effects were delayed 6 to 8 hours after dosage. [...]}} In contrast to psychedelic drugs like LSD, no hallucinogenic effects were reported. In other studies, serotonin, at low intravenous doses of 2 to 6{{nbsp}}mg, had no effects on electroencephalogram (EEG) readings in humans. In accordance with the preceding findings, it has been stated that administration of serotonin in humans produces no psychoactive effects that cannot be attributed to anxiety by its profound peripheral adverse effects including circulatory disturbance, other autonomic effects, and vomiting.{{cite book | last=Erspamer | first=V. | title=Fortschritte der Arzneimittelforschung / Progress in Drug Research / Progrès des Recherches Pharmaceutiques | chapter=Recent Research in the Field of 5-Hydroxytryptamine and Related Indolealkylamines | journal=Fortschritte der Arzneimittelforschung. Progress in Drug Research. Progres des Recherches Pharmaceutiques | publisher=Birkhäuser Basel | publication-place=Basel | date=1961 | volume=3 | isbn=978-3-0348-7043-6 | doi=10.1007/978-3-0348-7041-2_3 | pages=151–367 | pmid=13890703 | quote = 13.9 Indolealkylamines and the CNS in human beings 13.91 Central effects of 5-HT [...]}}{{cite journal | vauthors = Marrazzi AS | title = The effects of certain drugs on cerebral synapses | journal = Ann N Y Acad Sci | volume = 66 | issue = 3 | pages = 496–507 | date = March 1957 | pmid = 13425238 | doi = 10.1111/j.1749-6632.1957.tb40745.x | bibcode = 1957NYASA..66..496M | url = | quote = Unfortunately, except for the intraventricular injections described by Sherwood,7 there have been, thus far, no documented reports of serotonin-induced mental disturbance* in man that are clearly separable from the natural anxiety initiated by the profound peripheral effects such as circulatory disturbance, other autonomic effects, and emesis. [...] 7. SHERWOOD, S, L. 1955. The responses of psychotic patients to intraventricular injections. Proc. Roy. Soc. Med. 48: 855.}} Intracerebroventricular injection of serotonin has been studied in patient with severe psychiatric conditions, but little information about its psychoactive effects is provided.{{cite journal | vauthors = Feldberg W, Sherwood SL, Richter D | title = Recent experiments with injections of drugs into the ventricular system of the brain: The Response of Psychotic Patients to Intraventricular Injections | journal = Proc R Soc Med | volume = 48 | issue = 10 | pages = 853–864 | date = October 1955 | pmid = 13266838 | pmc = 1919229 | doi = 10.1177/003591575504801031| url = | quote = Serotonin. [...] 4 patients received this drug in doses of 15 to 75 μg. [...]}}

It is thought that exogenous serotonin is too hydrophilic to cross the blood–brain barrier and has too poor of metabolic stability due to rapid metabolism by monoamine oxidase (MAO) such that it cannot produce drug-like central effects in humans with peripheral administration.{{cite book | author1 = Alexander T. Shulgin | author2 = Ann Shulgin | title = TiHKAL: The Continuation | publisher = Transform Press | date = 1997 | edition = 1st | location = Berkeley, CA | isbn = 978-0-9630096-9-2 | oclc = 38503252 | url = https://books.google.com/books?id=jl_ik66IumUC | access-date = 30 January 2025 | quote = Two obstacles effectively prohibit this availability. Serotonin has a free hydroxy group (the 5-hydroxy which is the H of 5-HT). This is a big polar water-loving pimple which denies it any passage across the brain’s defensive Maginot Line, the blood-brain barrier. And there is the second problem. There is a exposed amino group, the amine of T of 5-HT, the tryptamine, which is immediately removed by the body’s monoamine oxidase enzyme. In short, it is blocked from entry into the brain because it is both too polar and too metabolically fragile.}} However, close analogues of serotonin that are more lipophilic and metabolically stable, like bufotenin (N,N-dimethylserotonin), 5-MeO-DMT (N,N,O-trimethylserotonin), and 5-MeO-AMT (α,O-dimethylserotonin), among many others, are active and produce pronounced centrally mediated effects in humans.{{cite journal | vauthors = Araújo AM, Carvalho F, Bastos Mde L, Guedes de Pinho P, Carvalho M | title = The hallucinogenic world of tryptamines: an updated review | journal = Arch Toxicol | volume = 89 | issue = 8 | pages = 1151–1173 | date = August 2015 | pmid = 25877327 | doi = 10.1007/s00204-015-1513-x | bibcode = 2015ArTox..89.1151A | url = https://psilosybiini.info/paperit/The%20hallucinogenic%20world%20of%20tryptamines,%20an%20updated%20review%20(Ara%FAjo%20et%20al.,%202015).pdf}} These drugs are non-selective serotonin receptor agonists like serotonin and are serotonergic psychedelics due to activation of the serotonin 5-HT_2A receptor.{{cite journal | vauthors = Holze F, Singh N, Liechti ME, D'Souza DC | title = Serotonergic Psychedelics: A Comparative Review of Efficacy, Safety, Pharmacokinetics, and Binding Profile | journal = Biol Psychiatry Cogn Neurosci Neuroimaging | volume = 9 | issue = 5 | pages = 472–489 | date = May 2024 | pmid = 38301886 | doi = 10.1016/j.bpsc.2024.01.007 | url = | doi-access = free }} α-Methylserotonin is well-studied in preclinical research, but is not known to have been tested in humans.

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• {{cite journal | vauthors = Gutknecht L, Jacob C, Strobel A, Kriegebaum C, Müller J, Zeng Y, Markert C, Escher A, Wendland J, Reif A, Mössner R, Gross C, Brocke B, Lesch KP | title = Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation | journal = The International Journal of Neuropsychopharmacology | volume = 10 | issue = 3 | pages = 309–320 | date = June 2007 | pmid = 17176492 | doi = 10.1017/S1461145706007437 | doi-access = free }}

{{Refend}}

{{Commons category}}

• [http://gmd.mpimp-golm.mpg.de/Spectrums/a1a3167e-cbab-45fd-adb6-9addc14e0ec2.aspx 5-Hydroxytryptamine MS Spectrum]
• [http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=SRO Serotonin bound to proteins] in the PDB
• [http://www.psychotropical.com/ PsychoTropicalResearch] Extensive reviews on serotonergic drugs and Serotonin Syndrome.
• [https://www.chm.bris.ac.uk/motm/serotonin/home1.htm Molecule of the Month: Serotonin] at University of Bristol
• 60-Second Psych: [https://www.scientificamerican.com/podcast/episode/68FC98F1-E48A-251D-8F65277181DB9A4E/ No Fair! My Serotonin Level Is Low], Scientific American
• [http://www.clinlabnavigator.com/Tests/Serotonin.html Serotonin Test Interpretation on ClinLab Navigator] {{Webarchive|url=https://web.archive.org/web/20100201024400/http://www.clinlabnavigator.com/Tests/Serotonin.html |date=1 February 2010 }}.

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