5-HT2A receptor#Anti-inflammatory effects

5-HT receptors were split into two classes by John Gaddum and Picarelli when it was discovered that some of the serotonin-induced changes in the gut could be blocked by morphine, while the remainder of the response was inhibited by dibenzyline, leading to the naming of M and D receptors, respectively. 5-HT_2A is thought to correspond to what was originally described as D subtype of 5-HT receptors by Gaddum and Picarelli.{{cite book | vauthors = Sanders-Bush E, Mayer SE | veditors = Brunton LL, Lazo JS, Parker K | chapter = Chapter 11: 5-Hydroxytryptamine (Serotonin): Receptor Agonists and Antagonists | title = Goodman & Gilman's the Pharmacological Basis of Therapeutics | location = New York | year = 2006 | edition = 11th | publisher = McGraw-Hill | isbn = 0-07-142280-3 }} In the era before molecular cloning, when radioligand binding and displacement was the only major tool, spiperone and LSD were shown to label two different 5-HT receptors, and neither of them displaced morphine, leading to naming of the 5-HT₁, 5-HT₂ and 5-HT₃ receptors, corresponding to high affinity sites from LSD, spiperone and morphine, respectively.{{cite book | vauthors = Siegel GJ, Albers RW | title = Basic neurochemistry: molecular, cellular, and medical aspects | volume = 1 | pages = 241 | year = 2005 | edition = 7th | isbn = 0-12-088397-X | publisher = Academic Press | url = https://books.google.com/books?id=Af0IyHtGCMUC&pg=PA241 }} Later it was shown that the 5-HT₂ was very close to 5-HT_1C and thus were grouped together, renaming the 5-HT₂ into 5-HT_2A. Thus, the 5-HT₂ receptor family is composed of three separate molecular entities: the 5-HT_2A (formerly known as 5-HT₂ or D), the 5-HT_2B (formerly known as 5-HT_2F) and the 5-HT_2C (formerly known as 5-HT_1C) receptors.{{cite journal | vauthors = Hoyer D, Hannon JP, Martin GR | title = Molecular, pharmacological and functional diversity of 5-HT receptors | journal = Pharmacology, Biochemistry, and Behavior | volume = 71 | issue = 4 | pages = 533–554 | date = April 2002 | pmid = 11888546 | doi = 10.1016/S0091-3057(01)00746-8 | s2cid = 25543069 }}

File:Chromosome 13.jpeg.]]

The 5-HT_2A receptors is coded by the HTR2A gene. In humans the gene is located on chromosome 13. The gene has previously been called just HTR2 until the description of two related genes HTR2B and HTR2C. Several interesting polymorphisms have been identified for HTR2A: A-1438G (rs6311), C102T (rs6313), and His452Tyr (rs6314). Many more polymorphisms exist for the gene. A 2006 paper listed 255.{{cite journal | vauthors = Bonis J, Furlong LI, Sanz F | title = OSIRIS: a tool for retrieving literature about sequence variants | journal = Bioinformatics | volume = 22 | issue = 20 | pages = 2567–2569 | date = October 2006 | pmid = 16882651 | doi = 10.1093/bioinformatics/btl421 | quote = Supplementary material to article | doi-access = free }}

Probable role in fibromyalgia as the T102C polymorphisms of the gene 5HT2A were common in fibromyalgia patients.{{cite book | vauthors = Goldstein AT, Pukall C, Goldstein IL | chapter = Fibromyalgia and Female Sexual Pain Disorders | title = Female Sexual Pain Disorders: Evaluation and Management | year = 2020 | publisher = Wiley | isbn = 978-1119482666 | edition = 2 }}

Human HTR2A gene is thought to consist of 3 introns and 4 exons and to overlap with human gene HTR2A-AS1 which consists of 18 exons.{{cite journal | vauthors = Ruble CL, Smith RM, Calley J, Munsie L, Airey DC, Gao Y, Shin JH, Hyde TM, Straub RE, Weinberger DR, Nisenbaum LK | title = Genomic structure and expression of the human serotonin 2A receptor gene (HTR2A) locus: identification of novel HTR2A and antisense (HTR2A-AS1) exons | journal = BMC Genetics | volume = 17 | issue = 1 | pages = 16 | date = January 2016 | pmid = 26738766 | pmc = 4702415 | doi = 10.1186/s12863-015-0325-6 | doi-access = free }} There are over 200 organisms that have orthologs with the human HTR2A. Currently, the best documented orthologs for HTR2A gene are the mouse,{{cite journal | vauthors = Medrihan L, Sagi Y, Inde Z, Krupa O, Daniels C, Peyrache A, Greengard P | title = Initiation of Behavioral Response to Antidepressants by Cholecystokinin Neurons of the Dentate Gyrus | journal = Neuron | volume = 95 | issue = 3 | pages = 564–576.e4 | date = August 2017 | pmid = 28735749 | doi = 10.1016/j.neuron.2017.06.044 | doi-access = free }} and zebrafish.{{cite journal | vauthors = Griffin A, Hamling KR, Knupp K, Hong S, Lee LP, Baraban SC | title = Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome | journal = Brain | volume = 140 | issue = 3 | pages = 669–683 | date = March 2017 | pmid = 28073790 | pmc = 6075536 | doi = 10.1093/brain/aww342 }} There are 8 paralogs for the HTR2A gene. The HTR2A gene is known to interact and activate G-protein genes such as GNA14, GNAI1, GNAI3, GNAQ, and GNAZ.{{cite journal | vauthors = Giulietti M, Vivenzio V, Piva F, Principato G, Bellantuono C, Nardi B | title = How much do we know about the coupling of G-proteins to serotonin receptors? | journal = Molecular Brain | volume = 7 | issue = 1 | pages = 49 | date = July 2014 | pmid = 25011628 | pmc = 4105882 | doi = 10.1186/s13041-014-0049-y | doi-access = free }} These interactions are critical for cell signaling{{cite journal | vauthors = Lal D, May P, Perez-Palma E, Samocha KE, Kosmicki JA, Robinson EB, Møller RS, Krause R, Nürnberg P, Weckhuysen S, De Jonghe P, Guerrini R, Niestroj LM, Du J, Marini C, Ware JS, Kurki M, Gormley P, Tang S, Wu S, Biskup S, Poduri A, Neubauer BA, Koeleman BP, Helbig KL, Weber YG, Helbig I, Majithia AR, Palotie A, Daly MJ | title = Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders | journal = Genome Medicine | volume = 12 | issue = 1 | pages = 28 | date = March 2020 | pmid = 32183904 | pmc = 7079346 | doi = 10.1186/s13073-020-00725-6 | doi-access = free }}{{cite journal | vauthors = Gao W, Guo N, Zhao S, Chen Z, Zhang W, Yan F, Liao H, Chi K | title = HTR2A promotes the development of cardiac hypertrophy by activating PI3K-PDK1-AKT-mTOR signaling | journal = Cell Stress & Chaperones | volume = 25 | issue = 6 | pages = 899–908 | date = November 2020 | pmid = 32519137 | pmc = 7591670 | doi = 10.1007/s12192-020-01124-x }} and homeostasis {{cite journal | vauthors = Cao X, Wang Y, Shu D, Qu H, Luo C, Hu X | title = Food intake-related genes in chicken determined through combinatorial genome-wide association study and transcriptome analysis | journal = Animal Genetics | volume = 51 | issue = 5 | pages = 741–751 | date = October 2020 | pmid = 32720725 | doi = 10.1111/age.12980 | s2cid = 220839883 }} in many organisms.{{cite journal | vauthors = Garza-Brenner E, Sifuentes-Rincón AM, Randel RD, Paredes-Sánchez FA, Parra-Bracamonte GM, Arellano Vera W, Rodríguez Almeida FA, Segura Cabrera A | title = Association of SNPs in dopamine and serotonin pathway genes and their interacting genes with temperament traits in Charolais cows | journal = Journal of Applied Genetics | volume = 58 | issue = 3 | pages = 363–371 | date = August 2017 | pmid = 27987181 | doi = 10.1007/s13353-016-0383-0 | s2cid = 34463383 }}

In human brain tissue, regulation of HTR2A varies depending on the region: frontal cortex, amygdala, thalamus, brain stem and cerebellum. In a paper from 2016, they found that HTR2A undergoes a variety of different splicing events, including utilization of alternative splice acceptor sites, exon skipping, rare exon usage, and intron retention.

There are a few mechanisms of regulation for HTR2A gene such regulated by DNA methylation at particular transcript binding sites.{{cite journal | vauthors = Cheah SY, Lawford BR, Young RM, Morris CP, Voisey J | title = mRNA Expression and DNA Methylation Analysis of Serotonin Receptor 2A (HTR2A) in the Human Schizophrenic Brain | journal = Genes | volume = 8 | issue = 1 | pages = 14 | date = January 2017 | pmid = 28054990 | pmc = 5295009 | doi = 10.3390/genes8010014 | doi-access = free }}{{cite journal | vauthors = Falkenberg VR, Gurbaxani BM, Unger ER, Rajeevan MS | title = Functional genomics of serotonin receptor 2A (HTR2A): interaction of polymorphism, methylation, expression and disease association | journal = Neuromolecular Medicine | volume = 13 | issue = 1 | pages = 66–76 | date = March 2011 | pmid = 20941551 | pmc = 3044825 | doi = 10.1007/s12017-010-8138-2 }} Another mechanism for the correct regulation of gene expression is achieved through alternative splicing. This is a co-transcriptional process, which allows the generation of multiple forms of mRNA transcript from a single coding unit and is emerging as an important control point for gene expression. In this process, exons or introns can be either included or excluded from precursor-mRNA resulting in multiple mature mRNA variants.{{cite journal | vauthors = Kelemen O, Convertini P, Zhang Z, Wen Y, Shen M, Falaleeva M, Stamm S | title = Function of alternative splicing | journal = Gene | volume = 514 | issue = 1 | pages = 1–30 | date = February 2013 | pmid = 22909801 | pmc = 5632952 | doi = 10.1016/j.gene.2012.07.083 }} These mRNA variants result in different isoforms which may have antagonistic functions or differential expression patterns, yielding plasticity and adaptability to the cells.{{cite journal | vauthors = Wang ET, Ward AJ, Cherone JM, Giudice J, Wang TT, Treacy DJ, Lambert NJ, Freese P, Saxena T, Cooper TA, Burge CB | title = Antagonistic regulation of mRNA expression and splicing by CELF and MBNL proteins | journal = Genome Research | volume = 25 | issue = 6 | pages = 858–871 | date = June 2015 | pmid = 25883322 | pmc = 4448682 | doi = 10.1101/gr.184390.114 }} One study found that the common genetic variant rs6311 regulates expression of HTR2A transcripts containing the extended 5' UTR.

5-HT_2A is expressed widely throughout the central nervous system (CNS).{{cite journal | vauthors = Beliveau V, Ganz M, Feng L, Ozenne B, Højgaard L, Fisher PM, Svarer C, Greve DN, Knudsen GM | title = A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System | journal = The Journal of Neuroscience | volume = 37 | issue = 1 | pages = 120–128 | date = January 2017 | pmid = 28053035 | pmc = 5214625 | doi = 10.1523/JNEUROSCI.2830-16.2016 }}

It is expressed near most of the serotonergic terminal rich areas, including neocortex (mainly prefrontal, parietal, and somatosensory cortex) and the olfactory tubercle {{Citation needed|date=November 2024}}. Especially high concentrations of this receptor on the apical dendrites of pyramidal cells in layer V of the cortex may modulate cognitive processes, working memory, and attention{{cite journal | vauthors = Aghajanian GK, Marek GJ | title = Serotonin, via 5-HT_2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release | journal = Brain Research | volume = 825 | issue = 1–2 | pages = 161–171 | date = April 1999 | pmid = 10216183 | doi = 10.1016/S0006-8993(99)01224-X | s2cid = 20081913 | doi-access = free }}{{cite journal | vauthors = Marek GJ, Wright RA, Gewirtz JC, Schoepp DD | title = A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex | journal = Neuroscience | volume = 105 | issue = 2 | pages = 379–392 | year = 2001 | pmid = 11672605 | doi = 10.1016/S0306-4522(01)00199-3 | s2cid = 19764312 }}{{cite journal | vauthors = Bortolozzi A, Díaz-Mataix L, Scorza MC, Celada P, Artigas F | title = The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity | journal = Journal of Neurochemistry | volume = 95 | issue = 6 | pages = 1597–1607 | date = December 2005 | pmid = 16277612 | doi = 10.1111/j.1471-4159.2005.03485.x | hdl-access = free | s2cid = 18350703 | hdl = 10261/33026 }} by enhancing glutamate release followed by a complex range of interactions with the 5-HT_1A,{{cite journal | vauthors = Amargós-Bosch M, Bortolozzi A, Puig MV, Serrats J, Adell A, Celada P, Toth M, Mengod G, Artigas F | title = Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex | journal = Cerebral Cortex | volume = 14 | issue = 3 | pages = 281–299 | date = March 2004 | pmid = 14754868 | doi = 10.1093/cercor/bhg128 | doi-access = free | hdl = 10261/34683 | hdl-access = free }} GABA_A,{{cite journal | vauthors = Feng J, Cai X, Zhao J, Yan Z | title = Serotonin receptors modulate GABA(A) receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons | journal = The Journal of Neuroscience | volume = 21 | issue = 17 | pages = 6502–6511 | date = September 2001 | pmid = 11517239 | pmc = 6763081 | doi = 10.1523/JNEUROSCI.21-17-06502.2001 }} adenosine A₁,{{cite journal | vauthors = Marek GJ | title = Activation of adenosine(1) (A(1)) receptors suppresses head shakes induced by a serotonergic hallucinogen in rats | journal = Neuropharmacology | volume = 56 | issue = 8 | pages = 1082–1087 | date = June 2009 | pmid = 19324062 | pmc = 2706691 | doi = 10.1016/j.neuropharm.2009.03.005 }} AMPA,{{cite journal | vauthors = Zhang C, Marek GJ | title = AMPA receptor involvement in 5-hydroxytryptamine2A receptor-mediated pre-frontal cortical excitatory synaptic currents and DOI-induced head shakes | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 32 | issue = 1 | pages = 62–71 | date = January 2008 | pmid = 17728034 | doi = 10.1016/j.pnpbp.2007.07.009 | s2cid = 44889209 }} mGluR_2/3,{{cite journal | vauthors = Gewirtz JC, Marek GJ | title = Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors | journal = Neuropsychopharmacology | volume = 23 | issue = 5 | pages = 569–576 | date = November 2000 | pmid = 11027922 | doi = 10.1016/S0893-133X(00)00136-6 | doi-access = free }} mGlu5,{{cite journal | vauthors = Marek GJ, Zhang C | title = Activation of metabotropic glutamate 5 (mGlu5) receptors induces spontaneous excitatory synaptic currents in layer V pyramidal cells of the rat prefrontal cortex | journal = Neuroscience Letters | volume = 442 | issue = 3 | pages = 239–243 | date = September 2008 | pmid = 18621097 | pmc = 2677702 | doi = 10.1016/j.neulet.2008.06.083 }} and OX₂ receptors.{{cite journal | vauthors = Lambe EK, Liu RJ, Aghajanian GK | title = Schizophrenia, hypocretin (orexin), and the thalamocortical activating system | journal = Schizophrenia Bulletin | volume = 33 | issue = 6 | pages = 1284–1290 | date = November 2007 | pmid = 17656637 | pmc = 2779889 | doi = 10.1093/schbul/sbm088 }}{{cite journal | vauthors = Liu RJ, Aghajanian GK | title = Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 1 | pages = 359–364 | date = January 2008 | pmid = 18172209 | pmc = 2224217 | doi = 10.1073/pnas.0706679105 | doi-access = free | bibcode = 2008PNAS..105..359L }} In the rat cerebellum, the protein has also been found in the Golgi cells of the granular layer,{{cite journal | vauthors = Geurts FJ, De Schutter E, Timmermans JP | title = Localization of 5-HT_2A, 5-HT3, 5-HT5A and 5-HT7 receptor-like immunoreactivity in the rat cerebellum | journal = Journal of Chemical Neuroanatomy | volume = 24 | issue = 1 | pages = 65–74 | date = June 2002 | pmid = 12084412 | doi = 10.1016/S0891-0618(02)00020-0 | s2cid = 16510169 }} and in the Purkinje cells.{{cite journal | vauthors = Maeshima T, Shutoh F, Hamada S, Senzaki K, Hamaguchi-Hamada K, Ito R, Okado N | title = Serotonin2A receptor-like immunoreactivity in rat cerebellar Purkinje cells | journal = Neuroscience Letters | volume = 252 | issue = 1 | pages = 72–74 | date = August 1998 | pmid = 9756362 | doi = 10.1016/S0304-3940(98)00546-1 | s2cid = 28549709 }}{{cite journal | vauthors = Maeshima T, Shiga T, Ito R, Okado N | title = Expression of serotonin2A receptors in Purkinje cells of the developing rat cerebellum | journal = Neuroscience Research | volume = 50 | issue = 4 | pages = 411–417 | date = December 2004 | pmid = 15567478 | doi = 10.1016/j.neures.2004.08.010 | s2cid = 5772490 }}

