Editing Serotonin (section)

==Pharmacology==
Several classes of [[drugs]] target the serotonin system, including some [[antidepressant]]s, [[anxiolytic]]s, [[antipsychotic]]s, [[analgesic]]s, [[antimigraine drug]]s, [[antiemetic]]s, [[appetite suppressant]]s, and [[anticonvulsant]]s, as well as [[psychedelic drug|psychedelic]]s and [[entactogen]]s.

===Mechanism of action===
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.<ref>{{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 }}</ref>

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

Drugs that alter serotonin levels are used in treating [[Major depressive disorder|depression]], [[generalized anxiety disorder]], and [[social anxiety disorder|social phobia]]. [[Monoamine oxidase inhibitor]]s (MAOIs) prevent the breakdown of [[monoamine neurotransmitter]]s (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 and non-selective|selective]] serotonin reuptake inhibitors ([[SSRI]]s) have fewer side-effects and fewer interactions with other drugs.<ref>{{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 }}</ref>

Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases.<ref name="pmid10575045">{{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 }}</ref> 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.<ref>{{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 }}</ref> The 5-HTTLPR polymorphism (l/l) causing more serotonin transporters to be formed is also found to be more resilient against depression and anxiety.<ref>{{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 }}</ref><ref>{{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 }}</ref>

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]].<ref name="O'MalleyJacksonSantoro1999">{{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 = }}</ref><ref name="WelschÜçeylerKlose2018">{{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 = }}</ref>

===Anxiolytics===
[[Azapirone]] [[anxiolytic]]s like [[buspirone]] and [[tandospirone]] act as serotonin [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]] [[agonist]]s.<ref name="TaylorMoon1991">{{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 = }}</ref><ref name="KishiMeltzerMatsuda2014">{{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 = }}</ref>

===Antipsychotics===
Many [[antipsychotic]]s bind to and modulate [[serotonin receptor]]s, including the serotonin [[5-HT1A receptor|5-HT<sub>1A</sub>]], [[5-HT2A receptor|5-HT<sub>2A</sub>]], [[5-HT2B receptor|5-HT<sub>2B</sub>]], [[5-HT2C receptor|5-HT<sub>2C</sub>]], [[5-HT6 receptor|5-HT<sub>6</sub>]], and [[5-HT7 receptor|5-HT<sub>7</sub> receptor]]s, among others.<ref name="Meltzer1999">{{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 = }}</ref><ref name="Meltzer2012">{{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 = }}</ref> Activation of serotonin 5-HT<sub>1A</sub> receptors and blockade of serotonin 5-HT<sub>2A</sub> receptors may contribute to the therapeutic antipsychotic effects of these agents, whereas antagonism of serotonin 5-HT<sub>2C</sub> receptors has been especially implicated in [[side effect]]s of antipsychotics.<ref name="Meltzer1999" /><ref name="Meltzer2012" />

===Antimigraine agents===
[[Antimigraine agent]]s such as the [[triptan]]s like [[sumatriptan]] act as [[agonist]]s of the serotonin [[5-HT1B receptor|5-HT<sub>1B</sub>]], [[5-HT1D receptor|5-HT<sub>1D</sub>]], and/or [[5-HT1F receptor|5-HT<sub>1F</sub> receptor]]s.<ref name="Tfelt-HansenDeVriesSaxena2000">{{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 = }}</ref><ref name="RamírezRosasLabruijereVillalón2013" /> Earlier antimigraine agents were the [[ergoline]] [[chemical derivative|derivative]]s and [[ergot]]-related drugs such as [[ergotamine]], [[dihydroergotamine]], and [[methysergide]], which act as [[binding selectivity|non-selective]] [[serotonin receptor agonist]]s.<ref name="RamírezRosasLabruijereVillalón2013">{{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 = }}</ref><ref name="SaxenaDenBoer1991">{{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 = }}</ref><ref name="WhealyBecker2024">{{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 = }}</ref>

