Serotonin 5-HT2C Receptor Signaling Analysis Reveals Psychedelic Biased Agonism.
Emma M. Bonniwell, Rana Alabdali, Joseph J. Hennessey, John L. McKee, Natalie G. Cavalco, Josie C. Lammers, Ethan J. Moore, Luca Franchini, Cesare Orlandi, John D. Mccorvy
ACS Chemical Neuroscience September 13, 2025 DOI: 10.1021/acschemneuro.5c00647 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Laboratory study Peer reviewed |
|---|---|
| Topics | Serotonin |
| Keywords | Psychedelics Hallucinogens Entheogens Mind-altering drugs Psychedelic compounds Biased agonism Selective agonism Receptor modulation Pathway-specific activation Receptor fine-tuning Selective engagement Serotonin receptors 5-ht2c receptor 5-HT Receptors Brain receptors Neurotransmitter receptors Therapeutic potential Novel treatments Drug development Psychiatric treatments Mental health Precise therapeutic benefits |
| Citations | 3 |
| Key points | The serotonin 2C receptor engages Gi/o/z and G12/13 proteins in addition to its primary Gq/11 pathway, and psychedelic ligands such as LSD and psilocin exhibit a striking Gq/11 bias due to minimal secondary G protein activation. |
Abstract
The serotonin 2C receptor (5-HT 2C ) is a G protein-coupled receptor implicated in multiple physiological and psychological processes and has been investigated as a therapeutic target for neuropsychiatric conditions such as obesity, drug abuse, and depression. With renewed interest in serotonergic psychedelics for treating depression, 5-HT 2C may contribute to psychedelic-induced therapeutic effects. Despite earlier evidence of 5-HT 2C G protein coupling promiscuity, the full signaling landscape remains incompletely characterized, which may help explain the limited efficacy and potential cancer risks associated with lorcaserin. Here, we provide a comprehensive analysis of 5-HT 2C signaling, confirming and building upon previous findings that the receptor engages Gi/o/z and G12/13 proteins in addition to its primary Gq/11 pathway, and that it preferentially recruits β-arrestin2 over β-arrestin1. We also show that increased RNA editing of the receptor attenuates signaling across all G protein pathways, particularly for G12/13, while preserving β-arrestin recruitment. Profiling of both 5-HT 2C -selective and psychedelic ligands reveals diverse signaling profiles, with serotonergic psychedelics such as LSD and psilocin exhibiting a striking Gq/11 bias due to minimal secondary G protein activation. Altogether, this work provides a foundation for incorporating a broader view of 5-HT 2C signaling modalities into future investigations of 5-HT 2C drug development efforts.
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
Cites 17
- 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
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology November 8, 2017
- Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial Psychological Medicine June 15, 2018
- Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years Therapeutic Advances in Psychopharmacology March 18, 2016
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