In a remarkable leap forward for neuroscience and psychedelic research, scientists at the University of Michigan have unveiled evidence that a single administration of a psychedelic compound can elicit profound and durable enhancements in cognitive flexibility. Cognitive flexibility — the brain’s capacity to adjust behaviors and thoughts in response to shifting rules or environments — is crucial for healthy mental functioning and adaptive behavior. This discovery could signal a paradigm shift in the therapeutic potential of psychedelics, suggesting that their effects may extend far beyond the acute perceptual changes traditionally associated with these substances.
The study, published in the peer-reviewed journal Psychedelics, centers on the selective serotonin 2A receptor agonist 25CN-NBOH. This compound, a novel psychedelic, was administered once to experimental mice, and the animals’ cognitive flexibility was assessed using rigorous reversal learning tasks 15 to 20 days post-treatment. Remarkably, the treated mice displayed superior performance during these tasks compared to their control counterparts, highlighting sustained improvements in their ability to adapt and learn new rules after changing conditions.
Central to this research was the use of an automated sequential learning paradigm, which refined the precision and throughput of behavioral testing. This method involved requiring mice to perform a sequence of nose-poke responses within a 30-second window to earn a reward. Initially, mice had to poke left and then right to receive a pellet reward; however, during the reversal phase, the rule switched such that they had to poke right followed by left. The psychedelic-treated mice adapted to these reversals with significantly more efficiency, demonstrating elevated percentages of correct trials and an enhanced rate of reward acquisition.
Professor Omar J. Ahmed, senior author of the study and psychologist at the University of Michigan, highlights the significance of these findings: “Our data showed that the cognitive enhancements induced by a single psychedelic dose were not only substantial but remarkably persistent. The longevity of these effects suggests the psychedelic may instigate durable neuroplastic changes within the prefrontal cortex, a brain region integral to flexible cognitive control and complex decision-making.”
Neuroplasticity—the brain’s ability to remodel its structural and functional networks in response to experience—has long been a target of novel therapeutics for conditions characterized by rigid thinking patterns or diminished adaptability, such as depression, post-traumatic stress disorder, and neurodegenerative diseases. Previous cellular studies have documented that psychedelics can promote dendritic growth and synaptic remodeling, but this study is among the first to connect these molecular changes to lasting functional improvements in behavior.
One compelling question arising from this work pertains to the molecular underpinnings mediating the long-term cognitive benefits observed. Engagement of the serotonin 2A receptor by psychedelic molecules is known to trigger a cascade of intracellular signaling pathways involving brain-derived neurotrophic factor (BDNF), immediate early genes such as c-fos, and modulation of glutamatergic transmission. These mechanisms are believed to facilitate synaptic remodeling and the stabilization of new neural circuits, yet precisely how this translates into durable behavioral enhancements remains a rich area for further inquiry.
Moreover, this study raises provocative considerations about whether psychedelics could potentially reopen critical windows of plasticity in the adult brain. Such “critical period reopening” might enable more effective behavioral reprogramming and therapeutic interventions for psychiatric disorders that have traditionally been challenging to treat. The possibility of a pharmacologically induced “reset” of neural adaptability adds a conceptual dimension rarely seen in the pharmacotherapy of cognitive deficits.
Gender differences in response to psychedelics have often been a subject of scientific debate. The current findings show that improvements in cognitive flexibility were evident in both male and female mice, underscoring the broad utility of these compounds across sexes. This inclusive effect opens the door to more generalized therapeutic strategies, minimizing concerns regarding sex-specific variability in treatment outcomes.
Elizabeth J. Brouns, the study’s first author, emphasizes the transformative potential of these findings for clinical practice: “Our research indicates that a single dose of a psychedelic works not only in the short term by altering perception, but also induces enduring beneficial modifications in brain function. This suggests new avenues for dosing regimens that maximize therapeutic benefits while minimizing exposure and potential side effects.”
Methodologically, the use of an automated and high-throughput behavioral testing apparatus stands out as a substantial advancement for the field. This system permits a more objective, reproducible, and scalable assessment of cognitive flexibility and can be easily adapted to screen future psychedelic compounds or other neuroactive drugs. By reducing human intervention and bias, automated testing bolsters reproducibility and accelerates the pace of discovery.
Looking ahead, the researchers highlight several critical questions that must be addressed to leverage these findings for clinical application. Notably, how do multiple dosing schedules affect neuroplasticity and cognitive outcomes? Does the benefit plateau or potentially wane with repeated administration? Could there be threshold or tolerance effects that constrain long-term efficacy? Systematic investigations into these parameters will be crucial to designing optimized and mechanistically informed psychedelic treatment protocols.
The implications of this work extend beyond neuropsychiatry to the broader landscape of brain science. By illustrating how a single psychedelic dose can promote long-term cognitive enhancements and adaptive flexibility, the findings challenge prior assumptions regarding the temporal window of psychedelic action and encourage deeper exploration into the interaction between pharmacology and enduring neurocognitive remodeling.
Support for this study was provided by the National Institutes of Health and the University of Michigan Eisenberg Family Depression Center. The research team included co-author Dr. Tyler Ekins, alongside Professors Ahmed and Brouns. The full publication is accessible through the journal Psychedelics, which is dedicated to broad multidisciplinary investigations of consciousness-altering substances and their diverse biological, clinical, and societal implications.
As the resurgence of psychedelic science gathers momentum, these findings illuminate the tantalizing possibility that these compounds may possess the capacity to rewrite the rules of brain plasticity, offering hope for innovative treatments that target the core neurobiological substrates of mental health disorders. Continued interdisciplinary research combining behavioral neuroscience, cellular biology, and clinical science promises to unravel the complex neuropharmacology of psychedelics, ultimately translating groundbreaking basic science into tangible therapeutic advances.
Subject of Research: Animals
Article Title: Single-dose psychedelic enhances cognitive flexibility and reversal learning in mice weeks after administration
News Publication Date: 22-Apr-2025
Web References: http://dx.doi.org/10.61373/pp025r.0002
Image Credits: Dr. Omar J. Ahmed
Keywords: psychedelics, cognitive flexibility, 25CN-NBOH, reversal learning, neuroplasticity, serotonin 2A receptor, prefrontal cortex, behavioral neuroscience, psychedelic therapy, neuropsychiatry, automated behavioral testing, sex differences
