biostudies-literatureCasey ABNational Institute of Neurological Disorders and StrokeNIDA NIH HHSU.S. Department of DefenseNINDS NIH HHSNational Institute on Drug AbuseNortheastern University115028https://www.ebi.ac.uk/biostudies/studies/S-EPMC9252399biostudies-literatureUnknown200Blockade of the serotonin 5-HT_2A G protein-coupled receptor (5-HT_2AR) is a fundamental pharmacological characteristic of numerous antipsychotic medications, which are FDA-approved to treat schizophrenia, bipolar disorder, and as adjunctive therapies in major depressive disorder. Meanwhile, activation of the 5-HT_2AR by serotonergic psychedelics may be useful in treating neuropsychiatric indications, including major depressive and substance use disorders. Serotonergic psychedelics and other 5-HT_2AR agonists, however, often bind other receptors, and standard 5-HT_2AR antagonists lack sufficient selectivity to make well-founded mechanistic conclusions about the 5-HT_2AR-dependent effects of these compounds and the general neurobioBiochemical pharmacology"Selective" serotonin 5-HT_2A receptor antagonists.PMC9252399R01 DA030989W81XWH-17-1-0329R01DA047130R01 DA047130R15 NS118352R01DA030989R15 NS118352-01Cui MBooth RGCasey ABCanal CEfalse"Selective" serotonin 5-HT_2A receptor antagonists.Blockade of the serotonin 5-HT_2A G protein-coupled receptor (5-HT_2AR) is a fundamental pharmacological characteristic of numerous antipsychotic medications, which are FDA-approved to treat schizophrenia, bipolar disorder, and as adjunctive therapies in major depressive disorder. Meanwhile, activation of the 5-HT_2AR by serotonergic psychedelics may be useful in treating neuropsychiatric indications, including major depressive and substance use disorders. Serotonergic psychedelics and other 5-HT_2AR agonists, however, often bind other receptors, and standard 5-HT_2AR antagonists lack sufficient selectivity to make well-founded mechanistic conclusions about the 5-HT_2AR-dependent effects of these compounds and the general neurobio2022-01-01T00:00:00Z2022 Jun2025-04-22T04:51:12.007Z2025-04-05T21:08:49.028ZS-EPMC92523993538120810.1016/j.bcp.2022.115028