===Antiemetics===
Some serotonin [[5-HT3 antagonist|5-HT<sub>3</sub> receptor antagonist]]s, such as [[ondansetron]], [[granisetron]], and [[tropisetron]], are important [[antiemetic]] agents.<ref name="HoGan2006">{{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 = }}</ref><ref name="SeynaeveVerweijdeMulder1991">{{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 = }}</ref> They are particularly important in treating the [[nausea]] and [[vomiting]] that [[Chemotherapy-induced nausea and vomiting|occur during anticancer chemotherapy]] using [[cytotoxic drugs]].<ref name="SeynaeveVerweijdeMulder1991" /> Another application is in the treatment of [[postoperative nausea and vomiting]].<ref name="HoGan2006" />

===Appetite suppressants===
Some [[serotonin releasing agent]]s, [[serotonin reuptake inhibitor]]s, and/or serotonin [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]] [[agonist]]s, such as [[fenfluramine]], [[dexfenfluramine]], [[chlorphentermine]], [[sibutramine]], and [[lorcaserin]], have been approved and used as [[appetite suppressant]]s for purposes of [[weight loss]] in the treatment of [[overweightness]] or [[obesity]].<ref name="HalfordHarroldBoyland2007">{{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 = }}</ref><ref name="HurrenBerlie2011">{{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 = }}</ref><ref name="HalfordBoylandLawton2011">{{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 = }}</ref><ref name="HalfordHarrold2012">{{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 = }}</ref><ref name="PrzegalińskiWitekWydra2023">{{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 = }}</ref> Several of the preceding agents have been [[withdrawn drug|withdrawn from the market]] due to [[toxicity]], such as [[cardiac fibrosis]] or [[pulmonary hypertension]].<ref name="PrzegalińskiWitekWydra2023" />

===Anticonvulsants===
Although it was previously [[withdrawn drug|withdrawn from the market]] as an appetite suppressant, fenfluramine was reintroduced as an [[anticonvulsant]] for treatment of [[seizure]]s in certain rare forms of [[epilepsy]] like [[Dravet syndrome]] and [[Lennox–Gastaut syndrome]].<ref name="DiniDiCaraFerrara2023">{{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 = }}</ref> Selective serotonin 5-HT<sub>2C</sub> receptor agonists, like lorcaserin, [[bexicaserin]], and [[BMB-101]], are also being developed for this use.<ref name="DiniDiCaraFerrara2023" /><ref name="BialerPerucca2022">{{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 = }}</ref><ref name="Dell'isolaVerrottiSciaccaluga2024">{{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 = }}</ref><ref name="AdisInsight-BMB-101">{{cite web | title=BMB 101 | website=AdisInsight | date=23 October 2024 | url=https://adisinsight.springer.com/drugs/800065004 | access-date=30 October 2024}}</ref>

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

[[Serotonergic psychedelic]]s, including drugs like [[psilocybin]] (found in [[psilocybin mushroom]]s), [[dimethyltryptamine]] (DMT) (found in [[ayahuasca]]), [[lysergic acid diethylamide]] (LSD), [[mescaline]] (found in [[peyote|peyote cactus]]), and [[5-MeO-DMT]] (found in ''[[Anadenanthera]]'' trees and the ''[[Bufo alvarius]]'' toad), are [[binding selectivity|non-selective]] [[agonist]]s of the [[serotonin receptor]]s and mediate their [[hallucinogen]]ic effects specifically by activation of the serotonin [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]].<ref name="SlocumDiBertoRoth2022">{{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 = }}</ref><ref name="DuanCaoWang2024">{{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 = }}</ref><ref name="Nichols2018">{{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 = }}</ref> This is evidenced by the fact that serotonin 5-HT<sub>2A</sub> receptor antagonists and so-called "[[trip killer]]s" like [[ketanserin]] block the hallucinogenic effects of serotonergic psychedelics in humans, among many other findings.<ref name="SlocumDiBertoRoth2022" /><ref name="DuanCaoWang2024" /><ref name="HalmanKongSarris2024">{{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}}</ref> Some serotonergic psychedelics, like [[psilocin]], DMT, and 5-MeO-DMT, are [[substituted tryptamine]]s and are very similar in [[chemical structure]] to serotonin.<ref name="Nichols2018" />