In the periphery, it is highly expressed in platelets and many cell types of the cardiovascular system, in fibroblasts, and in neurons of the peripheral nervous system. Additionally, 5-HT_2A mRNA expression has been observed in human monocytes.{{cite journal | vauthors = Dürk T, Panther E, Müller T, Sorichter S, Ferrari D, Pizzirani C, Di Virgilio F, Myrtek D, Norgauer J, Idzko M | title = 5-Hydroxytryptamine modulates cytokine and chemokine production in LPS-primed human monocytes via stimulation of different 5-HTR subtypes | journal = International Immunology | volume = 17 | issue = 5 | pages = 599–606 | date = May 2005 | pmid = 15802305 | doi = 10.1093/intimm/dxh242 | doi-access = free }} Whole-body distribution of the 5-HT_2A/2C receptor agonist, [11C]Cimbi-36 show uptake in several internal organs and brown adipose tissue (BAT), but it is not clear if this represents specific 5-HT_2A receptor binding.{{cite journal | vauthors = Johansen A, Holm S, Dall B, Keller S, Kristensen JL, Knudsen GM, Hansen HD | title = Human biodistribution and radiation dosimetry of the 5-HT_2A receptor agonist Cimbi-36 labeled with carbon-11 in two positions | journal = EJNMMI Research | volume = 9 | issue = 1 | pages = 71 | date = July 2019 | pmid = 31367837 | pmc = 6669221 | doi = 10.1186/s13550-019-0527-4 | doi-access = free }}

The 5-HT_2A receptor is a member of the class A (rhodopsin-like) G protein-coupled receptor (GPCR) family, characterized by seven transmembrane α-helices connected by extracellular and intracellular loops.{{cite report | vauthors = Chalit JE, Ragan EJ | title = The Serotonin G-Protein Coupled Receptor 5HT2A: Molecular and Multiple Sequence Analysis. | url = https://www.msudenver.edu/wp-content/uploads/2021/07/Chalit_final.pdf }} Its ligand-binding pocket is composed of two adjacent subpockets: the orthosteric binding pocket (OBP) and an extended binding pocket (EBP), with a unique side-extended cavity near the orthosteric site that distinguishes it from related receptors.{{cite journal | vauthors = Kimura KT, Asada H, Inoue A, Kadji FM, Im D, Mori C, Arakawa T, Hirata K, Nomura Y, Nomura N, Aoki J, Iwata S, Shimamura T | title = Structures of the 5-HT2A receptor in complex with the antipsychotics risperidone and zotepine | journal = Nature Structural & Molecular Biology | volume = 26 | issue = 2 | pages = 121–128 | date = February 2019 | pmid = 30723326 | doi = 10.1038/s41594-018-0180-z }}{{cite journal | vauthors = Viohl N, Hakami Zanjani AA, Khandelia H | title = Molecular insights into the modulation of the 5HT2A receptor by serotonin, psilocin, and the G protein subunit Gqα | journal = FEBS Letters | volume = 599 | issue = 6 | pages = 876–891 | date = March 2025 | pmid = 39865564 | pmc = 11931985 | doi = 10.1002/1873-3468.15099 }} Ligands are anchored primarily through a conserved aspartate residue (D155^3.32) that interacts with their charged amine groups, while additional interactions involve hydrophobic contacts and hydrogen bonds with residues in both the OBP and EBP.{{cite journal | vauthors = Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, Hennessey JJ, Bock HA, Anderson EI, Sherwood AM, Morris H, de Klein R, Klein AK, Cuccurazzu B, Gamrat J, Fannana T, Zauhar R, Halberstadt AL, McCorvy JD | title = Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential | journal = Nature Communications | volume = 14 | issue = 1 | pages = 8221 | date = December 2023 | pmid = 38102107 | pmc = 10724237 | doi = 10.1038/s41467-023-44016-1 }} Structural studies reveal that the receptor undergoes significant conformational changes upon activation, particularly in transmembrane helices 3 and 6, which facilitate G protein coupling and signal transduction.{{cite journal | vauthors = Shan J, Khelashvili G, Mondal S, Mehler EL, Weinstein H | title = Ligand-dependent conformations and dynamics of the serotonin 5-HT(2A) receptor determine its activation and membrane-driven oligomerization properties | journal = PLOS Computational Biology | volume = 8 | issue = 4 | pages = e1002473 | date = 2012 | pmid = 22532793 | pmc = 3330085 | doi = 10.1371/journal.pcbi.1002473 | doi-access = free | bibcode = 2012PLSCB...8E2473S }} The extracellular ligand-binding pocket is closed by a flexible “lid,” and the intracellular region includes a short helix (H8) stabilized by π-stacking interactions, both of which contribute to the receptor's dynamic conformational landscape. These structural features underlie the receptor’s ability to recognize diverse ligands and mediate complex signaling behaviors.

The cryo-EM structures of the serotonin 5-HT_2A receptor with a variety of serotonin 5-HT_2A receptor agonists, including the tryptamines serotonin (neurotransmitter and endogenous agonist), psilocin (psychedelic), and dimethyltryptamine (DMT) (psychedelic), the lysergamides LSD (psychedelic) and 2-bromo-LSD (BOL-148) (non-hallucinogenic), and the phenethylamines mescaline (psychedelic) and RS130-180 (β-arrestin-biased agonist with unknown hallucinogenic potential), have been solved and published by Bryan 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 | pmc = 11923220 | doi = 10.1038/s41467-025-57956-7 | 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 | date = September 2022 | conference = University of North Carolina at Chapel Hill Department of Pharmacology Research Retreat September 16th, 2022 – William and Ida Friday Center | url = https://www.med.unc.edu/pharm/wp-content/uploads/sites/930/2022/07/COMPLETE-PHARM-RETREAT-PROGRAM-2022-UPDATE.pdf#page=37 | quote = Recently, there has been a resurgence in utilizing classical psychedelics to treat depression, addiction, anxiety disorders, and cluster headaches. The biological target of these compounds, and the route of its therapeutic actions, is the 5HT2A receptor (5HT2AR). It has been hypothesized that the hallucinations and therapeutic actions can be separated through biased agonism and G-protein activation. Here we present 8 new cryoEM structures covering all major compound classes for the 5HT2AR including a novel arrestin biased compound RS130-180. Utilizing the structural and functional data we noticed a correlation between ligand bias and the placement of the canonical “toggle-switch” tryptophan. These findings lead to a broader mechanistic understanding of 5HT2AR activation as well as potential for the development of biased ligands. }}

The 5-HT_2A receptor is a subtype of serotonin receptor that plays a critical role in the central nervous system, particularly in regions involved in cognition, learning, and memory.{{cite journal | vauthors = Zhang G, Stackman RW | title = The role of serotonin 5-HT2A receptors in memory and cognition | journal = Frontiers in Pharmacology | volume = 6 | pages = 225 | date = 2015 | pmid = 26500553 | pmc = 4594018 | doi = 10.3389/fphar.2015.00225 | doi-access = free }} It is highly expressed in the cerebral cortex, especially in layer V pyramidal neurons and certain interneurons, where it modulates thalamocortical information processing and may influence gamma oscillations, which are important for sensory integration and perception. Functionally, the 5-HT_2A receptor is a G protein-coupled receptor (GPCR) that primarily signals through the phospholipase C (PLC) pathway, leading to the production of inositol triphosphate (IP3) and diacylglycerol, but it can also activate other signaling cascades such as arachidonic acid and 2-arachidonylglycerol pathways. Notably, the receptor exhibits "functional selectivity," meaning different ligands can differentially activate these signaling pathways, which is relevant for the distinct effects of hallucinogens, antipsychotics, and antidepressants that target the receptor.{{cite book | vauthors = Raote I, Bhattacharya A, Panicker MM | veditors = Chattopadhyay A | chapter = Serotonin 2A (5-HT2A) Receptor Function: Ligand-Dependent Mechanisms and Pathways. | title = Serotonin Receptors in Neurobiology. | series = Frontiers in Neuroscience | location = Boca Raton (FL) | date = 2007 | publisher = CRC Press/Taylor & Francis | pmid = 21204452 | isbn = 978-0-8493-3977-6 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK1853/ }}{{cite journal | vauthors = Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, Hennessey JJ, Bock HA, Anderson EI, Sherwood AM, Morris H, de Klein R, Klein AK, Cuccurazzu B, Gamrat J, Fannana T, Zauhar R, Halberstadt AL, McCorvy JD | title = Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential | journal = Nature Communications | volume = 14 | issue = 1 | pages = 8221 | date = December 2023 | pmid = 38102107 | pmc = 10724237 | doi = 10.1038/s41467-023-44016-1 }} Activation of the 5-HT2A receptor by agonists is associated with enhanced cognition and hallucinogenic effects, while antagonists have antipsychotic and antidepressant properties. Dysregulation of 5-HT_2A receptor function has been implicated in psychiatric disorders such as depression, schizophrenia, and drug addiction. Additionally, the receptor undergoes unique regulatory processes, including desensitization and internalization that are partly independent of β-arrestin, further distinguishing it from other GPCRs and influencing its response to long-term pharmacological modulation.

The 5-HT_2A receptor is known primarily to couple to the Gα_q signal transduction pathway. Upon receptor stimulation with agonist, Gα_q and β-γ subunits dissociate to initiate downstream effector pathways. Gα_q stimulates phospholipase C (PLC) activity, which subsequently promotes the release of diacylglycerol (DAG) and inositol triphosphate (IP3), which in turn stimulate protein kinase C (PKC) activity and Ca²⁺ release.{{cite journal | vauthors = Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA, Roth BL, Christopoulos A, Sexton PM, Miller KJ, Spedding M, Mailman RB | title = Functional selectivity and classical concepts of quantitative pharmacology | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 320 | issue = 1 | pages = 1–13 | date = January 2007 | pmid = 16803859 | doi = 10.1124/jpet.106.104463 | s2cid = 447937 | url = https://cdr.lib.unc.edu/downloads/j9602272s }}

Physiological processes mediated by the receptor include:

• CNS: neuronal excitation, hallucinations, out-of-body experiences, and fear. Primarily responsible for the psychedelic effects associated with 5-HT_2A receptor agonists such as LSD, DMT, etc.{{cite journal | vauthors = Moreno JL, Holloway T, Albizu L, Sealfon SC, González-Maeso J | title = Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT_2A receptor agonists | journal = Neuroscience Letters | volume = 493 | issue = 3 | pages = 76–79 | date = April 2011 | pmid = 21276828 | pmc = 3064746 | doi = 10.1016/j.neulet.2011.01.046 }}{{cite journal | vauthors = Jalal B | title = The neuropharmacology of sleep paralysis hallucinations: serotonin 2A activation and a novel therapeutic drug | journal = Psychopharmacology | volume = 235 | issue = 11 | pages = 3083–3091 | date = November 2018 | pmid = 30288594 | pmc = 6208952 | doi = 10.1007/s00213-018-5042-1 }}
• Activation of the 5-HT_2A receptor with 2,5-dimethoxy-4-iodoamphetamine (DOI) produces potent anti-inflammatory effects in several tissues including cardiovascular and gut. Other 5-HT_2A agonists like LSD also have potent anti-inflammatory effects against TNF-alpha-induced inflammation.{{cite journal | vauthors = Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD | title = Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 327 | issue = 2 | pages = 316–323 | date = November 2008 | pmid = 18708586 | doi = 10.1124/jpet.108.143461 | s2cid = 25374241 }}{{cite journal | vauthors = Nau F, Yu B, Martin D, Nichols CD | title = Serotonin 5-HT_2A receptor activation blocks TNF-α mediated inflammation in vivo | journal = PLOS ONE | volume = 8 | issue = 10 | pages = e75426 | year = 2013 | pmid = 24098382 | pmc = 3788795 | doi = 10.1371/journal.pone.0075426 | doi-access = free | bibcode = 2013PLoSO...875426N }}
• Activation of the 5-HT_2A receptor in hypothalamus causes increases in hormonal levels of oxytocin, prolactin, ACTH, corticosterone, and renin.{{cite journal | vauthors = Van de Kar LD, Javed A, Zhang Y, Serres F, Raap DK, Gray TS | title = 5-HT_2A receptors stimulate ACTH, corticosterone, oxytocin, renin, and prolactin release and activate hypothalamic CRF and oxytocin-expressing cells | journal = The Journal of Neuroscience | volume = 21 | issue = 10 | pages = 3572–3579 | date = May 2001 | pmid = 11331386 | pmc = 6762485 | doi = 10.1523/JNEUROSCI.21-10-03572.2001 }}{{cite journal | vauthors = Zhang Y, Damjanoska KJ, Carrasco GA, Dudas B, D'Souza DN, Tetzlaff J, Garcia F, Hanley NR, Scripathirathan K, Petersen BR, Gray TS, Battaglia G, Muma NA, Van de Kar LD | title = Evidence that 5-HT_2A receptors in the hypothalamic paraventricular nucleus mediate neuroendocrine responses to (−)DOI | journal = The Journal of Neuroscience | volume = 22 | issue = 21 | pages = 9635–9642 | date = November 2002 | pmid = 12417689 | pmc = 6758011 | doi = 10.1523/JNEUROSCI.22-21-09635.2002 }}
• Role in memory and learning.{{cite journal | vauthors = Harvey JA | title = Role of the serotonin 5-HT(2A) receptor in learning | journal = Learning & Memory | volume = 10 | issue = 5 | pages = 355–362 | year = 2003 | pmid = 14557608 | pmc = 218001 | doi = 10.1101/lm.60803 }}{{cite journal | vauthors = Williams GV, Rao SG, Goldman-Rakic PS, Foresta M, Ropolo M, Degan P, Pettinati I, Kow YW, Damonte G, Poggi A, Frosina G | title = Defective repair of 5-hydroxy-2'-deoxycytidine in Cockayne syndrome cells and its complementation by Escherichia coli formamidopyrimidine DNA glycosylase and endonuclease III | journal = Free Radical Biology & Medicine | volume = 48 | issue = 5 | pages = 681–690 | date = March 2010 | pmid = 11923449 | pmc = 6758292 | doi = 10.1016/j.freeradbiomed.2009.12.007 }}
• Role in arthralgia.{{cite journal | vauthors = Passier A, van Puijenbroek E | title = Mirtazapine-induced arthralgia | journal = British Journal of Clinical Pharmacology | volume = 60 | issue = 5 | pages = 570–572 | date = November 2005 | pmid = 16236049 | pmc = 1884949 | doi = 10.1111/j.1365-2125.2005.02481.x }}{{cite journal | vauthors = Adwan MH | title = An update on drug-induced arthritis | journal = Rheumatology International | volume = 36 | issue = 8 | pages = 1089–1097 | date = August 2016 | pmid = 27000044 | doi = 10.1007/s00296-016-3462-y | s2cid = 25401280 }}
• Role in Alzheimer's disease.{{cite journal | vauthors = Herth MM, Knudsen GM | title = Current radiosynthesis strategies for 5-HT_2A receptor PET tracers | journal = Journal of Labelled Compounds & Radiopharmaceuticals | volume = 58 | issue = 7 | pages = 265–273 | date = June 2015 | pmid = 25997728 | doi = 10.1002/jlcr.3288 }}
• Smooth muscle contraction in the gut.
• Probable role in sleep paralysis.
• Probable role in aging.{{Cite web | vauthors = Beer R | title = Anblick von toten Fliegen lässt Fliegen altern | date = 2023-06-13 | url = https://science.orf.at/stories/3219729/ | access-date = 2023-06-14 | website = science.ORF.at | language = de }}{{cite journal | vauthors = Gendron CM, Chakraborty TS, Duran C, Dono T, Pletcher SD | title = Ring neurons in the Drosophila central complex act as a rheostat for sensory modulation of aging | journal = PLOS Biology | volume = 21 | issue = 6 | pages = e3002149 | date = June 2023 | pmid = 37310911 | pmc = 10263353 | doi = 10.1371/journal.pbio.3002149 | doi-access = free }}

