Single-dose psychedelic boosts cognitive flexibility for weeks in “breakthrough” research

A single dose of a psychedelic compound can enhance cognitive flexibility for weeks after administration, according to new research from the University of Michigan, US. The team notes that their “groundbreaking” research could potentially revolutionize treatments for depression, post-traumatic stress disorder, and neurodegenerative diseases.

Mice treated with one dose of 25CN-NBOH, a selective serotonin 2A receptor agonist, showed significantly improved performance in reversal learning tasks two to three weeks after treatment compared to control groups. This is a standard test for cognitive flexibility — adapting previously learned rules to new situations. 

“What makes this discovery particularly significant is the sustained duration of cognitive benefits following just one psychedelic dose,” explains professor Omar J. Ahmed, the study’s senior author from 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.”

Reversal learning tasks

For the study, published in Psychedelics, researchers injected female and male mice with a single dose of 25CN-NBOH or saline (control group). After a one-day waiting period, the researchers reduced the mice’s food intake by two days and trained them to use a feeding experimentation device for five days. 

Afterward, the team used a forward sequence learning protocol, where mice learned to obtain food from the device for six days. The researchers reversed the task order for the mice to get food for another six days. 

The researchers explain that this reversal of the experimental protocol indicates flexible learning, measuring the degree to which a mouse can adapt a previously learned sequence to a reversed direction. 

The mice treated with psychedelics were better able to adapt to this new order. They demonstrated enhanced task efficiency, a higher percentage of correct trials, and increased reward acquisition during the reversal phase. Both male and female mice showed significant improvements. 

Sustained cognitive benefits

The authors say that their findings complement existing cellular research showing psychedelic-induced structural remodeling in the brain’s prefrontal cortex. However, their study focused on longer-term therapeutic effects — mice were injected with psychedelic or saline control 15 days before the start of the reversal protocol. 

The researchers recommend additional research to determine if psychedelics can boost cognitive flexibility in people with Alzheimer’s disease.“The most striking aspect of our findings is that these cognitive benefits were measured 15–20 days after a single psychedelic administration,” says Elizabeth J. Brouns, first author of the study. “This suggests that a single dose of a psychedelic isn’t just temporarily altering perception but potentially inducing lasting beneficial changes in brain function.”

According to the researchers, this longer-term enhancement of cognitive flexibility allows for many further directions of research. For example, future studies will examine psychedelics’ effects on mice across ages and determine the impact of different drugs, dose levels, number of doses, or timing. 

“The current study focused on the long-term effects of a single psychedelic dose. A key question is what happens with two, three, or even twenty doses taken over several months,” adds Ahmed. 

“Is every additional dose increasingly beneficial for flexible learning, or is there a plateau effect or a negative effect of too many doses? These are important questions to answer next in the quest to make psychedelic medicine more rational and mechanistic.” 

Human implications

Research continues to explore psychedelics and their impact on mental health and symptoms of depression. For example, researchers note that psilocybin, a compound of “magic” mushrooms, is a more effective treatment for symptoms of depression, although more research is needed. 

There is growing support for using psychedelics for mental health benefits. A 2024 online survey found that 79% of Canadians support using psilocybin for patients at end-of-life. As the use of psilocybin and other psychedelics grows in the US, researchers caution there was a substantial increase in poison center calls — growing 201% among adults and 723% in children between 2019 and 2023. 

The authors of the 25CN-NBOH study note that long-term positive psychedelic-induced cognitive flexibility enhancement may benefit human psychedelic medicine. For example, they say this process is impaired in many disorders, such as depression, post-traumatic stress disorder, and Alzheimer’s disease. 

They highlight that psychedelics have not yet been used to try to treat Alzheimer’s disease and related neurodegenerative diseases. They recommend additional research to demonstrate that psychedelics can boost flexibility in this disease and long-term synaptic activity in brain regions related to cognitive flexibility.