Evidence that 5-HT2A receptor signalling efficacy and not biased agonism differentiates serotonergic psychedelic from non-psychedelic drugs

Background and Purpose Serotonergic psychedelic drugs are under investigation as therapies for various psychiatric disorders, including major depression. Although serotonergic psychedelic drugs are 5-HT2A receptor agonists, some such agonists are not psychedelic, potentially due to differences in 5-HT2A receptor ligand bias or signalling efficacy. Here, we investigated 5-HT2A receptor signalling properties of selected psychedelic and non-psychedelic drugs. Experimental Approach G(q)-coupled (Ca2+ and IP1) and beta-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-HT2A 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-HT2A receptors. Key Results In SH-SY5Y cells, all psychedelic drugs were partial agonists at both 5-HT2A 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-HT2A 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-HT2A 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-HT2A receptor signalling efficacy may explain why some 5-HT2A receptor agonists are not psychedelic, although a larger panel of drugs should be tested to confirm this idea.