{{Further|List of miscellaneous 5-HT2A receptor agonists}}

Activation of the 5-HT_2A receptor is necessary for the effects of the "classic" psychedelics like LSD, psilocin and mescaline, which act as full or partial agonists at this receptor, and represent the three main classes of 5-HT_2A agonists, the ergolines, tryptamines and phenethylamines, respectively. A very large family of derivatives from these three classes has been developed, and their structure-activity relationships have been extensively researched.{{cite journal | vauthors = Nichols DE | title = Hallucinogens | journal = Pharmacology & Therapeutics | volume = 101 | issue = 2 | pages = 131–181 | date = February 2004 | pmid = 14761703 | doi = 10.1016/j.pharmthera.2003.11.002 }}{{cite journal | vauthors = Blaazer AR, Smid P, Kruse CG | title = Structure-activity relationships of phenylalkylamines as agonist ligands for 5-HT(2A) receptors | journal = ChemMedChem | volume = 3 | issue = 9 | pages = 1299–1309 | date = September 2008 | pmid = 18666267 | doi = 10.1002/cmdc.200800133 | s2cid = 7537908 }} Agonists acting at 5-HT_2A receptors located on the apical dendrites of pyramidal cells within regions of the prefrontal cortex are believed to mediate hallucinogenic activity. Some findings reveal that psychoactive effects of classic psychedelics are mediated by the receptor heterodimer 5-HT_2A–mGlu2 and not by monomeric 5-HT_2A receptors.{{cite journal | vauthors = Moreno JL, Muguruza C, Umali A, Mortillo S, Holloway T, Pilar-Cuéllar F, Mocci G, Seto J, Callado LF, Neve RL, Milligan G, Sealfon SC, López-Giménez JF, Meana JJ, Benson DL, González-Maeso J | title = Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT_2A·mGlu2) receptor heteromerization and its psychoactive behavioral function | journal = The Journal of Biological Chemistry | volume = 287 | issue = 53 | pages = 44301–44319 | date = December 2012 | pmid = 23129762 | pmc = 3531745 | doi = 10.1074/jbc.M112.413161 | doi-access = free }}{{cite journal | vauthors = González-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, López-Giménez JF, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC | title = Identification of a serotonin/glutamate receptor complex implicated in psychosis | journal = Nature | volume = 452 | issue = 7183 | pages = 93–97 | date = March 2008 | pmid = 18297054 | pmc = 2743172 | doi = 10.1038/nature06612 | bibcode = 2008Natur.452...93G }} However, newer research suggests that 5HT_2A and mGlu2 receptors do not physically associate with each other, so the former findings have questionable relevance.{{cite journal | vauthors = Taddeucci A, Olivero G, Roggeri A, Milanese C, Giorgio FP, Grilli M, Marchi M, Garrone B, Pittaluga A | title = Presynaptic 5-HT_2A-mGlu2/3 Receptor-Receptor Crosstalk in the Prefrontal Cortex: Metamodulation of Glutamate Exocytosis | journal = Cells | volume = 11 | issue = 19 | pages = 3035 | date = September 2022 | pmid = 36230998 | pmc = 9562019 | doi = 10.3390/cells11193035 | doi-access = free }} Agonists enhance dopamine in PFC, enhance memory and play an active role in attention and learning.{{cite journal | vauthors = Wingen M, Kuypers KP, Ramaekers JG | title = The role of 5-HT1a and 5-HT_2A receptors in attention and motor control: a mechanistic study in healthy volunteers | journal = Psychopharmacology | volume = 190 | issue = 3 | pages = 391–400 | date = February 2007 | pmid = 17124621 | doi = 10.1007/s00213-006-0614-x | s2cid = 25125461 }}{{cite journal | vauthors = Wingen M, Kuypers KP, Ramaekers JG | title = Selective verbal and spatial memory impairment after 5-HT1A and 5-HT_2A receptor blockade in healthy volunteers pre-treated with an SSRI | journal = Journal of Psychopharmacology | volume = 21 | issue = 5 | pages = 477–485 | date = July 2007 | pmid = 17092965 | doi = 10.1177/0269881106072506 | s2cid = 19575488 }}

Serotonin 5-HT_2A receptor agonists include serotonergic psychedelics{{cite journal | vauthors = Nichols DE | title = Psychedelics | journal = Pharmacol Rev | volume = 68 | issue = 2 | pages = 264–355 | date = April 2016 | pmid = 26841800 | pmc = 4813425 | doi = 10.1124/pr.115.011478 }} and non-hallucinogenic agents.{{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 }}{{cite journal | vauthors = Atiq MA, Baker MR, Voort JL, Vargas MV, Choi DS | title = Disentangling the acute subjective effects of classic psychedelics from their enduring therapeutic properties | journal = Psychopharmacology (Berl) | date = May 2024 | pmid = 38743110 | doi = 10.1007/s00213-024-06599-5 | doi-access = free }} Psychedelics have widely been encountered as recreational drug or drugs of misuse, with potential clinical consequences such as overdose, hospitalization, bad trips and worsened mental health, and rare adverse effects such as seizures, psychosis, and hallucinogen persisting perception disorder (HPPD).{{cite journal | vauthors = Hinkle JT, Graziosi M, Nayak SM, Yaden DB | title = Adverse Events in Studies of Classic Psychedelics: A Systematic Review and Meta-Analysis | journal = JAMA Psychiatry | volume = 81 | issue = 12 | pages = 1225–1235 | date = December 2024 | pmid = 39230883 | pmc = 11375525 | doi = 10.1001/jamapsychiatry.2024.2546 | pmc-embargo-date = September 4, 2025 | url = https://www.researchgate.net/publication/383754442 }}{{cite journal | vauthors = Schlag AK, Aday J, Salam I, Neill JC, Nutt DJ | title = Adverse effects of psychedelics: From anecdotes and misinformation to systematic science | journal = J Psychopharmacol | volume = 36 | issue = 3 | pages = 258–272 | date = March 2022 | pmid = 35107059 | pmc = 8905125 | doi = 10.1177/02698811211069100 }} On the other hand, psychedelics and non-hallucinogenic serotonin 5-HT_2A receptor agonists are under development as novel treatments for psychiatric disorders like depression, anxiety, and addiction as well as other conditions like cluster headaches.{{cite journal | vauthors = Roth BL, Gumpper RH | title = Psychedelics as Transformative Therapeutics | journal = Am J Psychiatry | volume = 180 | issue = 5 | pages = 340–347 | date = May 2023 | pmid = 37122272 | doi = 10.1176/appi.ajp.20230172 | url = https://cdr.lib.unc.edu/downloads/37720q20d }}{{cite journal | vauthors = Rhee TG, Davoudian PA, Sanacora G, Wilkinson ST | title = Psychedelic renaissance: Revitalized potential therapies for psychiatric disorders | journal = Drug Discov Today | volume = 28 | issue = 12 | pages = 103818 | date = December 2023 | pmid = 37925136 | doi = 10.1016/j.drudis.2023.103818 | url = https://drive.google.com/file/d/1mztRkW7vJu7KjpE1xKUyZoObWJ5QvEmt/view }}{{cite journal | vauthors = Nutt D, Spriggs M, Erritzoe D | title = Psychedelics therapeutics: What we know, what we think, and what we need to research | journal = Neuropharmacology | volume = 223 | pages = 109257 | date = February 2023 | pmid = 36179919 | doi = 10.1016/j.neuropharm.2022.109257 | doi-access = free }}{{cite journal | vauthors = Vargas MV, Meyer R, Avanes AA, Rus M, Olson DE | title = Psychedelics and Other Psychoplastogens for Treating Mental Illness | journal = Front Psychiatry | volume = 12 | pages = 727117 | date = 2021 | pmid = 34671279 | pmc = 8520991 | doi = 10.3389/fpsyt.2021.727117 | doi-access = free }}{{cite journal | vauthors = Aday JS, Barnett BS, Grossman D, Murnane KS, Nichols CD, Hendricks PS | title = Psychedelic Commercialization: A Wide-Spanning Overview of the Emerging Psychedelic Industry | journal = Psychedelic Medicine | volume = 1 | issue = 3 | pages = 150–165 | date = September 2023 | pmid = 40046566 | pmc = 11661494 | doi = 10.1089/psymed.2023.0013 }} Both psychedelics and non-hallucinogenic serotonin 5-HT_2A receptor agonists are claimed to act as psychoplastogens and this might be involved in their therapeutic effects.{{cite journal | vauthors = Hatzipantelis CJ, Olson DE | title = The Effects of Psychedelics on Neuronal Physiology | journal = Annu Rev Physiol | volume = 86 | pages = 27–47 | date = February 2024 | pmid = 37931171 | pmc = 10922499 | doi = 10.1146/annurev-physiol-042022-020923 }}{{cite journal | vauthors = Olson DE | title = Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity | journal = Biochemistry | volume = 61 | issue = 3 | pages = 127–136 | date = February 2022 | pmid = 35060714 | pmc = 9004607 | doi = 10.1021/acs.biochem.1c00812 }}

Various serotonergic psychedelics, acting as serotonin 5-HT_2A receptor agonists, have been found to be highly potent and efficacious anti-inflammatory and immunomodulatory agents in preclinical research (i.e., animal and in-vitro studies).{{cite journal | vauthors = Nichols DE, Johnson MW, Nichols CD | title = Psychedelics as Medicines: An Emerging New Paradigm | journal = Clin Pharmacol Ther | volume = 101 | issue = 2 | pages = 209–219 | date = February 2017 | pmid = 28019026 | doi = 10.1002/cpt.557 }}{{cite book | vauthors = Flanagan TW, Nichols CD | chapter = Psychedelics and Anti-inflammatory Activity in Animal Models | title = Disruptive Psychopharmacology | volume = 56 | pages = 229–245 | date = 2022 | pmid = 35546383 | doi = 10.1007/7854_2022_367 | series = Current Topics in Behavioral Neurosciences | isbn = 978-3-031-12183-8 }}{{cite journal | vauthors = Nichols CD | title = Psychedelics as potent anti-inflammatory therapeutics | journal = Neuropharmacology | volume = 219 | pages = 109232 | date = November 2022 | pmid = 36007854 | doi = 10.1016/j.neuropharm.2022.109232 | doi-access = free }}{{cite journal | vauthors = Flanagan TW, Nichols CD | title = Psychedelics as anti-inflammatory agents | journal = Int Rev Psychiatry | volume = 30 | issue = 4 | pages = 363–375 | date = August 2018 | pmid = 30102081 | doi = 10.1080/09540261.2018.1481827 | url = http://usdbiology.com/cliff/Courses/Advanced%20Seminars%20in%20Neuroendocrinology/Therapeutic%20Effects%20of%20Psychedelics%2019/Flanagan%20Nichols%2018%20IntRevPsychiatry%20Psychedelics%20as%20anti-inflammatory%20agents.pdf }}{{cite journal | vauthors = Thompson C, Szabo A | title = Psychedelics as a novel approach to treating autoimmune conditions | journal = Immunol Lett | volume = 228 | pages = 45–54 | date = December 2020 | pmid = 33035575 | doi = 10.1016/j.imlet.2020.10.001 | hdl = 10852/80687 | hdl-access = free }}{{cite journal | vauthors = Low ZX, Ng WS, Lim ES, Goh BH, Kumari Y | title = The immunomodulatory effects of classical psychedelics: A systematic review of preclinical studies | journal = Prog Neuropsychopharmacol Biol Psychiatry | volume = 136 | pages = 111139 | date = September 2024 | pmid = 39251080 | doi = 10.1016/j.pnpbp.2024.111139 | doi-access = free }}{{cite journal | vauthors = Flanagan TW, Billac GB, Landry AN, Sebastian MN, Cormier SA, Nichols CD | title = Structure-Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore | journal = ACS Pharmacol Transl Sci | volume = 4 | issue = 2 | pages = 488–502 | date = April 2021 | pmid = 33860179 | pmc = 8033619 | doi = 10.1021/acsptsci.0c00063 | url = https://www.researchgate.net/publication/360537036 }} In contrast to corticosteroids however, psychedelics with anti-inflammatory effects do not appear to suppress the immune system. Some psychedelics have been found to be far more potent in their anti-inflammatory effects than in their psychedelic effects. For instance, (R)-DOI is 30- to >50-fold more potent in producing anti-inflammatory effects than in producing psychedelic-like behavioral effects in animal research. Psilocin, the active form of psilocybin, has similar anti-inflammatory potency as (R)-DOI.