Serotonin itself, despite acting as a serotonin 5-HT<sub>2A</sub> receptor agonist, is thought to be non-hallucinogenic.<ref name="VargasDunlapDong2023" /> The hallucinogenic effects of serotonergic psychedelics appear to be mediated by activation of serotonin 5-HT<sub>2A</sub> receptors expressed in a population of [[Cerebral cortex|cortical]] [[neuron]]s in the [[medial prefrontal cortex]] (mPFC).<ref name="Sapienza2023">{{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}}</ref><ref name="VargasDunlapDong2023">{{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.}}</ref> These serotonin 5-HT<sub>2A</sub> receptors, unlike most serotonin and related receptors, are expressed [[intracellular]]ly.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> In addition, the neurons containing them lack [[gene expression|expression]] of the [[serotonin transporter]] (SERT), which normally [[active transport|transport]]s serotonin from the [[extracellular]] space to the intracellular space within neurons.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> Serotonin itself is too [[hydrophilic]] to enter serotonergic neurons without the SERT, and hence these serotonin 5-HT<sub>2A</sub> receptors are inaccessible to serotonin.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> Conversely, serotonergic psychedelics are more [[lipophilic]] than serotonin and readily enter these neurons.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> 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 inhibitor]]s (SSRIs) and various other types of serotonergic agents, do not produce psychedelic effects.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> Artificial expression of the SERT in these medial prefrontal cortex neurons resulted in the [[serotonin releasing agent]] [[para-chloroamphetamine|''para''-chloroamphetamine]] (PCA), which does not normally show psychedelic-like effects, being able to produce psychedelic-like effects in animals.<ref name="VargasDunlapDong2023" />

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.<ref name="SchmidBohn2018">{{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}}</ref><ref name="KozlenkovGonzález-Maeso2013">{{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}}</ref><ref name="SchmidBohn2010">{{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 = }}</ref> These psychedelic-like effects can be abolished by [[indolethylamine N-methyltransferase|indolethylamine ''N''-methyltransferase]] (INMT) [[enzyme inhibitor|inhibitor]]s, which block conversion of serotonin and other endogenous tryptamines into ''N''-[[methyl group|methylated]] tryptamines, including [[N-Methylserotonin|''N''-methylserotonin]] (NMS; norbufotenin), [[bufotenin]] (5-hydroxy-''N'',''N''-dimethyltryptamine; 5-HO-DMT), [[N-methyltryptamine|''N''-methyltryptamine]] (NMT), and [[dimethyltryptamine|''N'',''N''-dimethyltryptamine]] (DMT).<ref name="KozlenkovGonzález-Maeso2013" /><ref name="HalberstadtGeyer2018">{{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 = }}</ref><ref name="SchmidBohn2010" /> These ''N''-methyltryptamines are much more lipophilic than serotonin and, in contrast, are able to [[passive diffusion|diffuse]] into serotonergic neurons and activate intracellular serotonin 5-HT<sub>2A</sub> receptors.<ref name="KozlenkovGonzález-Maeso2013" /><ref name="SchmidBohn2010" /><ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> Another possible metabolite of serotonin with psychedelic-like effects in animals is [[5-methoxytryptamine]] (5-MT).<ref name="Pévet1983">{{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 = }}</ref><ref name="TanHardelandBack2016">{{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 = }}</ref><ref name="PrzegalińskiZebrowska-LupinaWójcik1977">{{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 = }}</ref>

DMT is a [[natural product|naturally occurring]] [[endogenous]] compound in the body.<ref name="JiménezBouso2022">{{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 = }}</ref><ref name="Barker2018">{{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 = }}</ref><ref name="CameronOlson2018">{{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 = }}</ref> In relation to the fact that serotonin itself is unable to activate intracellular serotonin 5-HT<sub>2A</sub> receptors, it is possible that DMT might be the endogenous [[ligand (biochemistry)|ligand]] of these receptors rather than serotonin.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" />

