Increased 5-HT2Areceptor signalling efficacy differentiates serotonergic psychedelics from non-psychedelics

ABSTRACT Background and Purpose Serotonergic psychedelic drugs are under renewed investigation for the potential treatment of several psychiatric disorders. While all serotonergic psychedelics have 5-HT 2A receptor activity, the explanation for why some 5-HT 2A receptor agonists are not psychedelic is unknown. To address this question, we investigated the 5-HT 2A receptor signalling bias and efficacy of a panel of psychedelics and non-psychedelics. Experimental Approach G -coupled (Ca 2+ and IP) and β-arrestin2 signalling effects of eight chemically diverse psychedelics (psilocin, 5-MeO-DMT, LSD, mescaline, 25B-NBOMe and DOI) and non-psychedelics (lisuride and TBG) were characterised using SH-SY5Y cells expressing recombinant human 5-HT 2A receptors. Measurements of signalling efficacy and bias were derived from dose-responses curves for each agonist, compared to 5-HT. Follow-up experiments sought to confirm the generality of findings using rat C6 cells expressing endogenous 5-HT 2A receptors. Key Results In SH-SY5Y cells, all psychedelics were partial agonists at both 5-HT 2A receptor signalling pathways and none showed significant signalling bias. In comparison, in SH-SY5Y cells the non-psychedelics lisuride and TBG were not distinguishable from psychedelics in terms of biased agonist properties, but both exhibited the lowest 5-HT 2A receptor signalling efficacy of all drugs tested, a result confirmed in C6 cells. Conclusion and Implications In summary, all psychedelics tested were unbiased, partial 5-HT 2A receptor agonists. Importantly, the non-psychedelics lisuride and TBG were discriminated from psychedelics, not through biased signalling but rather by relatively low efficacy. Thus, 5-HT 2A receptor signalling efficacy and not bias provides a possible explanation for why some 5-HT 2A receptor agonists are not psychedelic.