The potencies of psychedelics and other serotonin 5-HT_2A receptor agonists as anti-inflammatory drugs vary, with 2C-I, DOIB, 2C-B, 4-HO-DiPT, DOI, 2,5-DMA, DOET, DOM, psilocin, and 2C-H being highly potent and fully efficacious anti-inflammatories; TMA-2, 2C-B-Fly, TCB-2, ETH-LAD, LSD, and 2C-T-33 being partially efficacious anti-inflammatories; and lisuride, 1-methylpsilocin, 5-MeO-DMT, and DMT having negligible efficacy. Both non-hallucinogenic agents with full anti-inflammatory effects, such as 2,5-DMA, and non-anti-inflammatory agents with full psychedelic effects, such as DOTFM, are known.{{cite journal | vauthors = Flanagan TW, Billac G, Nichols CD | title = Differential Regulation of Inflammatory Responses Following 5-HT 2 Receptor Activation in Pulmonary Tissues | journal = The FASEB Journal | volume = 36 | issue = S1 | date = 2022 | doi = 10.1096/fasebj.2022.36.S1.R2617 | issn = 0892-6638 | doi-access = free }}{{cite journal | vauthors = Flanagan TW, Foster TP, Galbato TE, Lum PY, Louie B, Song G, Halberstadt AL, Billac GB, Nichols CD | title = Serotonin-2 Receptor Agonists Produce Anti-inflammatory Effects through Functionally Selective Mechanisms That Involve the Suppression of Disease-Induced Arginase 1 Expression | journal = ACS Pharmacology & Translational Science | volume = 7 | issue = 2 | pages = 478–492 | date = February 2024 | pmid = 38357283 | pmc = 10863441 | doi = 10.1021/acsptsci.3c00297 | quote = The effects of (R)-DOTFM were examined in the head-twitch response (HTR) assay. (R)-DOTFM produced a strong HTR with a potent ED 50 of 0.60 μmol/kg. These values are equivalent to (R)-DOI, as previously determined. }} Hence, the psychedelic and anti-inflammatory effects of serotonin 5-HT_2A receptor agonists appear to be fully dissociable. These effects appear to be mediated by different intracellular signaling pathways, although the exact pathways are unclear.

Serotonin 5-HT_2A receptor agonists with anti-inflammatory effects but reduced psychedelic effects, such as 2C-iBu (ELE-02), are under development for the potential treatment of inflammatory conditions.{{cite web | title = Eleusis Draws on Research Into Psychedelics To Develop New Medicines for Inflammation | date = 8 July 2020 | vauthors = Newvine C | website = Lucid News - Psychedelics, Consciousness Technology, and the Future of Wellness | url = https://www.lucid.news/eleusis-research-on-psychedelics-develop-inflammation-medicines/ | access-date = 16 February 2025 }}{{cite conference | title = Eleusis Drug Development Overview | date = February 2020 | author = Shlomi Raz, Eleusis | conference = LSX World Congress 2020 | url = https://www.youtube.com/watch?v=VwblUOQQwMI }}{{cite patent | title = Compounds and methods for treating inflammatory disorders | country = WO | number = 2020210823 | invent1 = Charles D. Nichols | invent2 = Gerald Billac | invent3 = David E. Nichols | status = published | pubdate = 15 October 2020 | fdate = 13 April 2020 | pridate = 13 April 2020 | url = https://patents.google.com/patent/WO2020210823A1/en }} They may also have applications in the treatment of neuroinflammation. The anti-inflammatory effects of psychedelics might be involved in the claimed effects of psychedelic microdosing.{{cite journal | vauthors = Kuypers KP, Ng L, Erritzoe D, Knudsen GM, Nichols CD, Nichols DE, Pani L, Soula A, Nutt D | title = Microdosing psychedelics: More questions than answers? An overview and suggestions for future research | journal = J Psychopharmacol | volume = 33 | issue = 9 | pages = 1039–1057 | date = September 2019 | pmid = 31303095 | pmc = 6732823 | doi = 10.1177/0269881119857204 }}{{cite journal | vauthors = Kinderlehrer DA | title = Mushrooms, Microdosing, and Mental Illness: The Effect of Psilocybin on Neurotransmitters, Neuroinflammation, and Neuroplasticity | journal = Neuropsychiatr Dis Treat | volume = 21 | pages = 141–155 | date = 2025 | pmid = 39897712 | pmc = 11787777 | doi = 10.2147/NDT.S500337 | doi-access = free }} Relatedly, LSD microdosing is being studied in the treatment of Alzheimer's disease specifically for its anti-inflammatory effects.{{cite journal | vauthors = Kozlowska U, Nichols C, Wiatr K, Figiel M | title = From psychiatry to neurology: Psychedelics as prospective therapeutics for neurodegenerative disorders | journal = J Neurochem | volume = 162 | issue = 1 | pages = 89–108 | date = July 2022 | pmid = 34519052 | doi = 10.1111/jnc.15509 }}{{cite journal | vauthors = Family N, Maillet EL, Williams LT, Krediet E, Carhart-Harris RL, Williams TM, Nichols CD, Goble DJ, Raz S | title = Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers | journal = Psychopharmacology (Berl) | volume = 237 | issue = 3 | pages = 841–853 | date = March 2020 | pmid = 31853557 | pmc = 7036065 | doi = 10.1007/s00213-019-05417-7 }}

• 25B-NBOMe{{snd}} also known as Cimbi-36; used as a PET imaging tool for visualizing the 5-HT_2A receptor{{cite journal | vauthors = Ettrup A, da Cunha-Bang S, McMahon B, Lehel S, Dyssegaard A, Skibsted AW, Jørgensen LM, Hansen M, Baandrup AO, Bache S, Svarer C, Kristensen JL, Gillings N, Madsen J, Knudsen GM | title = Serotonin 2A receptor agonist binding in the human brain with [¹¹C]Cimbi-36 | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 34 | issue = 7 | pages = 1188–1196 | date = July 2014 | pmid = 24780897 | pmc = 4083382 | doi = 10.1038/jcbfm.2014.68 }}
• 25I-NBOH and its 2-methoxy-analog 25I-NBOMe{{cite journal | vauthors = Braden MR, Parrish JC, Naylor JC, Nichols DE | title = Molecular interaction of serotonin 5-HT_2A receptor residues Phe339(6.51) and Phe340(6.52) with superpotent N-benzyl phenethylamine agonists | journal = Molecular Pharmacology | volume = 70 | issue = 6 | pages = 1956–1964 | date = December 2006 | pmid = 17000863 | doi = 10.1124/mol.106.028720 | s2cid = 15840304 }}
• BMB-202{{snd}} highly selective
• ¹⁸F FECIMBI-36{{snd}} radiolabelled agonist ligand for mapping 5-HT_2A / 5-HT_2C receptor distribution{{cite journal | vauthors = Prabhakaran J, Solingapuram Sai KK, Zanderigo F, Rubin-Falcone H, Jorgensen MJ, Kaplan JR, Tooke KI, Mintz A, Mann JJ, Kumar JS | title = In vivo evaluation of [¹⁸F]FECIMBI-36, an agonist 5-HT_2A/2C receptor PET radioligand in nonhuman primate | journal = Bioorganic & Medicinal Chemistry Letters | volume = 27 | issue = 1 | pages = 21–23 | date = January 2017 | pmid = 27889455 | pmc = 5348621 | doi = 10.1016/j.bmcl.2016.11.043 }}
• 5-Methoxytryptamine{{snd}} full agonist to several serotonin receptors.
• O-4310{{snd}} 5-HT_2A selective, claimed to have 100× selectivity over 5-HT_2C and be inactive at 5-HT_2B
• PHA-57378{{snd}} dual 5-HT_2A / 5-HT_2C agonist, anxiolytic effects in animal studies.{{cite journal | vauthors = Ennis MD, Hoffman RL, Ghazal NB, Olson RM, Knauer CS, Chio CL, Hyslop DK, Campbell JE, Fitzgerald LW, Nichols NF, Svensson KA, McCall RB, Haber CL, Kagey ML, Dinh DM | title = 2,3,4,5-tetrahydro- and 2,3,4,5,11,11a-hexahydro-1H-[1,4]diazepino[1,7-a]indoles: new templates for 5-HT(2C) agonists | journal = Bioorganic & Medicinal Chemistry Letters | volume = 13 | issue = 14 | pages = 2369–2372 | date = July 2003 | pmid = 12824036 | doi = 10.1016/S0960-894X(03)00403-7 }}
• TCB-2{{cite journal | vauthors = McLean TH, Parrish JC, Braden MR, Marona-Lewicka D, Gallardo-Godoy A, Nichols DE | title = 1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT_2A receptor agonists | journal = Journal of Medicinal Chemistry | volume = 49 | issue = 19 | pages = 5794–5803 | date = September 2006 | pmid = 16970404 | doi = 10.1021/jm060656o }}

• 25C-NBOMe
• 25CN-NBOH{{snd}} 100× selectivity for 5-HT_2A over 5-HT_2C, 46× selectivity over 5-HT_2B.{{Cite thesis | vauthors = Hansen M | degree = Ph.D. | publisher = University of Copenhagen | title = Design and Synthesis of Selective Serotonin Receptor Agonists for Positron Emission Tomography Imaging of the Brain (Revised, Duplex print).pdf | url = https://drive.google.com/file/d/0BwXelgjm5BeEaEJJU0lPa1NnaGM/view?usp=drive_open&usp=embed_facebook | via = Google Docs }}
• 3-Carboxy indole PB-22 (1-pentyl-indole-3-carboxylic acid){{snd}} a metabolite of the synthetic cannabinoid PB-22, partial agonist at 5-HT_2A{{cite journal | vauthors = Åstrand A, Guerrieri D, Vikingsson S, Kronstrand R, Green H | title = In vitro characterization of new psychoactive substances at the μ-opioid, CB1, 5HT_1A, and 5-HT_2A receptors-On-target receptor potency and efficacy, and off-target effects | journal = Forensic Science International | volume = 317 | pages = 110553 | date = December 2020 | pmid = 33160102 | doi = 10.1016/j.forsciint.2020.110553 | doi-access = free }}
• BMB-201{{snd}} non-hallucinogenic-like in animals{{cite conference | vauthors = Vasilkevich A, Duan J, Lovera A, McCorvy J, Pedersen JT | title = Novel 5-HT2A/2C mixed and partial agonist and its efficacy in preclinical pain models | date = October 2024 | conference = Society for Neuroscience 2024 Annual Meeting, Chicago, October 5–9 | url = https://brightmindsbio.com/wp-content/uploads/2024/10/BMB-201-poster-PSPP-final.pdf }}
• Bromo-DragonFLY{{cite journal | vauthors = Chambers JJ, Kurrasch-Orbaugh DM, Parker MA, Nichols DE | title = Enantiospecific synthesis and pharmacological evaluation of a series of super-potent, conformationally restricted 5-HT(2A/2C) receptor agonists | journal = Journal of Medicinal Chemistry | volume = 44 | issue = 6 | pages = 1003–1010 | date = March 2001 | pmid = 11300881 | doi = 10.1021/jm000491y }}
• DMBMPP{{snd}} a structurally constrained derivative of 25B-NBOMe, which acts as a potent partial agonist with 124× selectivity for 5-HT_2A over 5-HT_2C, making it the most selective agonist ligand identified to date.{{cite journal | vauthors = Juncosa JI, Hansen M, Bonner LA, Cueva JP, Maglathlin R, McCorvy JD, Marona-Lewicka D, Lill MA, Nichols DE | title = Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT_2A serotonin receptor agonist ligands | journal = ACS Chemical Neuroscience | volume = 4 | issue = 1 | pages = 96–109 | date = January 2013 | pmid = 23336049 | pmc = 3547484 | doi = 10.1021/cn3000668 }}
• (R)-DOI{{snd}} traditionally the most common 5-HT_2A reference agonist used in research{{cite journal | vauthors = Canal CE, Morgan D | title = Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model | journal = Drug Testing and Analysis | volume = 4 | issue = 7–8 | pages = 556–576 | date = July 2012 | pmid = 22517680 | pmc = 3722587 | doi = 10.1002/dta.1333 }}
• Efavirenz{{snd}} an antiretroviral drug, produces psychiatric side effects thought to be mediated by 5-HT_2A.{{cite journal | vauthors = Gatch MB, Kozlenkov A, Huang RQ, Yang W, Nguyen JD, González-Maeso J, Rice KC, France CP, Dillon GH, Forster MJ, Schetz JA | title = The HIV antiretroviral drug efavirenz has LSD-like properties | journal = Neuropsychopharmacology | volume = 38 | issue = 12 | pages = 2373–2384 | date = November 2013 | pmid = 23702798 | pmc = 3799056 | doi = 10.1038/npp.2013.135 }}
• IHCH-7113{{snd}} 5-HT_2A agonist derived by simplification of the 5-HT_2A antagonist antipsychotic lumateperone.{{cite journal | vauthors = Cao D, Yu J, Wang H, Luo Z, Liu X, He L, Qi J, Fan L, Tang L, Chen Z, Li J, Cheng J, Wang S | title = Structure-based discovery of nonhallucinogenic psychedelic analogs | journal = Science | volume = 375 | issue = 6579 | pages = 403–411 | date = January 2022 | pmid = 35084960 | doi = 10.1126/science.abl8615 | s2cid = 246360313 | bibcode = 2022Sci...375..403C }}
• Lisuride{{snd}} an antiparkinson dopamine agonist of the ergoline class, that is also a dual 5-HT_2A / 5-HT_2C agonist{{cite journal | vauthors = Egan CT, Herrick-Davis K, Miller K, Glennon RA, Teitler M | title = Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors | journal = Psychopharmacology | volume = 136 | issue = 4 | pages = 409–414 | date = April 1998 | pmid = 9600588 | doi = 10.1007/s002130050585 | s2cid = 3021798 }} and 5-HT_2B antagonist.{{cite journal | vauthors = Hofmann C, Penner U, Dorow R, Pertz HH, Jähnichen S, Horowski R, Latté KP, Palla D, Schurad B | title = Lisuride, a dopamine receptor agonist with 5-HT_2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT_2B receptor agonism in cardiac valvular fibrosis | journal = Clinical Neuropharmacology | volume = 29 | issue = 2 | pages = 80–86 | year = 2006 | pmid = 16614540 | doi = 10.1097/00002826-200603000-00005 | s2cid = 33849447 }}
• Mefloquine{{snd}} an antimalarial drug, also produces psychiatric side effects which may be mediated through 5-HT_2A and/or 5-HT_2C receptors.{{cite journal | vauthors = Janowsky A, Eshleman AJ, Johnson RA, Wolfrum KM, Hinrichs DJ, Yang J, Zabriskie TM, Smilkstein MJ, Riscoe MK | title = Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro | journal = Psychopharmacology | volume = 231 | issue = 14 | pages = 2771–2783 | date = July 2014 | pmid = 24488404 | pmc = 4097020 | doi = 10.1007/s00213-014-3446-0 }}
• Methysergide{{snd}} a congener of methylergonovine, used in treatment of migraine blocks 5-HT_2A and 5-HT_2C receptors, but sometimes acts as partial agonist, in some preparations.
• Piperidine derivatives such as OSU-6162, which acts as a partial agonist at both 5-HT_2A and dopamine D₂ receptors, and Z3517967757.
• Quipazine{{snd}} 5-HT_2A agonist but also potent 5-HT₃ agonist.{{cite journal | vauthors = de la Fuente Revenga M, Shah UH, Nassehi N, Jaster AM, Hemanth P, Sierra S, Dukat M, González-Maeso J | title = Psychedelic-like Properties of Quipazine and Its Structural Analogues in Mice | journal = ACS Chemical Neuroscience | volume = 12 | issue = 5 | pages = 831–844 | date = March 2021 | pmid = 33400504 | pmc = 7933111 | doi = 10.1021/acschemneuro.0c00291 }}
• SN-22{{snd}} partial agonist at all three 5-HT₂ subtypes
• Some benzazepines and similar compounds related to lorcaserin such as SCHEMBL5334361 are potent 5-HT_2A agonists as well as showing action at 5-HT_2C.{{cite journal | vauthors = Ennis MD, Hoffman RL, Ghazal NB, Olson RM, Knauer CS, Chio CL, Hyslop DK, Campbell JE, Fitzgerald LW, Nichols NF, Svensson KA, McCall RB, Haber CL, Kagey ML, Dinh DM | title = 2,3,4,5-tetrahydro- and 2,3,4,5,11,11a-hexahydro-1H-[1,4]diazepino[1,7-a]indoles: new templates for 5-HT(2C) agonists | journal = Bioorganic & Medicinal Chemistry Letters | volume = 13 | issue = 14 | pages = 2369–2372 | date = July 2003 | pmid = 12824036 | doi = 10.1016/s0960-894x(03)00403-7 }}{{cite journal | vauthors = Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Thomsen WJ, Saldana HR, Whelan KT, Menzaghi F, Webb RR, Beeley NR | title = Discovery and SAR of new benzazepines as potent and selective 5-HT(2C) receptor agonists for the treatment of obesity | journal = Bioorganic & Medicinal Chemistry Letters | volume = 15 | issue = 5 | pages = 1467–1470 | date = March 2005 | pmid = 15713408 | doi = 10.1016/j.bmcl.2004.12.080 }}{{cite patent | title = Aryl and heteroaryl tetrahydrobenzazepine derivatives and their use for treating glaucoma | country = WO | number = WO2007149728 | inventor = Mohapatra S, Hellberg MR, Feng Z | assign1 = Alcon Manufacturing, Ltd. }}{{cite journal | vauthors = Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Dosa PI, Covel JA, Ren A, Webb RR, Beeley NR, Martin M, Morgan M, Espitia S, Saldana HR, Bjenning C, Whelan KT, Grottick AJ, Menzaghi F, Thomsen WJ | title = Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity | journal = Journal of Medicinal Chemistry | volume = 51 | issue = 2 | pages = 305–313 | date = January 2008 | pmid = 18095642 | doi = 10.1021/jm0709034 }}{{cite journal | vauthors = Jensen AA, Plath N, Pedersen MH, Isberg V, Krall J, Wellendorph P, Stensbøl TB, Gloriam DE, Krogsgaard-Larsen P, Frølund B | title = Design, synthesis, and pharmacological characterization of N- and O-substituted 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol analogues: novel 5-HT(2A)/5-HT(2C) receptor agonists with pro-cognitive properties | journal = Journal of Medicinal Chemistry | volume = 56 | issue = 3 | pages = 1211–1227 | date = February 2013 | pmid = 23301527 | doi = 10.1021/jm301656h }}
• Substituted tetrahydro-β-carboline{{cite journal | vauthors = Orr MJ, Cao AB, Wang CT, Gaisin A, Csakai A, Friswold AP, Meltzer HY, McCorvy JD, Scheidt KA | title = Discovery of Highly Potent Serotonin 5-HT2 Receptor Agonists Inspired by Heteroyohimbine Natural Products | journal = ACS Medicinal Chemistry Letters | volume = 13 | issue = 4 | pages = 648–657 | date = April 2022 | pmid = 35450369 | pmc = 9014500 | doi = 10.1021/acsmedchemlett.1c00694 }}
• Tetrahydropyridine derivatives such as (R)-69,{{cite journal | vauthors = Kaplan AL, Confair DN, Kim K, Barros-Álvarez X, Rodriguiz RM, Yang Y, Kweon OS, Che T, McCorvy JD, Kamber DN, Phelan JP, Martins LC, Pogorelov VM, DiBerto JF, Slocum ST, Huang XP, Kumar JM, Robertson MJ, Panova O, Seven AB, Wetsel AQ, Wetsel WC, Irwin JJ, Skiniotis G, Shoichet BK, Roth BL, Ellman JA | title = Bespoke library docking for 5-HT_2A receptor agonists with antidepressant activity | journal = Nature | volume = 610 | issue = 7932 | pages = 582–591 | date = October 2022 | pmid = 36171289 | pmc = 9996387 | doi = 10.1038/s41586-022-05258-z | bibcode = 2022Natur.610..582K | s2cid = 252598838 }} Z4154032166 and WXVL_BT0793LQ2118.{{cite journal | vauthors = Lyu J, Kapolka N, Gumpper R, Alon A, Wang L, Jain MK, Barros-Álvarez X, Sakamoto K, Kim Y, DiBerto J, Kim K, Tummino TA, Huang S, Irwin JJ, Tarkhanova OO, Moroz Y, Skiniotis G, Kruse AC, Shoichet BK, Roth BL | title = AlphaFold2 structures template ligand discovery | journal = bioRxiv | date = December 2023 | pmid = 38187536 | pmc = 10769324 | doi = 10.1101/2023.12.20.572662 }}
• Zalsupindole (DLX-001; AAZ-A-154){{snd}} non-hallucinogenic but retains antidepressant effects in animals.{{cite journal | vauthors = Dong C, Ly C, Dunlap LE, Vargas MV, Sun J, Hwang IW, Azinfar A, Oh WC, Wetsel WC, Olson DE, Tian L | title = Psychedelic-inspired drug discovery using an engineered biosensor | journal = Cell | volume = 184 | issue = 10 | pages = 2779–2792.e18 | date = May 2021 | pmid = 33915107 | pmc = 8122087 | doi = 10.1016/j.cell.2021.03.043 | doi-access = free }}

