Evidence that 5-HT2A receptor signalling efficacy and not biased agonism differentiates serotonergic psychedelic from non-psychedelic drugs.
Aurelija Ippolito, Sridhar Vasudevan, Shaun Hurley, Gary Gilmour, Frederick Westhorpe, Grant Churchill, Trevor Sharp
British Journal of Pharmacology June 22, 2025 DOI: 10.1111/bph.70109 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | SH-SY5Y cells expressing human 5-HT2A receptors and rat C6 cells with endogenous 5-HT2A receptors |
| Interventions | psilocin 5-MeO-DMT LSD mescaline 25B-NBOMe DOI lisuride TBG IHCH-7079 |
| Topics | Serotonin |
| Keywords | 5‐ht2a receptor Biased agonism Psychedelic drugs 5-ht2a receptor pharmacology Serotonin neurotransmission Psychoactive drugs Hallucinogens Drug effects Psychedelic properties Serotonin receptor Receptor signalling Receptor activation Drug mechanism Neuropharmacology Drug efficacy Receptor studies Neurotransmitter Neurochemistry Serotonin system |
| Citations | 9 |
| Key findings | Non-psychedelic 5-HT2A receptor agonists are discriminated from psychedelic ones by low signaling efficacy rather than by ligand bias. |
Abstract
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. Gq-coupled (Ca2+ and IP1) 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-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. 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. 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.