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Single-dose psychedelic enhances cognitive flexibility and reversal learning in mice weeks after administration.

Elizabeth J. Brouns, Tyler G. Ekins, Omar J. Ahmed

Psychedelics April 22, 2025 DOI: 10.61373/pp025r.0002 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Preclinical experiment Peer reviewed
Population Male and female mice
Intervention 25CN-NBOH
Duration 2-3 weeks posttreatment
Topics Neuroplasticity Psychedelic-assisted therapy
Keywords Cognitive flexibility Reversal learning Serotonin 2a receptor
Key findings A single administration of 25CN-NBOH produces significant, long-lasting improvements in cognitive flexibility in mice 2-3 weeks posttreatment.

Abstract

Psychedelic compounds have demonstrated remarkable therapeutic potential for treating neuropsychiatric disorders by promoting sustained neuroplasticity in the prefrontal cortex (PFC). Cognitive flexibility-the ability to adapt previously learned rules to novel situations-represents a critical PFC function that is frequently impaired in depression, PTSD, and neurodegenerative conditions. In this study, we demonstrate that a single administration of the selective serotonin 2A receptor agonist 25CN-NBOH produces significant, long-lasting improvements in cognitive flexibility in both male and female mice when measured 2-3 weeks posttreatment. Using a novel automated sequential learning paradigm, psychedelic-treated mice showed superior adaptability in rule reversal tasks compared to saline controls, as evidenced by enhanced poke efficiency, higher percentages of correct trials, and increased reward acquisition. These behavioral findings complement existing cellular research showing psychedelic-induced structural remodeling in the PFC and uniquely demonstrate sustained cognitive benefits persisting weeks after a single psychedelic dose. Our automated behavioral task provides a high-throughput method for evaluating cognitive flexibility effects of various psychedelic compounds, offering important implications for therapeutic applications in conditions characterized by cognitive rigidity, including depression, PTSD, and potentially Alzheimer's disease.

Comparable studies

Other preclinical and animal studies on neuroplasticity, most cited first.

Study Year Design Participants
Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models 2023 Experimental study
Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Mice 2023 Experimental study
Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice 2013 Experimental study
The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains 2017 In vitro experimental study
N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice 2020 In vitro and in vivo experimental study

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Neuroplasticity Psychedelic-assisted therapy Depression PTSD Serotonin