• 25CN-NBOH{{cite journal | vauthors = Märcher Rørsted E, Jensen AA, Kristensen JL | title = 25CN-NBOH: A Selective Agonist for in vitro and in vivo Investigations of the Serotonin 2A Receptor | journal = ChemMedChem | volume = 16 | issue = 21 | pages = 3263–3270 | date = November 2021 | pmid = 34288515 | doi = 10.1002/cmdc.202100395 }}{{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 }}
• BMB-202{{cite conference | vauthors = Vasilkevich A, Halberstadt AL, Duan J, Merritt CR, Cunningham KA, McCorvy J, Kozikowski A, Pedersen J | title = Novel 5-HT2A selective agonists with well-characterized PK profile and short duration of action | date = October 2024 | conference = Society for Neuroscience 2024 Annual Meeting (Chicago), October 5–9 | url = https://brightmindsbio.com/wp-content/uploads/2024/10/BMB-202-sfn-poster-final-compressed.pdf }}
• DMBMPP{{cite journal | vauthors = Juncosa JI, Hansen M, Bonner LA, Cueva JP, Maglathlin R, McCorvy JD, Marona-Lewicka D, Lill MA, Nichols DE | title = Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands | journal = ACS Chem Neurosci | volume = 4 | issue = 1 | pages = 96–109 | date = January 2013 | pmid = 23336049 | pmc = 3547484 | doi = 10.1021/cn3000668 }}
• LPH-5{{cite journal | vauthors = M Ro Rsted E, Jensen AA, Smits G, Frydenvang K, Kristensen JL | title = Discovery and Structure-Activity Relationships of 2,5-Dimethoxyphenylpiperidines as Selective Serotonin 5-HT_2A Receptor Agonists | journal = Journal of Medicinal Chemistry | volume = 67 | issue = 9 | pages = 7224–7244 | date = May 2024 | pmid = 38648420 | pmc = 11089506 | doi = 10.1021/acs.jmedchem.4c00082 }}{{cite journal | vauthors = Jensen AA, Cecchi CR, Hibicke M, Bach AH, Kaadt E, Marcher-Rorsted E, Nichols CD, Elfving B, Kristensen JL | title = The selective 5-HT 2A receptor agonist LPH-5 induces persistent and robust antidepressant-like effects in rodents | journal = bioRxiv | date = 22 April 2024 | doi = 10.1101/2024.04.19.590212 | doi-access = free }}
• LPH-48{{cite web | title = LPH 48 | date = 22 May 2024 | website = AdisInsight | url = https://adisinsight.springer.com/drugs/800078258 | access-date = 30 October 2024 }}
• Lysergine{{cite journal | vauthors = Yuan H, Guo Z, Luo T | title = Synthesis of (+)-Lysergol and Its Analogues To Assess Serotonin Receptor Activity | journal = Org Lett | volume = 19 | issue = 3 | pages = 624–627 | date = February 2017 | pmid = 28106398 | doi = 10.1021/acs.orglett.6b03779 }}
• O-4310{{cite patent | title = Indole compounds useful as serotonin selective agents. | country = US | number = 7655691 | inventor = Kumaran G, Morency C, Roth B, Sard HP, Shuster L Xu L | assign1 = Organix Inc | pubdate = 11 May 2006 }}{{cite journal | vauthors = Motaghinejad O, Motaghinejad M, Motevalian M, Rahimi-Sharbaf F, Beiranvand T | title = The effect of maternal forced exercise on offspring pain perception, motor activity and anxiety disorder: the role of 5-HT2 and D2 receptors and CREB gene expression | journal = Journal of Exercise Rehabilitation | volume = 13 | issue = 5 | pages = 514–525 | date = October 2017 | pmid = 29114525 | pmc = 5667597 | doi = 10.12965/jer.1734992.496 }}

One effect of 5-HT_2A receptor activation is a reduction in intraocular pressure, and so 5-HT_2A agonists can be useful for the treatment of glaucoma. This has led to the development of compounds such as AL-34662 that are hoped to reduce pressure inside the eyes but without crossing the blood–brain barrier and producing hallucinogenic side effects.{{cite journal | vauthors = Sharif NA, McLaughlin MA, Kelly CR | title = AL-34662: a potent, selective, and efficacious ocular hypotensive serotonin-2 receptor agonist | journal = Journal of Ocular Pharmacology and Therapeutics | volume = 23 | issue = 1 | pages = 1–13 | date = February 2007 | pmid = 17341144 | doi = 10.1089/jop.2006.0093 }} Animal studies with this compound showed it to be free of hallucinogenic effects at doses up to 30 mg/kg, although several of its more lipophilic analogues did produce the head-twitch response known to be characteristic of hallucinogenic effects in rodents.{{cite journal | vauthors = May JA, Dantanarayana AP, Zinke PW, McLaughlin MA, Sharif NA | title = 1-((S)-2-aminopropyl)-1H-indazol-6-ol: a potent peripherally acting 5-HT2 receptor agonist with ocular hypotensive activity | journal = Journal of Medicinal Chemistry | volume = 49 | issue = 1 | pages = 318–328 | date = January 2006 | pmid = 16392816 | doi = 10.1021/jm050663x }}

