Increased 5-HT 2A receptor signalling efficacy differentiates serotonergic psychedelics from non-psychedelics
Aurelija Ippolito, Sridhar Vasudevan, Shaun Hurley, Gary Gilmour, Frederick Westhorpe, Grant Churchill, Trevor Sharp, Trevor Sharp
bioRxiv (Cold Spring Harbor Laboratory) June 16, 2024 preprint DOI: 10.1101/2024.06.13.594677 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro experimental study |
|---|---|
| Population | SH-SY5Y cells expressing recombinant human 5-HT2A receptors and rat C6 cells expressing endogenous 5-HT2A receptors |
| Interventions | Psilocin 5-MeO-DMT LSD mescaline 25B-NBOMe DOI lisuride TBG |
| Topics | Serotonin |
| Keywords | Signalling 5-HT Receptor |
| Citations | 1 |
| Key findings | Non-psychedelic 5-HT2A receptor agonists are distinguished from psychedelics by lower signalling efficacy, not by biased agonism. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cites 26
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Structural Features for Functional Selectivity at Serotonin Receptors Science March 21, 2013
and 21 more in the library