{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T21:36:49Z","timestamp":1792532209249,"version":"4.5.0"},"reference-count":63,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2025,6,22]],"date-time":"2025-06-22T00:00:00Z","timestamp":1750550400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,6,22]],"date-time":"2025-06-22T00:00:00Z","timestamp":1750550400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>\n                      Serotonergic psychedelic drugs are under investigation as therapies for various psychiatric disorders, including major depression. Although serotonergic psychedelic drugs are 5\u2010HT\n                      <jats:sub>2A<\/jats:sub>\n                      receptor agonists, some such agonists are not psychedelic, potentially due to differences in 5\u2010HT\n                      <jats:sub>2A<\/jats:sub>\n                      receptor ligand bias or signalling efficacy. Here, we investigated 5\u2010HT\n                      <jats:sub>2A<\/jats:sub>\n                      receptor signalling properties of selected psychedelic and non\u2010psychedelic drugs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      G\n                      <jats:sub>q<\/jats:sub>\n                      \u2010coupled (Ca\n                      <jats:sup>2+<\/jats:sup>\n                      and IP\n                      <jats:sub>1<\/jats:sub>\n                      ) and \u03b2\u2010arrestin2 signalling effects of six psychedelic drugs (psilocin, 5\u2010MeO\u2010DMT, LSD, mescaline, 25B\u2010NBOMe and DOI) and three non\u2010psychedelic drugs (lisuride, TBG and IHCH\u20107079) were characterised using SH\u2010SY5Y cells expressing human 5\u2010HT\n                      <jats:sub>2A<\/jats:sub>\n                      receptors. Ligand bias and signalling efficacy were measured using concentration\u2013responses curves, compared with 5\u2010HT. The generality of findings was tested using rat C6 cells which express endogenous 5\u2010HT\n                      <jats:sub>2A<\/jats:sub>\n                      receptors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      In SH\u2010SY5Y cells, all psychedelic drugs were partial agonists at both 5\u2010HT\n                      <jats:sub>2A<\/jats:sub>\n                      receptor signalling pathways and none showed significant ligand bias. In comparison, the non\u2010psychedelic drugs were not distinguishable from psychedelic drugs in terms of ligand bias properties but exhibited the lowest 5\u2010HT\n                      <jats:sub>2A<\/jats:sub>\n                      receptor signalling efficacy of all drugs tested. The latter result was confirmed in C6 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>\n                      In summary, all psychedelic drugs tested were unbiased, partial 5\u2010HT\n                      <jats:sub>2A<\/jats:sub>\n                      receptor agonists. Importantly, the non\u2010psychedelic drugs lisuride, TBG and IHCH\u20107079 were discriminated from psychedelic drugs, not through ligand bias but rather by low efficacy. Therefore, low 5\u2010HT\n                      <jats:sub>2A<\/jats:sub>\n                      receptor signalling efficacy may explain why some 5\u2010HT\n                      <jats:sub>2A<\/jats:sub>\n                      receptor agonists are not psychedelic, although a larger panel of drugs should be tested to confirm this idea.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LINKED ARTICLES<\/jats:title>\n                    <jats:p>\n                      This article is part of a themed issue Emerging Therapeutic Opportunities for Psychedelic and Related Drugs. To view the other articles in this section visit\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v183.14\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v183.14\/issuetoc<\/jats:ext-link>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70109","type":"journal-article","created":{"date-parts":[[2025,6,22]],"date-time":"2025-06-22T20:40:12Z","timestamp":1750624812000},"page":"4058-4071","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Evidence that 5\u2010HT\n                    <sub>2A<\/sub>\n                    receptor signalling efficacy and not biased agonism differentiates serotonergic psychedelic from non\u2010psychedelic drugs"],"prefix":"10.1111","volume":"183","author":[{"given":"Aurelija","family":"Ippolito","sequence":"first","affiliation":[{"name":"University Department of Pharmacology  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sridhar","family":"Vasudevan","sequence":"additional","affiliation":[{"name":"University Department of Pharmacology  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaun","family":"Hurley","sequence":"additional","affiliation":[{"name":"Compass Pathways plc  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Gilmour","sequence":"additional","affiliation":[{"name":"Compass Pathways plc  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick","family":"Westhorpe","sequence":"additional","affiliation":[{"name":"Compass Pathways plc  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant","family":"Churchill","sequence":"additional","affiliation":[{"name":"University Department of Pharmacology  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7434-9713","authenticated-orcid":false,"given":"Trevor","family":"Sharp","sequence":"additional","affiliation":[{"name":"University Department of Pharmacology  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,22]]},"reference":[{"issue":"2","key":"e_1_2_13_2_1","first-page":"S23","article-title":"The Concise Guide to PHARMACOLOGY 2023\/24: G protein\u2010coupled receptors","volume":"180","author":"Alexander S. 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