Serotonin 5-HT_2A receptor antagonists, including many atypical antipsychotics, more selective agents like pimavanserin, and certain antidepressants and hypnotics like trazodone, mirtazapine, tricyclic antidepressants, and hydroxyzine, are used in the treatment of psychiatric disorders and other conditions such as depression, anxiety, psychosis, and insomnia.{{cite journal | vauthors = Mestre TA, Zurowski M, Fox SH | title = 5-Hydroxytryptamine 2A receptor antagonists as potential treatment for psychiatric disorders | journal = Expert Opin Investig Drugs | volume = 22 | issue = 4 | pages = 411–421 | date = April 2013 | pmid = 23409724 | doi = 10.1517/13543784.2013.769957 }}{{cite journal | vauthors = de Angelis L | title = 5-HT2A antagonists in psychiatric disorders | journal = Curr Opin Investig Drugs | volume = 3 | issue = 1 | pages = 106–112 | date = January 2002 | pmid = 12054060 }}{{cite journal | vauthors = Casey AB, Cui M, Booth RG, Canal CE | title = "Selective" serotonin 5-HT2A receptor antagonists | journal = Biochem Pharmacol | volume = 200 | pages = 115028 | date = June 2022 | pmid = 35381208 | pmc = 9252399 | doi = 10.1016/j.bcp.2022.115028 }} Ketanserin, a dual serotonin 5-HT_2A receptor antagonist and α₁-adrenergic receptor antagonist, is used as an antihypertensive agent.{{cite journal | vauthors = Brogden RN, Sorkin EM | title = Ketanserin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in hypertension and peripheral vascular disease | journal = Drugs | volume = 40 | issue = 6 | pages = 903–949 | date = December 1990 | pmid = 2079001 | doi = 10.2165/00003495-199040060-00010 }} The non-selective serotonin 5-HT_2A receptor antagonist cyproheptadine is frequently used off-label to treat serotonin syndrome, albeit based on limited clinical evidence.{{cite journal | vauthors = Badr B, Naguy A | title = Cyproheptadine: a psychopharmacological treasure trove? | journal = CNS Spectr | volume = 27 | issue = 5 | pages = 533–535 | date = October 2022 | pmid = 33632345 | doi = 10.1017/S1092852921000250 | url = }}{{cite journal | vauthors = Badar A | title = Serotonin syndrome: An often-neglected medical emergency | journal = J Family Community Med | volume = 31 | issue = 1 | pages = 1–8 | date = 2024 | pmid = 38406216 | pmc = 10883429 | doi = 10.4103/jfcm.jfcm_236_23 | doi-access = free | url = }}{{cite journal | vauthors = King E, Rotella JA | title = Review article: Efficacy of cyproheptadine in the management of serotonin toxicity following deliberate self-poisoning - A systematic review | journal = Emerg Med Australas | volume = 37 | issue = 1 | pages = e14554 | date = February 2025 | pmid = 39791184 | doi = 10.1111/1742-6723.14554 | url = }} Serotonin 5-HT_2A receptor antagonists like ketanserin have been used as psychedelic antidotes or "trip killers" to manage the hallucinogenic effects of serotonergic psychedelics.{{Cite journal | vauthors = Halman A, Kong G, Sarris J, Perkins D | title = Drug-drug interactions involving classic psychedelics: A systematic review | journal = J Psychopharmacol | volume = 38 | issue = 1 | pages = 3–18 | date = January 2024 | pmid = 37982394 | pmc = 10851641 | doi = 10.1177/02698811231211219 }}{{cite book | vauthors = Halberstadt AL, Nichols DE | chapter = Serotonin and serotonin receptors in hallucinogen action | title = Handbook of the Behavioral Neurobiology of Serotonin | volume = 31 | pages = 843–863 | year = 2020 | doi = 10.1016/B978-0-444-64125-0.00043-8 | series = Handbook of Behavioral Neuroscience | issn = 1569-7339 | isbn = 9780444641250 | s2cid = 241134396 }}{{Cite journal | vauthors = Yates G, Melon E | title = Trip-killers: a concerning practice associated with psychedelic drug use | journal = Emerg Med J | volume = 41 | issue = 2 | pages = 112–113 | date = January 2024 | pmid = 38123961 | doi = 10.1136/emermed-2023-213377 | url = https://s3.amazonaws.com/crawl.prod.proquest.com/fpcache/71f445805bfb61341cbc438c8ae23bd3.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEBMaCXVzLWVhc3QtMSJIMEYCIQDETX7YpaG5THA%2FNbKR0d92wr6h%2Bgg9preNcKjAsEqo%2BQIhAIlPGGWOeUc23LqhBzRYbxvSXB9aqSe2vVonl4nacAhhKp0CCLz%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEQABoMNTE4MzQ2ODQ4MzQxIgy9ji58Qtbi%2BavuKeYq8QEDL1U5KZDQ0bXFyVapeqJgE%2FX6x8DcJfFU8DAXYZPSQEwrIdfPbZWcYsH340deru%2FUHnNaGGpuHFoVzui%2FMbqBz7MANcowj%2FL1%2BQZzQ5hXh5KM3BW8E6NRzrQyuPRmBy7kQUkx8%2BjTN%2BXSMgF%2FCAs6Dn9fScgBGz3ddkwRZXDkjasqMP65RCPKhagK68cyMbf3oX%2BKS8a4Kltc2rk3CnWEhOKrZU4mIxq07DikLAXQbl8YRZJIkeOhN5TgBaLWJqyn1td2VWCMymAaFsqtPWHwXnEfsolRlfDooe6QXfE2YwX5PxBVJU7GPXRgrAqPjwtJMOCHgsEGOpwBYif%2BaDMBdz3IEghuvCvorAS0mkHzdcOz%2Fi7AzuN9nch%2FIm8llhMsN41aAWHuSG25pnhhftauFsg7rbGsrW2nl2kq2upi9zP7y%2Fnqk93jcP0kr0jM8zU12bYoSTsToQJsshH4N%2BTQUMwlzRQfeVv8MXdq%2BgSTTzJrWNwT1yNzye3rSHjvOumbNl6sgBISw7QqRzhB6hZTuf8AcI%2B7&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20250511T111826Z&X-Amz-SignedHeaders=host&X-Amz-Credential=ASIAXRL7BHBKRAKCQVVB%2F20250511%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Expires=3600&X-Amz-Signature=20bb1b90e4c8dbaa4115c954387617ebe2f55269bdd517692f1380193ed3f769 | archive-url = https://web.archive.org/web/20250511111827/https://s3.amazonaws.com/crawl.prod.proquest.com/fpcache/71f445805bfb61341cbc438c8ae23bd3.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEBMaCXVzLWVhc3QtMSJIMEYCIQDETX7YpaG5THA%2FNbKR0d92wr6h%2Bgg9preNcKjAsEqo%2BQIhAIlPGGWOeUc23LqhBzRYbxvSXB9aqSe2vVonl4nacAhhKp0CCLz%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEQABoMNTE4MzQ2ODQ4MzQxIgy9ji58Qtbi%2BavuKeYq8QEDL1U5KZDQ0bXFyVapeqJgE%2FX6x8DcJfFU8DAXYZPSQEwrIdfPbZWcYsH340deru%2FUHnNaGGpuHFoVzui%2FMbqBz7MANcowj%2FL1%2BQZzQ5hXh5KM3BW8E6NRzrQyuPRmBy7kQUkx8%2BjTN%2BXSMgF%2FCAs6Dn9fScgBGz3ddkwRZXDkjasqMP65RCPKhagK68cyMbf3oX%2BKS8a4Kltc2rk3CnWEhOKrZU4mIxq07DikLAXQbl8YRZJIkeOhN5TgBaLWJqyn1td2VWCMymAaFsqtPWHwXnEfsolRlfDooe6QXfE2YwX5PxBVJU7GPXRgrAqPjwtJMOCHgsEGOpwBYif%2BaDMBdz3IEghuvCvorAS0mkHzdcOz%2Fi7AzuN9nch%2FIm8llhMsN41aAWHuSG25pnhhftauFsg7rbGsrW2nl2kq2upi9zP7y%2Fnqk93jcP0kr0jM8zU12bYoSTsToQJsshH4N%2BTQUMwlzRQfeVv8MXdq%2BgSTTzJrWNwT1yNzye3rSHjvOumbNl6sgBISw7QqRzhB6hZTuf8AcI%2B7&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20250511T111826Z&X-Amz-SignedHeaders=host&X-Amz-Credential=ASIAXRL7BHBKRAKCQVVB%2F20250511%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Expires=3600&X-Amz-Signature=20bb1b90e4c8dbaa4115c954387617ebe2f55269bdd517692f1380193ed3f769 | url-status = dead | archive-date = 2025-05-11 }}

• 2-Alkyl-4-aryl-tetrahydro-pyrimido-azepines{{snd}} subtype selective antagonists (35 g: 60-fold).{{cite journal | vauthors = Shireman BT, Dvorak CA, Rudolph DA, Bonaventure P, Nepomuceno D, Dvorak L, Miller KL, Lovenberg TW, Carruthers NI | title = 2-Alkyl-4-aryl-pyrimidine fused heterocycles as selective 5-HT_2A antagonists | journal = Bioorganic & Medicinal Chemistry Letters | volume = 18 | issue = 6 | pages = 2103–2108 | date = March 2008 | pmid = 18282705 | doi = 10.1016/j.bmcl.2008.01.090 }}
• 5-MeO-NBpBrT
• AMDA and related derivatives{{snd}} family of selective 5-HT_2A antagonists.{{cite journal | vauthors = Westkaemper RB, Runyon SP, Bondarev ML, Savage JE, Roth BL, Glennon RA | title = 9-(Aminomethyl)-9,10-dihydroanthracene is a novel and unlikely 5-HT_2A receptor antagonist | journal = European Journal of Pharmacology | volume = 380 | issue = 1 | pages = R5–R7 | date = September 1999 | pmid = 10513561 | doi = 10.1016/S0014-2999(99)00525-7 }}{{cite journal | vauthors = Westkaemper RB, Glennon RA | title = Application of ligand SAR, receptor modeling and receptor mutagenesis to the discovery and development of a new class of 5-HT(2A) ligands | journal = Current Topics in Medicinal Chemistry | volume = 2 | issue = 6 | pages = 575–598 | date = June 2002 | pmid = 12052195 | doi = 10.2174/1568026023393741 | s2cid = 23576058 }}{{cite journal | vauthors = Peddi S, Roth BL, Glennon RA, Westkaemper RB | title = Spiro[9,10-dihydroanthracene]-9,3'-pyrrolidine-a structurally unique tetracyclic 5-HT_2A receptor antagonist | journal = European Journal of Pharmacology | volume = 482 | issue = 1–3 | pages = 335–337 | date = December 2003 | pmid = 14660041 | doi = 10.1016/j.ejphar.2003.09.059 }}{{cite journal | vauthors = Runyon SP, Mosier PD, Roth BL, Glennon RA, Westkaemper RB | title = Potential modes of interaction of 9-aminomethyl-9,10-dihydroanthracene (AMDA) derivatives with the 5-HT_2A receptor: a ligand structure-affinity relationship, receptor mutagenesis and receptor modeling investigation | journal = Journal of Medicinal Chemistry | volume = 51 | issue = 21 | pages = 6808–6828 | date = November 2008 | pmid = 18847250 | pmc = 3088499 | doi = 10.1021/jm800771x }}{{cite journal | vauthors = Wilson KJ, van Niel MB, Cooper L, Bloomfield D, O'Connor D, Fish LR, MacLeod AM | title = 2,5-Disubstituted pyridines: the discovery of a novel series of 5-HT_2A ligands | journal = Bioorganic & Medicinal Chemistry Letters | volume = 17 | issue = 9 | pages = 2643–2648 | date = May 2007 | pmid = 17314044 | doi = 10.1016/j.bmcl.2007.01.098 }}
• Atypical antipsychotics{{snd}} e.g., quetiapine, and asenapine are relatively potent antagonists of 5-HT_2A
• Brexpiprazole{{snd}} an atypical antipsychotic, is a potent antagonist at 5-HT_2A receptors (K_i = 0.47 nM in humans).{{cite journal | vauthors = Ishima T, Futamura T, Ohgi Y, Yoshimi N, Kikuchi T, Hashimoto K | title = Potentiation of neurite outgrowth by brexpiprazole, a novel serotonin-dopamine activity modulator: a role for serotonin 5-HT1A and 5-HT_2A receptors | journal = European Neuropsychopharmacology | volume = 25 | issue = 4 | pages = 505–511 | date = April 2015 | pmid = 25687838 | doi = 10.1016/j.euroneuro.2015.01.014 | doi-access = free }}{{cite journal | vauthors = Das S, Barnwal P, Winston AB, Mondal S, Saha I | title = Brexpiprazole: so far so good | journal = Therapeutic Advances in Psychopharmacology | volume = 6 | issue = 1 | pages = 39–54 | date = February 2016 | pmid = 26913177 | pmc = 4749739 | doi = 10.1177/2045125315614739 }}
• Cariprazine
• Cyclobenzaprine{{snd}} a strong antagonist of both 5-HT_2A and 5-HT_2C receptors
• Cyproheptadine
• Ergot alkaloids are mostly nonspecific 5-HT receptor antagonists, but a few ergot derivatives such as metergoline and nicergoline bind preferentially to members of the 5-HT₂ receptor family.
• Hydroxyzine (Atarax) (minor effect)
• Ketanserin – The discovery of ketanserin was a landmark in the pharmacology of 5-HT₂ receptors. Ketanserin, though capable of blocking 5-HT induced platelet adhesion, however does not mediate its well-known antihypertensive action through 5-HT₂ receptor family, but through its high affinity for alpha₁ adrenergic receptors. It also has high affinity for H₁ histaminergic receptors equal to that at 5-HT_2A receptors. Compounds chemically related to ketanserin such as ritanserin are more selective 5-HT_2A receptor antagonists with low affinity for alpha-adrenergic receptors. However, ritanserin, like most other 5-HT_2A receptor antagonists, also potently inhibits 5-HT_2C receptors.
• LY-367,265{{snd}} dual 5-HT_2A antagonist / SSRI with antidepressant effects
• Nantenine
• Nefazodone{{snd}} blocks post-synaptic 5-HT_2A receptors, and to a lesser extent inhibits pre-synaptic serotonin and norepinephrine reuptake.
• Niaprazine
• Opipramol{{snd}} atypical antidepressant
• Pizotifen{{snd}} a non-selective antagonist.{{cite book | vauthors = Rang HP | title = Pharmacology | location = Edinburgh | year = 2003 | publisher = Churchill Livingstone | isbn = 0-443-07145-4 }} Page 187
• Trazodone{{snd}} a potent 5-HT_2A antagonist, as well as an antagonist on other serotonin receptors.
• Tetracyclic antidepressants{{snd}} mianserin, mirtazapine, maprotiline
• Tricyclic antidepressants (TCAs){{snd}} e.g., amitriptyline, nortriptyline, amoxapine, clomipramine, doxepin, maprotiline, imipramine, iprindole{{cite journal | vauthors = Pälvimäki EP, Roth BL, Majasuo H, Laakso A, Kuoppamäki M, Syvälahti E, Hietala J | title = Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor | journal = Psychopharmacology | volume = 126 | issue = 3 | pages = 234–240 | date = August 1996 | pmid = 8876023 | doi = 10.1007/bf02246453 | s2cid = 24889381 }}
• Typical antipsychotics{{snd}} e.g., haloperidol and chlorpromazine (minor)
• Volinanserin (MDL100907, M100907){{snd}} the most potent 5-HT_2A antagonist;{{cite journal | vauthors = Marek GJ, Martin-Ruiz R, Abo A, Artigas F | title = The selective 5-HT_2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine | journal = Neuropsychopharmacology | volume = 30 | issue = 12 | pages = 2205–2215 | date = December 2005 | pmid = 15886717 | doi = 10.1038/sj.npp.1300762 | doi-access = free }} underwent a few clinical trials but was ultimately never marketed.

• BW-501C67
• Sarpogrelate
• Xylamidine

Increased 5-HT_2A expression is observed in patients with coronary thrombosis, and the receptor has been associated with processes that influence atherosclerosis.{{cite journal | vauthors = Marcinkowska M, Kubacka M, Zagorska A, Jaromin A, Fajkis-Zajaczkowska N, Kolaczkowski M | title = Exploring the antiplatelet activity of serotonin 5-HT_2A receptor antagonists bearing 6-fluorobenzo[d]isoxazol-3-yl)propyl) motif- as potential therapeutic agents in the prevention of cardiovascular diseases | journal = Biomedicine & Pharmacotherapy | volume = 145 | pages = 112424 | date = January 2022 | pmid = 34785417 | doi = 10.1016/j.biopha.2021.112424 | s2cid = 244111116 | doi-access = free }} As the receptor is present in coronary arteries{{cite journal | vauthors = Nilsson T, Longmore J, Shaw D, Pantev E, Bard JA, Branchek T, Edvinsson L | title = Characterisation of 5-HT receptors in human coronary arteries by molecular and pharmacological techniques | journal = European Journal of Pharmacology | volume = 372 | issue = 1 | pages = 49–56 | date = May 1999 | pmid = 10374714 | doi = 10.1016/S0014-2999(99)00114-4 }} and capable of mediating vasoconstriction, 5-HT_2A has also been linked to coronary artery spasms.{{cite journal | vauthors = Nagatomo T, Rashid M, Abul Muntasir H, Komiyama T | title = Functions of 5-HT_2A receptor and its antagonists in the cardiovascular system | journal = Pharmacology & Therapeutics | volume = 104 | issue = 1 | pages = 59–81 | date = October 2004 | pmid = 15500909 | doi = 10.1016/j.pharmthera.2004.08.005 }} 5-HT antagonism, therefore, has potential in the prevention of cardiovascular disease, however, no studies have been published so far.

