Pathway-selective signaling of serotonergic psychedelics at 5-HT receptors: Implications for psychoactivity, safety, and therapeutic potential
Deborah Rudin, Jan Valenta, Helene Rolli, Matthias E. Liechti, Dino Luethi
European Neuropsychopharmacology April 10, 2026 DOI: 10.1016/j.euroneuro.2026.112835 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro pharmacological study Peer reviewed |
|---|---|
| Population | Stable cell lines expressing 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT1A receptors |
| Topics | Serotonin |
| Keywords | Signal transduction Phospholipase c 5-HT Receptor Pharmacology Intracellular Drugs of abuse |
| Citations | 2 |
| Key points | IP1 formation via PLC activation offers the most robust measure of 5-HT2 receptor activation and correlates strongly with known psychoactive doses of serotonergic psychedelics. |
Abstract
Serotonergic psychedelics primarily exert their effects through activation of the serotonin (5-HT) 2A receptor (5-HT 2A R). However, the full pharmacological profiles of these substances involve multiple serotonin receptor subtypes and intracellular signaling pathways. This study characterized the signaling behavior of a panel of serotonergic psychedelics using stable cell lines and a series of bioassays targeting phospholipase C (PLC) activation via inositol monophosphate (IP1) formation, phospholipase A 2 (PLA 2 ) activation, β-arrestin2 recruitment, and Gα i -protein dissociation across 5-HT 2A , 5-HT 2B , 5-HT 2C , and 5-HT 1A receptors. The results of the study indicate that IP1 formation offers the most robust and reproducible measure of 5-HT 2 R receptor activation and aligns most closely with human dosing data. Particularly for the 5-HT 2A R, PLC-IP1 activation exhibited a strong correlation with known psychoactive doses, contrasting with assays that relied on Ca²⁺ release. The majority of psychedelics exhibited a signaling bias toward the PLC-IP1 or the PLA 2 -AA pathway at the 5-HT₂ A R. The 5-HT 2A /5-HT 1A activation ratio may provide information about seizure risk and therapeutic potential. Furthermore, the low activation efficacy at the 5-HT₂ B R potentially suggests reduced cardiac risk with intermittent use, and the strong activation of the 5-HT₂ C R is in accordance with the reported low abuse potential of serotonergic psychedelics. This study underscores the importance of pathway-specific profiling in understanding the pharmacology of serotonergic psychedelics. It provides a framework for predicting efficacy and adverse effect potential and lays the groundwork for the rational design of next-generation psychedelics with improved safety and efficacy.
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
Cited by 3
- Preclinical Comparison of DMT and 5-MeO-DMT Reveals Behavioral Dissociation, Distinct TrkB Activation and Differential Plasticity Profiles bioRxiv (Cold Spring Harbor Laboratory) August 12, 2026
- Blocking 5-HT2B receptors abolishes psilocybin’s efficacy in the rat forced swim test Journal of Psychopharmacology June 23, 2026
- Mapping excitatory synaptic plasticity evoked by single-dose psilocybin in mice
Cites 51
- Structural Features for Functional Selectivity at Serotonin Receptors Science March 21, 2013
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
- Crystal structure of an LSD-bound human serotonin receptor Cell January 26, 2017
- Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology May 20, 2016
and 46 more in the library