Evidence that 5‐HT_2A receptor signalling efficacy and not biased agonism differentiates serotonergic psychedelic from non‐psychedelic drugs

Abstract

Background and Purpose Serotonergic psychedelic drugs are under investigation as therapies for various psychiatric disorders, including major depression. Although serotonergic psychedelic drugs are 5‐HT 2A receptor agonists, some such agonists are not psychedelic, potentially due to differences in 5‐HT 2A receptor ligand bias or signalling efficacy. Here, we investigated 5‐HT 2A receptor signalling properties of selected psychedelic and non‐psychedelic drugs. Experimental Approach G q ‐coupled (Ca 2+ and IP 1 ) and β‐arrestin2 signalling effects of six psychedelic drugs (psilocin, 5‐MeO‐DMT, LSD, mescaline, 25B‐NBOMe and DOI) and three non‐psychedelic drugs (lisuride, TBG and IHCH‐7079) were characterised using SH‐SY5Y cells expressing human 5‐HT 2A receptors. Ligand bias and signalling efficacy were measured using concentration–responses curves, compared with 5‐HT. The generality of findings was tested using rat C6 cells which express endogenous 5‐HT 2A receptors. Key Results In SH‐SY5Y cells, all psychedelic drugs were partial agonists at both 5‐HT 2A receptor signalling pathways and none showed significant ligand bias. In comparison, the non‐psychedelic drugs were not distinguishable from psychedelic drugs in terms of ligand bias properties but exhibited the lowest 5‐HT 2A receptor signalling efficacy of all drugs tested. The latter result was confirmed in C6 cells. Conclusion and Implications In summary, all psychedelic drugs tested were unbiased, partial 5‐HT 2A receptor agonists. Importantly, the non‐psychedelic drugs lisuride, TBG and IHCH‐7079 were discriminated from psychedelic drugs, not through ligand bias but rather by low efficacy. Therefore, low 5‐HT 2A receptor signalling efficacy may explain why some 5‐HT 2A receptor agonists are not psychedelic, although a larger panel of drugs should be tested to confirm this idea.