• AC-90179{{snd}} potent and selective inverse agonist at 5-HT_2A, also 5-HT_2C antagonist.{{cite journal | vauthors = Weiner DM, Burstein ES, Nash N, Croston GE, Currier EA, Vanover KE, Harvey SC, Donohue E, Hansen HC, Andersson CM, Spalding TA, Gibson DF, Krebs-Thomson K, Powell SB, Geyer MA, Hacksell U, Brann MR | title = 5-hydroxytryptamine2A receptor inverse agonists as antipsychotics | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 299 | issue = 1 | pages = 268–276 | date = October 2001 | pmid = 11561089 | doi = 10.1016/S0022-3565(24)29327-7 }}{{cite journal | vauthors = Vanover KE, Harvey SC, Son T, Bradley SR, Kold H, Makhay M, Veinbergs I, Spalding TA, Weiner DM, Andersson CM, Tolf BR, Brann MR, Hacksell U, Davis RE | title = Pharmacological characterization of AC-90179 [2-(4-methoxyphenyl)-N-(4-methyl-benzyl)-N-(1-methyl-piperidin-4-yl)-acetamide hydrochloride]: a selective serotonin 2A receptor inverse agonist | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 310 | issue = 3 | pages = 943–951 | date = September 2004 | pmid = 15102927 | doi = 10.1124/jpet.104.066688 | s2cid = 12205122 }}
• Atypical antipsychotics – clozapine, iloperidone, olanzapine, paliperidone, risperidone
• Eplivanserin (Sanofi Aventis){{snd}} sleeping pill that reached phase II trials (but for which the application for approval was withdrawn), acts as a selective 5-HT_2A inverse agonist.
• Nelotanserin (APD-125){{snd}} selective 5-HT_2A inverse agonist developed by Arena Pharmaceuticals for the treatment of insomnia. APD-125 was shown to be effective and well tolerated in clinical trials.{{cite journal | vauthors = Rosenberg R, Seiden DJ, Hull SG, Erman M, Schwartz H, Anderson C, Prosser W, Shanahan W, Sanchez M, Chuang E, Roth T | title = APD125, a selective serotonin 5-HT(2A) receptor inverse agonist, significantly improves sleep maintenance in primary insomnia | journal = Sleep | volume = 31 | issue = 12 | pages = 1663–1671 | date = December 2008 | pmid = 19090322 | pmc = 2603489 | doi = 10.1093/sleep/31.12.1663 }}
• Pimavanserin (ACP-103){{snd}} more selective than AC-90179, orally active, antipsychotic in vivo, now FDA approved for the treatment of hallucinations and delusions associated with Parkinson's disease.{{cite journal | vauthors = Vanover KE, Weiner DM, Makhay M, Veinbergs I, Gardell LR, Lameh J, Del Tredici AL, Piu F, Schiffer HH, Ott TR, Burstein ES, Uldam AK, Thygesen MB, Schlienger N, Andersson CM, Son TY, Harvey SC, Powell SB, Geyer MA, Tolf BR, Brann MR, Davis RE | title = Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inverse agonist | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 317 | issue = 2 | pages = 910–918 | date = May 2006 | pmid = 16469866 | doi = 10.1124/jpet.105.097006 | s2cid = 22681576 }}{{cite journal | vauthors = Gardell LR, Vanover KE, Pounds L, Johnson RW, Barido R, Anderson GT, Veinbergs I, Dyssegaard A, Brunmark P, Tabatabaei A, Davis RE, Brann MR, Hacksell U, Bonhaus DW | title = ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 322 | issue = 2 | pages = 862–870 | date = August 2007 | pmid = 17519387 | doi = 10.1124/jpet.107.121715 | s2cid = 28861527 }}{{cite journal | vauthors = Vanover KE, Betz AJ, Weber SM, Bibbiani F, Kielaite A, Weiner DM, Davis RE, Chase TN, Salamone JD | title = A 5-HT_2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model | journal = Pharmacology, Biochemistry, and Behavior | volume = 90 | issue = 4 | pages = 540–544 | date = October 2008 | pmid = 18534670 | pmc = 2806670 | doi = 10.1016/j.pbb.2008.04.010 }}{{cite journal | vauthors = Abbas A, Roth BL | title = Pimavanserin tartrate: a 5-HT_2A inverse agonist with potential for treating various neuropsychiatric disorders | journal = Expert Opinion on Pharmacotherapy | volume = 9 | issue = 18 | pages = 3251–3259 | date = December 2008 | pmid = 19040345 | doi = 10.1517/14656560802532707 | s2cid = 71240383 | url = https://zenodo.org/record/1236273 }}{{Cite web | title = FDA approves first drug to treat hallucinations and delusions associated with Parkinson's disease | date = 10 September 2019 | url = http://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-hallucinations-and-delusions-associated-parkinsons-disease | archive-url = https://web.archive.org/web/20190907164751/https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-hallucinations-and-delusions-associated-parkinsons-disease | url-status = dead | archive-date = 7 September 2019 | author = Office of the Commissioner | website = FDA }}

Positive allosteric modulators of the serotonin 5-HT_2A receptor have been identified.{{cite journal | vauthors = Merritt C, Bolinger A, Anastasio N, Zhou J, Cunningham K | title = ACNP 61st Annual Meeting: Poster Abstracts P541 - P809: P722. Novel Positive Allosteric Modulators Augment 5-HT2A Receptor Functionality | journal = Neuropsychopharmacology | volume = 47 | issue = Suppl 1 | pages = 371–520 (470–470) | date = December 2022 | pmid = 36456695 | pmc = 9714408 | doi = 10.1038/s41386-022-01486-z }}{{cite journal | vauthors = Zamora JC, Merritt CR, Bolinger AA, Fox RG, Wild CT, Wold EA, Garcia EJ, Pazdrak K, Mifflin RC, Stafford SJ, Anastasio NC | title = Serendipitous Discovery of Novel 5-HT2AR Positive Allosteric Modulators (PAMs) Derived From 5-HT2CR PAM Scaffolds | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 389 | date = 2024 | doi = 10.1124/jpet.087.985400 | page = 87 }} These include CTW0404 and CTW0419. They selectively potentiated the serotonin 5-HT_2A receptor without affecting the serotonin 5-HT_2B and 5-HT_2C receptors. Unlike serotonin 5-HT_2A receptor agonists, they did not substitute for the serotonergic psychedelic (R)-DOI in drug discrimination tests and did not produce the head-twitch response, suggesting that they lack hallucinogenic effects. Instead, they blunted the (R)-DOI-induced head-twitch response. The (R)-enantiomer of glaucine has also been reported to be a serotonin 5-HT_2A receptor positive allosteric modulator.{{cite journal | vauthors = Heng HL, Chee CF, Thy CK, Tee JT, Chin SP, Herr DR, Buckle MJ, Paterson IC, Doughty SW, Abd Rahman N, Chung LY | title = In vitro functional evaluation of isolaureline, dicentrine and glaucine enantiomers at 5-HT2 and α1 receptors | journal = Chem Biol Drug Des | volume = 93 | issue = 2 | pages = 132–138 | date = February 2019 | pmid = 30216681 | doi = 10.1111/cbdd.13390 }} A dual serotonin 5-HT_2C and 5-HT_2A receptor positive allosteric modulator is the oleamide analogue JPC0323.{{cite journal | vauthors = Brunetti L, Francavilla F, Leopoldo M, Lacivita E | title = Allosteric Modulators of Serotonin Receptors: A Medicinal Chemistry Survey | journal = Pharmaceuticals (Basel) | volume = 17 | issue = 6 | date = May 2024 | page = 695 | pmid = 38931362 | pmc = 11206742 | doi = 10.3390/ph17060695 | doi-access = free | url = | quote = Several compounds of this series showed significant efficacy at 1 nM in improving 5-HT-mediated calcium efflux. Interestingly, while some of them were selective PAMs of 5-HT2CR, others were described as dual 5-HT2AR/5-HT2CR PAMs. None of these compounds were reported as PAMs of 5-HT2BR. A full characterization was conducted for dual PAM JPC0323 (Figure 6), which evoked a 44% increase in maximum 5-HT-induced Ca2+ intake and also showed negligible displacement at orthosteric binding sites of a number of GPCRs and transporters and exhibited favorable pharmacokinetic parameters. In rats, JPC0323 suppressed spontaneous ambulation in a 5-HT2CR-dependent manner, suggesting that the compound has a preference for 5-HT2CR over 5-HT2AR [75].}}{{cite journal | vauthors = Chen J, Garcia EJ, Merritt CR, Zamora JC, Bolinger AA, Pazdrak K, Stafford SJ, Mifflin RC, Wold EA, Wild CT, Chen H, Anastasio NC, Cunningham KA, Zhou J | title = Discovery of Novel Oleamide Analogues as Brain-Penetrant Positive Allosteric Serotonin 5-HT2C Receptor and Dual 5-HT2C/5-HT2A Receptor Modulators | journal = J Med Chem | volume = 66 | issue = 14 | pages = 9992–10009 | date = July 2023 | pmid = 37462530 | pmc = 10853020 | doi = 10.1021/acs.jmedchem.3c00908 | url = }}

5-HT_2A-receptor ligands may differentially activate the transductional pathways (see above). Studies evaluated the activation of two effectors, PLC and PLA2, by means of their second messengers. Compounds displaying more pronounced functional selectivity are 2,5-DMA and 2C-N. The former induces IP accumulation without activating the PLA2 mediated response, while the latter elicits AA release without activating the PLC mediated response.{{cite journal | vauthors = Moya PR, Berg KA, Gutiérrez-Hernandez MA, Sáez-Briones P, Reyes-Parada M, Cassels BK, Clarke WP | title = Functional selectivity of hallucinogenic phenethylamine and phenylisopropylamine derivatives at human 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 321 | issue = 3 | pages = 1054–1061 | date = June 2007 | pmid = 17337633 | doi = 10.1124/jpet.106.117507 | s2cid = 11651502 }}

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Recent research has suggested potential signaling differences within the somatosensory cortex between 5-HT_2A agonists that produce headshakes in the mouse and those that do not, such as lisuride, as these agents are also non-hallucinogenic in humans despite being active 5-HT_2A agonists.{{cite journal | vauthors = González-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, Lira A, Bradley-Moore M, Ge Y, Zhou Q, Sealfon SC, Gingrich JA | title = Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior | journal = Neuron | volume = 53 | issue = 3 | pages = 439–452 | date = February 2007 | pmid = 17270739 | doi = 10.1016/j.neuron.2007.01.008 | s2cid = 16309730 | doi-access = free }}{{cite journal | vauthors = Cussac D, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Martel JC, Danty N, Rauly-Lestienne I | title = Agonist-directed trafficking of signalling at serotonin 5-HT_2A, 5-HT_2B and 5-HT2C-VSV receptors mediated Gq/11 activation and calcium mobilisation in CHO cells | journal = European Journal of Pharmacology | volume = 594 | issue = 1–3 | pages = 32–38 | date = October 2008 | pmid = 18703043 | doi = 10.1016/j.ejphar.2008.07.040 }} One known example of differences in signal transduction is between the two 5-HT_2A agonists serotonin and DOI that involves differential recruitment of intracellular proteins called β-arrestins, more specifically arrestin beta 2.{{cite journal | vauthors = Schmid CL, Raehal KM, Bohn LM | title = Agonist-directed signaling of the serotonin 2A receptor depends on beta-arrestin-2 interactions in vivo | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 3 | pages = 1079–1084 | date = January 2008 | pmid = 18195357 | pmc = 2242710 | doi = 10.1073/pnas.0708862105 | doi-access = free }}{{cite journal | vauthors = Abbas A, Roth BL | title = Arresting serotonin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 3 | pages = 831–832 | date = January 2008 | pmid = 18195368 | pmc = 2242676 | doi = 10.1073/pnas.0711335105 | doi-access = free | bibcode = 2008PNAS..105..831A }} Cyclopropylmethanamine derivatives such as (−)-19 have also been shown to act as 5-HT_2A/2C agonists with functional selectivity for Gq-mediated signaling compared with β-arrestin recruitment.{{cite journal | vauthors = Zhang G, Cheng J, McCorvy JD, Lorello PJ, Caldarone BJ, Roth BL, Kozikowski AP | title = Discovery of N-Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications | journal = Journal of Medicinal Chemistry | volume = 60 | issue = 14 | pages = 6273–6288 | date = July 2017 | pmid = 28657744 | pmc = 7374938 | doi = 10.1021/acs.jmedchem.7b00584 }}

Besides direct serotonin 5-HT_2A receptor agonists, many drugs elevate serotonin levels and indirectly activate serotonin 5-HT_2A receptors.{{cite journal | vauthors = Blier P, El Mansari M | title = Serotonin and beyond: therapeutics for major depression | journal = Philos Trans R Soc Lond B Biol Sci | volume = 368 | issue = 1615 | pages = 20120536 | date = 2013 | pmid = 23440470 | pmc = 3638389 | doi = 10.1098/rstb.2012.0536 }}{{cite journal | vauthors = Pourhamzeh M, Moravej FG, Arabi M, Shahriari E, Mehrabi S, Ward R, Ahadi R, Joghataei MT | title = The Roles of Serotonin in Neuropsychiatric Disorders | journal = Cell Mol Neurobiol | volume = 42 | issue = 6 | pages = 1671–1692 | date = August 2022 | pmid = 33651238 | pmc = 11421740 | doi = 10.1007/s10571-021-01064-9 }} Examples include antidepressants and anxiolytics such as selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and serotonin precursors like tryptophan and 5-hydroxytryptophan (5-HTP). In addition, serotonin releasing agents (SRAs), including appetite suppressants like fenfluramine and chlorphentermine and entactogens like MDMA, elevate serotonin levels and indirectly activate serotonin 5-HT_2A receptors similarly.{{cite journal | vauthors = Rothman RB, Baumann MH | title = Serotonin releasing agents. Neurochemical, therapeutic and adverse effects | journal = Pharmacol Biochem Behav | volume = 71 | issue = 4 | pages = 825–836 | date = April 2002 | pmid = 11888573 | doi = 10.1016/s0091-3057(01)00669-4 }}{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic and adverse actions of serotonin transporter substrates | journal = Pharmacol Ther | volume = 95 | issue = 1 | pages = 73–88 | date = July 2002 | pmid = 12163129 | doi = 10.1016/s0163-7258(02)00234-6 }}{{cite journal | title = Neurochemical mechanisms of phentermine and fenfluramine: Therapeutic and adverse effects | journal = Drug Development Research | volume = 51 | issue = 2 | pages = 52–65 | date = 2000 | doi = 10.1002/1098-2299(200010)51:2<52::AID-DDR2>3.0.CO;2-H | vauthors = Rothman RB, Baumann MH | issn = 0272-4391 }}{{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 }}{{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 = https://shaunlacob.com/wp-content/uploads/2020/12/DC-MDMA.pdf }}{{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 }} Serotonin 5-HT_2A receptor activation may be involved in the therapeutic effects of serotonin-elevating medications and appears to be importantly involved in the subjective effects of SRAs like MDMA.{{cite book | vauthors = Halberstadt AL, Nichols DE | chapter = Serotonin and serotonin receptors in hallucinogen action | title = Handbook of the Behavioral Neurobiology of Serotonin | volume = 31 | pages = 843–863 | year = 2020 | doi = 10.1016/B978-0-444-64125-0.00043-8 | series = Handbook of Behavioral Neuroscience | issn = 1569-7339 | isbn = 9780444641250 | s2cid = 241134396 }} Serotonin-elevating drugs can cause serotonin syndrome under certain circumstances, for instance in overdose or with combination of multiple serotonergic drugs, and the serotonin 5-HT_2A receptor appears to be a key serotonin receptor in mediating this syndrome.{{cite journal | vauthors = Gillman PK | title = Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review | journal = Headache | volume = 50 | issue = 2 | pages = 264–272 | date = February 2010 | pmid = 19925619 | doi = 10.1111/j.1526-4610.2009.01575.x }}{{cite journal | vauthors = Sun-Edelstein C, Tepper SJ, Shapiro RE | title = Drug-induced serotonin syndrome: a review | journal = Expert Opin Drug Saf | volume = 7 | issue = 5 | pages = 587–596 | date = September 2008 | pmid = 18759711 | doi = 10.1517/14740338.7.5.587 }}{{cite journal | vauthors = Chiew AL, Isbister GK | title = [Not Available] | journal = Br J Clin Pharmacol | volume = 91 | issue = 3 | pages = 654–661 | date = March 2025 | pmid = 38926083 | pmc = 11862804 | doi = 10.1111/bcp.16152 | language = French }}

The receptor can be analysed by neuroimaging, radioligand, genetic analysis, measurements of ion flows, and other ways.{{Citation needed|date=February 2025}}

