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.
Comparable studies
Other experimental studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain | 1997 | Experimental study |
Citations in the library
Cited by 12
- Are we hallucinating or can psychedelic drugs modulate the immune system to control inflammation? British Journal of Pharmacology July 28, 2025
- Pathway-selective signaling of serotonergic psychedelics at 5-HT receptors: Implications for psychoactivity, safety, and therapeutic potential European Neuropsychopharmacology April 10, 2026
- N -Benzyl-Tryptamine Derivatives as Serotonin 5-HT 2 Receptor Ligands: Synthesis and Structure-Affinity/Activity Relationships ACS Omega May 13, 2026
- The Emergence of Isotryptamine Analogs as Novel Serotonergic Agents with Psychotherapeutic Potential ACS Pharmacology & Translational Science August 18, 2026
- Sex-dependent effects of psychedelics: review of evidence from rodent models Frontiers in Psychiatry July 15, 2026
and 7 more in the library
Cites 28
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Structural Features for Functional Selectivity at Serotonin Receptors Science March 21, 2013
- Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels Neuropsychopharmacology January 26, 2019
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
and 23 more in the library