Investigation of the pharmacological and circuit basis for psychedelic drug effects on interval timing in mice.
Landon M. Klein, Jared M. Kopelman, Richard F Sharp, Susan B Powell, Mark A. Geyer, Jared W Young, Adam L. Halberstadt
Psychopharmacology October 19, 2026 DOI: 10.1007/s00213-026-07181-x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Male C57BL/6J mice |
| Interventions | Psilocin DOI M100907 WAY-100 635 MDL 11 939 |
| Dose | 0.8 mg/kg SC (psilocin) |
| Measures | discrete-trials temporal discrimination task (TDT) |
| Topics | Psilocybin |
| Keywords | 5-ht2a Hallucinogen Mice Prefrontal Psychedelic Timing |
| Key findings | Psilocin (0.8 mg/kg SC) altered timing accuracy and precision in the discrete-trials temporal discrimination task, an effect blocked by the 5-HT2A antagonist M100907 but not by the 5-HT1A antagonist WAY-100,635. Bilateral microinfusion of DOI into the medial prefrontal cortex mimicked systemic DOI effects, and the 5-HT2A inverse agonists M100907 and MDL 11,939 also altered timing accuracy, suggesting both increases and reductions in 5-HT2A activation can modulate perceived clock speed. |
Abstract
Classical psychedelic drugs such as the tryptamine psilocybin can alter temporal perception. Previously, the phenylethylamine psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI), a 5-HT2A receptor agonist, altered timing precision and accuracy in mice performing the discrete-trials temporal discrimination task (TDT), a retrospective timing task where subjects differentially respond depending on whether a light is illuminated for shorter or longer than 6.5 s. Although DOI alters TDT performance, it is unclear whether timing is altered by tryptamine psychedelics, which are less selective for 5-HT2 subtypes and also activate the 5-HT1A receptor. To address this knowledge gap, we tested psilocin (the active metabolite of psilocybin) in male C57BL/6J mice performing the TDT and assessed the involvement of 5-HT1A and 5-HT2A receptors in its effects. Because the prefrontal cortex (PFC) is involved in psychedelic drug effects and temporal perception, additional experiments tested whether DOI microinfusion into the medial PFC (mPFC) replicates its systemic effects. Psilocin (0.8 mg/kg SC) altered timing accuracy and precision in mice performing the TDT, similarly to DOI. Psilocin effects were blocked by the 5-HT2A antagonist M100907 but were unaffected by the 5-HT1A antagonist WAY-100,635. Infusion of DOI bilaterally into mPFC mimicked the effect of systemic administration on TDT performance. Administration of the selective 5-HT2A inverse agonists M100907 and MDL 11,939 altered timing accuracy, demonstrating that both increases and reductions in 5-HT2A receptor activation can modulate perceived clock speed. The mPFC appears to play a role in TDT performance and may mediate the effects of psychedelic drugs on interval timing.
Comparable studies
Other preclinical and animal studies on psilocybin, 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 | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cites 40
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences April 11, 2016
- Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology May 20, 2016
- Control of Serotonergic Function in Medial Prefrontal Cortex by Serotonin-2A Receptors through a Glutamate-Dependent Mechanism Journal of Neuroscience December 15, 2001
and 35 more in the library