The 5-HT_2A receptors may be imaged with PET-scanners using the fluorine-18-altanserin,{{cite journal | vauthors = Lemaire C, Cantineau R, Guillaume M, Plenevaux A, Christiaens L | title = Fluorine-18-altanserin: a radioligand for the study of serotonin receptors with PET: radiolabeling and in vivo biologic behavior in rats | journal = Journal of Nuclear Medicine | volume = 32 | issue = 12 | pages = 2266–2272 | date = December 1991 | pmid = 1744713 }} MDL 100,907{{cite journal | vauthors = Lundkvist C, Halldin C, Ginovart N, Nyberg S, Swahn CG, Carr AA, Brunner F, Farde L | title = [11C]MDL 100907, a radioligland for selective imaging of 5-HT(2A) receptors with positron emission tomography | journal = Life Sciences | volume = 58 | issue = 10 | pages = PL 187-PL 192 | year = 1996 | pmid = 8602111 | doi = 10.1016/0024-3205(96)00013-6 }} or [¹¹C]Cimbi-36{{cite journal | vauthors = Johansen A, Hansen HD, Svarer C, Lehel S, Leth-Petersen S, Kristensen JL, Gillings N, Knudsen GM | title = The importance of small polar radiometabolites in molecular neuroimaging: A PET study with [¹¹C]Cimbi-36 labeled in two positions | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 38 | issue = 4 | pages = 659–668 | date = April 2018 | pmid = 29215308 | pmc = 5888860 | doi = 10.1177/0271678x17746179 }} radioligands that binds to the neuroreceptor, e.g., one study reported a reduced binding of altanserin particularly in the hippocampus in patients with major depressive disorder.{{cite journal | vauthors = Mintun MA, Sheline YI, Moerlein SM, Vlassenko AG, Huang Y, Snyder AZ | title = Decreased hippocampal 5-HT_2A receptor binding in major depressive disorder: in vivo measurement with [18F]altanserin positron emission tomography | journal = Biological Psychiatry | volume = 55 | issue = 3 | pages = 217–224 | date = February 2004 | pmid = 14744461 | doi = 10.1016/j.biopsych.2003.08.015 | s2cid = 24849671 }}

Altanserin uptake decreases with age reflecting a loss of specific 5-HT_2A receptors with age.{{cite journal | vauthors = Rosier A, Dupont P, Peuskens J, Bormans G, Vandenberghe R, Maes M, de Groot T, Schiepers C, Verbruggen A, Mortelmans L | title = Visualisation of loss of 5-HT_2A receptors with age in healthy volunteers using [18F]altanserin and positron emission tomographic imaging | journal = Psychiatry Research | volume = 68 | issue = 1 | pages = 11–22 | date = November 1996 | pmid = 9027929 | doi = 10.1016/S0925-4927(96)02806-5 | s2cid = 32317795 }}{{cite journal | vauthors = Meltzer CC, Smith G, Price JC, Reynolds CF, Mathis CA, Greer P, Lopresti B, Mintun MA, Pollock BG, Ben-Eliezer D, Cantwell MN, Kaye W, DeKosky ST | title = Reduced binding of [18F]altanserin to serotonin type 2A receptors in aging: persistence of effect after partial volume correction | journal = Brain Research | volume = 813 | issue = 1 | pages = 167–171 | date = November 1998 | pmid = 9824691 | doi = 10.1016/S0006-8993(98)00909-3 | s2cid = 21884218 }}{{cite journal | vauthors = Adams KH, Pinborg LH, Svarer C, Hasselbalch SG, Holm S, Haugbøl S, Madsen K, Frøkjaer V, Martiny L, Paulson OB, Knudsen GM | title = A database of [(18)F]-altanserin binding to 5-HT(2A) receptors in normal volunteers: normative data and relationship to physiological and demographic variables | journal = NeuroImage | volume = 21 | issue = 3 | pages = 1105–1113 | date = March 2004 | pmid = 15006678 | doi = 10.1016/j.neuroimage.2003.10.046 | s2cid = 24403109 }}

Western blot with an affinity-purified antibody and examination of 5-HT_2A receptor protein samples by electrophoresis has been described. Immunohistochemical staining of 5-HT_2A receptors is also possible.

Several studies have seen links between the -1438G/A polymorphism and mood disorders, such as major depressive disorder.{{cite journal | vauthors = Choi MJ, Lee HJ, Lee HJ, Ham BJ, Cha JH, Ryu SH, Lee MS | title = Association between major depressive disorder and the -1438A/G polymorphism of the serotonin 2A receptor gene | journal = Neuropsychobiology | volume = 49 | issue = 1 | pages = 38–41 | year = 2004 | pmid = 14730199 | doi = 10.1159/000075337 | s2cid = 19528052 }}

and a strong link with an odds ratio of 1.3 has been found between the T102C polymorphism and schizophrenia.{{cite journal | vauthors = Williams J, Spurlock G, McGuffin P, Mallet J, Nöthen MM, Gill M, Aschauer H, Nylander PO, Macciardi F, Owen MJ | title = Association between schizophrenia and T102C polymorphism of the 5-hydroxytryptamine type 2a-receptor gene. European Multicentre Association Study of Schizophrenia (EMASS) Group | journal = Lancet | volume = 347 | issue = 9011 | pages = 1294–1296 | date = May 1996 | pmid = 8622505 | doi = 10.1016/s0140-6736(96)90939-3 | s2cid = 8510590 }}

The T102C polymorphism has also been studied in relation to suicide attempts, with a study finding excess of the C/C genotype among the suicide attempters.{{cite journal | vauthors = Vaquero-Lorenzo C, Baca-Garcia E, Diaz-Hernandez M, Perez-Rodriguez MM, Fernandez-Navarro P, Giner L, Carballo JJ, Saiz-Ruiz J, Fernandez-Piqueras J, Baldomero EB, de Leon J, Oquendo MA | title = Association study of two polymorphisms of the serotonin-2A receptor gene and suicide attempts | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 147B | issue = 5 | pages = 645–649 | date = July 2008 | pmid = 18163387 | doi = 10.1002/ajmg.b.30642 | s2cid = 31504282 }} A number of other studies were devoted to finding an association of the gene with schizophrenia, with diverging results.[http://www.schizophreniaforum.org/res/sczgene/geneoverview.asp?geneid=293 Gene Overview of All Published Schizophrenia-Association Studies for HTR2A] {{webarchive|url=https://web.archive.org/web/20090221125658/http://schizophreniaforum.org/res/sczgene/geneoverview.asp?geneid=293 |date=21 February 2009 }} – SzGene database at Schizophrenia Research Forum.

These individual studies may, however, not give a full picture: A review from 2007 looking at the effect of different SNPs reported in separate studies stated that "genetic association studies [of HTR2A gene variants with psychiatric disorders] report conflicting and generally negative results" with no involvement, small or a not replicated role for the genetic variant of the gene.{{cite journal | vauthors = Serretti A, Drago A, De Ronchi D | title = HTR2A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies | journal = Current Medicinal Chemistry | volume = 14 | issue = 19 | pages = 2053–2069 | year = 2007 | pmid = 17691947 | doi = 10.2174/092986707781368450 }}

Polymorphisms in the promoter gene coding Early growth response 3 (EGR3) are associated with schizophrenia. Studies have demonstrated a relationship between EGR3 and HTR2A, and schizophrenia-like behaviors in transgenic animals.{{cite journal | vauthors = Maple AM, Zhao X, Elizalde DI, McBride AK, Gallitano AL | title = Htr2a Expression Responds Rapidly to Environmental Stimuli in an Egr3-Dependent Manner | journal = ACS Chemical Neuroscience | volume = 6 | issue = 7 | pages = 1137–1142 | date = July 2015 | pmid = 25857407 | pmc = 4565721 | doi = 10.1021/acschemneuro.5b00031 }}{{cite journal | vauthors = Williams AA, Ingram WM, Levine S, Resnik J, Kamel CM, Lish JR, Elizalde DI, Janowski SA, Shoker J, Kozlenkov A, González-Maeso J, Gallitano AL | title = Reduced levels of serotonin 2A receptors underlie resistance of Egr3-deficient mice to locomotor suppression by clozapine | journal = Neuropsychopharmacology | volume = 37 | issue = 10 | pages = 2285–2298 | date = September 2012 | pmid = 22692564 | pmc = 3422493 | doi = 10.1038/npp.2012.81 }} Exactly how these results translate over to further biopsychological understanding of schizophrenia is still widely debated.{{cite journal | vauthors = Latorre E, Mesonero JE, Harries LW | title = Alternative splicing in serotonergic system: Implications in neuropsychiatric disorders | journal = Journal of Psychopharmacology | volume = 33 | issue = 11 | pages = 1352–1363 | date = November 2019 | pmid = 31210090 | doi = 10.1177/0269881119856546 | s2cid = 190531249 | url = http://zaguan.unizar.es/record/84343 }}{{cite journal | vauthors = Spies M, Nasser A, Ozenne B, Jensen PS, Knudsen GM, Fisher PM | title = Common HTR2A variants and 5-HTTLPR are not associated with human in vivo serotonin 2A receptor levels | journal = Human Brain Mapping | volume = 41 | issue = 16 | pages = 4518–4528 | date = November 2020 | pmid = 32697408 | pmc = 7555071 | doi = 10.1002/hbm.25138 }} There is some evidence that dysfunction of HTR2A can impact pharmacological interventions.{{cite journal | vauthors = Qesseveur G, Petit AC, Nguyen HT, Dahan L, Colle R, Rotenberg S, Seif I, Robert P, David D, Guilloux JP, Gardier AM, Verstuyft C, Becquemont L, Corruble E, Guiard BP | title = Genetic dysfunction of serotonin 2A receptor hampers response to antidepressant drugs: A translational approach | journal = Neuropharmacology | volume = 105 | pages = 142–153 | date = June 2016 | pmid = 26764241 | doi = 10.1016/j.neuropharm.2015.12.022 | s2cid = 15031564 }}

Several studies have assessed a relationship between 5-hydroxytryptamine (serotonin) 2A receptor (5-HTR2A) gene polymorphisms with an increased risk of suicidal behavior. One study revealed that T102C polymorphism is associated with suicidal behavior {{cite journal | vauthors = Ghasemi A, Seifi M, Baybordi F, Danaei N, Samadi Rad B | title = Association between serotonin 2A receptor genetic variations, stressful life events and suicide | journal = Gene | volume = 658 | pages = 191–197 | date = June 2018 | pmid = 29526601 | doi = 10.1016/j.gene.2018.03.023 | s2cid = 4854262 }} but other studies failed to replicate these findings and found no association between polymorphism and suicidal behavior.{{cite journal | vauthors = Videtic A, Pungercic G, Pajnic IZ, Zupanc T, Balazic J, Tomori M, Komel R | title = Association study of seven polymorphisms in four serotonin receptor genes on suicide victims | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 141B | issue = 6 | pages = 669–672 | date = September 2006 | pmid = 16856120 | doi = 10.1002/ajmg.b.30390 | s2cid = 9279191 }}

Genetics seems also to be associated to some extent with the amount of adverse events in treatment of major depression disorder.{{cite journal | vauthors = Laje G, McMahon FJ | title = The pharmacogenetics of major depression: past, present, and future | journal = Biological Psychiatry | volume = 62 | issue = 11 | pages = 1205–1207 | date = December 2007 | pmid = 17949692 | doi = 10.1016/j.biopsych.2007.09.016 | s2cid = 37225993 }}

Polymorphisms in the 5-HT_2A receptor coding gene HTR2A (rs6313 and s6311) have been shown to have conflicting associations with alcohol misuse. For example, A polymorphism in the 5-HT_2A receptor coding gene HTR2A (rs6313) was reported to predict lower positive alcohol expectancy, higher refusal self-efficacy, and lower alcohol misuse in a sample of 120 young adults. However, this polymorphism did not moderate the linkages between impulsivity, cognition, and alcohol misuse.{{cite journal | vauthors = Leamy TE, Connor JP, Voisey J, Young RM, Gullo MJ | title = Alcohol misuse in emerging adulthood: Association of dopamine and serotonin receptor genes with impulsivity-related cognition | journal = Addictive Behaviors | volume = 63 | pages = 29–36 | date = December 2016 | pmid = 27399274 | doi = 10.1016/j.addbeh.2016.05.008 }} There are conflicting results as other studies have found associations between T102C polymorphisms alcohol misuse.{{cite journal | vauthors = Jakubczyk A, Wrzosek M, Lukaszkiewicz J, Sadowska-Mazuryk J, Matsumoto H, Sliwerska E, Glass J, Burmeister M, Brower KJ, Wojnar M | title = The CC genotype in HTR2A T102C polymorphism is associated with behavioral impulsivity in alcohol-dependent patients | journal = Journal of Psychiatric Research | volume = 46 | issue = 1 | pages = 44–49 | date = January 2012 | pmid = 21930285 | pmc = 3224206 | doi = 10.1016/j.jpsychires.2011.09.001 }}{{Cite journal | vauthors = da Silva Junior FC, Araujo RM, Sarmento AS, de Carvalho MM, Fernandes HF, Yoshioka FK, Pinto GR, Motta FJ, Canalle R | title = The association of A-1438G and T102C polymorphisms in HTR2A and 120 bp duplication in DRD4 with alcoholic dependence in a northeastern Brazilian male population | journal = Gene Reports | volume = 21 | pages = 100889 | date = December 2020 | doi = 10.1016/j.genrep.2020.100889 | s2cid = 224859807 }}

There is some evidence that methylation patterns may contribute to relapse behaviors in people who use stimulants.{{cite journal | vauthors = Land MA, Ramesh D, Miller AL, Pyles RB, Cunningham KA, Moeller FG, Anastasio NC | title = Methylation Patterns of the HTR2A Associate With Relapse-Related Behaviors in Cocaine-Dependent Participants | journal = Frontiers in Psychiatry | volume = 11 | pages = 532 | date = 2020-06-10 | pmid = 32587535 | pmc = 7299072 | doi = 10.3389/fpsyt.2020.00532 | doi-access = free }} In mice, psychotropic drugs such as DOI, LSD, DOM, and DOB which produced differing transcriptional patterns among several different brain regions.

• Ultra-large-scale docking

{{Reflist}}

{{refbegin}}

• {{cite journal | vauthors = Perez-Aguilar JM, Shan J, LeVine MV, Khelashvili G, Weinstein H | title = A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2 | journal = Journal of the American Chemical Society | volume = 136 | issue = 45 | pages = 16044–16054 | date = November 2014 | pmid = 25314362 | pmc = 4235374 | doi = 10.1021/ja508394x | bibcode = 2014JAChS.13616044P }}

{{refend}}

{{refbegin}}

• {{cite web | title = 5-HT_2A | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2320 | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology }}

{{refend}}

• {{MeshName|5-HT_2A+Receptor}}
• {{UCSC gene info|HTR2A}}
• {{PDBe-KB2|P28223|5-hydroxytryptamine receptor 2A}}

{{G protein-coupled receptors}}

{{Serotonin receptor modulators}}

{{Psychedelics}}

Category:Biology of attention deficit hyperactivity disorder

Category:Biology of bipolar disorder

Category:Serotonin receptors