Researchers from the University of Michigan (UM) have found that a single dose of the psychedelic compound 25CN-NBOH significantly enhanced cognitive flexibility in mice for up to three weeks after administration. The findings, published in Psychedelics, suggest that this and other psychedelics may be used to promote long-lasting improvements in brain function, with potential therapeutic implications for conditions including depression, PTSD, and neurodegenerative diseases such as Alzheimer’s disease (AD).
“What makes this discovery particularly significant is the sustained duration of cognitive benefits following just one psychedelic dose,” said senior author Omar J. Ahmed, PhD, an assistant professor in the University of Michigan’s Department of Psychology. “We observed enhanced learning adaptability that persisted for weeks, suggesting these compounds may induce lasting and behaviorally meaningful neuroplasticity changes in the prefrontal cortex.”
The compound tested, 25CN-NBOH, is a selective serotonin 2A (5-HT2A) receptor agonist known for its high affinity and specificity for this receptor subtype. The 5-HT2A receptor is widely considered central to the neurological effects of psychedelics and has previously been implicated in promoting synaptogenesis and structural remodeling in the prefrontal cortex (PFC). In this study, researchers evaluated its behavioral effects on flexible learning, a cognitive function regulated by the PFC.
Cognitive flexibility is the capacity to adapt to changing rules and environments. Its function is often impaired in psychiatric and neurological disorders. For their research, the investigators used a novel automated reversal learning task to measure how well mice could adjust to changes in learned rules. Mice were administered either a single dose of 25CN-NBOH or a saline control. After a two-week delay, both male and female mice that received the psychedelic showed significantly greater adaptability in the reversal phase of the task, as measured by poke efficiency, accuracy of trials, and number of rewards earned.
“The most striking aspect of our findings is that these cognitive benefits were measured 15–20 days after a single psychedelic administration,” said first author Elizabeth J. Brouns, a research assistant at UM. “This suggests that a single dose of a psychedelic isn’t just temporarily altering perception but potentially inducing lasting beneficial changes in brain function.”
The long-term cognitive effects of psychedelics are particularly relevant for clinical applications. Impairments in cognitive flexibility are core features of numerous psychiatric and neurodegenerative conditions, and current treatments often fail to address this dimension.
The new findings build on the Ahmed lab’s prior research into changes in prefrontal cortical plasticity. The investigators noted that this study is among the first to link those changes to long-lasting improvements in observed behavior. The team emphasized that their paradigm was designed to isolate longer-term effects of the psychedelic by administering it two weeks before testing began, avoiding confounding from acute psychoactive impacts.
“This study contrasts with previous preclinical psychedelic reversal learning studies in terms of drug administration timepoints,” the researchers wrote. “Our study focuses on the longer-term therapeutic effects of the psychedelic drug. It is important to distinguish such longer-term effects from immediate or short-lasting acute effects, that may be more related to the mind-altering impact of psychedelics and not to their longer-term therapeutic effects.”
By including both male and female mice and analyzing performance across an entire estrous cycle, the study also offers additional insight into potential sex-independent applications of psychedelic therapy. In addition, the team’s use of an automated sequential learning task enabled a high-throughput, repeatable assessment of reversal learning, which could be used to support the research and screening of other psychoactive compounds or dosing regimens.
Future research from the team will examine the effects of other psychedelic compounds, varying dosing regimens, and performance across different age groups or disease models. “A key question is what happens with two, three, or even twenty doses taken over several months,” said Ahmed. “Is every additional dose increasingly beneficial for flexible learning, or is there a plateau effect or even a negative effect of too many doses?”