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

The [[entactogen]] [[MDMA]] is a [[serotonin releasing agent]] and, while it also possesses other actions such as concomitant [[norepinephrine releasing agent|release of norepinephrine]] and [[dopamine releasing agent|dopamine]] and weak direct [[receptor agonist|agonism]] of the serotonin [[5-HT2 receptor|5-HT<sub>2</sub> receptor]]s, its serotonin release plays a key role in its unique entactogenic effects.<ref name="DunlapAndrewsOlson2018">{{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 = }}</ref> Entactogens like MDMA should be distinguished from other drugs such as [[stimulant]]s like [[amphetamine]] and psychedelics like [[LSD]], although MDMA itself also has some characteristics of both of these types of agents.<ref name="DunlapAndrewsOlson2018" /><ref name="Nichols2022">{{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 = }}</ref> Coadministration of [[selective serotonin reuptake inhibitor]]s (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.<ref name="SarparastThomasMalcolm2022">{{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 = }}</ref> Serotonin releasing agents like MDMA achieve much greater increases in serotonin levels than SSRIs and have far more robust of subjective effects.<ref name="RothmanBaumann2006">{{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 = }}</ref><ref name="ScorzaSilveiraNichols1999">{{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 }}</ref><ref name="Marona-LewickaNichols1997">{{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 = }}</ref><ref name="Marona-LewickaNichols1998">{{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 = }}</ref> Besides MDMA, many other entactogens also exist and are known.<ref name="SimmlerLiechti2018">{{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 = }}</ref><ref name="Oeri2021">{{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 = }}</ref><ref name="Nichols2022" />

===Serotonin syndrome===
{{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.<ref name="New 285–293">{{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 }}</ref><ref>{{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 }}</ref> However, serotonin syndrome can occur with overdose of certain serotonin receptor agonists, like the [[25-NB|NBOMe]] series of serotonergic psychedelics.<ref name="ScottonHillWilliams2019">{{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 = }}</ref><ref name="OrdakZmysłowskaBielski2021">{{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 = }}</ref><ref name="JacbosAkersVohra2020">{{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}}</ref>

The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at nontoxic levels.<ref name="pmid12925718">{{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 }}</ref> It is estimated that 14% of patients experiencing serotonin syndrome overdose on SSRIs; meanwhile the fatality rate is between 2% and 12%.<ref name="New 285–293"/><ref name="pmid18625822">{{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 =  }}</ref><ref name="pmid15784664">{{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 }}</ref>

===Cardiac fibrosis and other fibroses===
Some serotonergic agonist drugs cause fibrosis anywhere in the body, particularly the syndrome of [[retroperitoneal fibrosis]], as well as [[cardiac fibrosis|cardiac valve fibrosis]].<ref name="Baskin">{{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}}</ref>

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]]),<ref name=Baskin/> the serotonergic appetite suppressant drugs ([[fenfluramine]], [[chlorphentermine]], and [[aminorex]]), and certain anti-Parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT<sub>2B</sub> receptors. These include [[pergolide]] and [[cabergoline]], but not the more dopamine-specific [[lisuride]].<ref name="urluserpage.fu-berlin.de">{{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<sub>2B</sub> Receptors| vauthors = Jähnichen S, Horowski R, Pertz H |access-date = 3 February 2010}}</ref>

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.<ref name="ADRAC_2004">{{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 }}</ref>

Two independent studies published in ''[[The New England Journal of Medicine]]'' in January 2007 implicated pergolide, along with [[cabergoline]], in causing [[valvular heart disease]].<ref name="pmid17202453">{{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 }}</ref><ref name="pmid17202454">{{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 }}</ref> As a result of this, the [[Food and Drug Administration|FDA]] removed pergolide from the United States market in March 2007.<ref>{{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}}</ref> (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).<ref name="FDAwithdraw">{{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}}</ref>