An artist's depiction of the brain on psychedelics. (Bruce Rolff/Shutterstock)
In a nutshell
- One dose of a psychedelic compound (25CN-NBOH) significantly improved cognitive flexibility in mice, even 2 to 3 weeks after the drug was administered.
- Treated mice adapted better to new learning rules in a reversal task, showing stronger performance across multiple behavioral measures compared to controls.
- These long-lasting effects suggest psychedelics may promote meaningful, enduring changes in brain plasticity, offering potential new approaches for treating conditions like depression, PTSD, and Alzheimer’s disease.
ANN ARBOR, Mich. — A single dose of a psychedelic compound could be key to helping your brain become more adaptable for weeks. University of Michigan researchers have discovered that mice given just one dose of a serotonin-activating psychedelic showed remarkable improvements in mental flexibility two to three weeks later, potentially revolutionizing how we might someday treat conditions like depression, PTSD, and even Alzheimer’s disease.
The research, published in the journal Psychedelics, reveals that mice given just one dose of a specific psychedelic compound called 25CN-NBOH were much better at adjusting to new rules in learning tests compared to those that didn’t when tested 2-3 weeks later.
For anyone who’s ever struggled to break a habit or adapt to new circumstances, this finding could point toward future treatments for conditions marked by cognitive rigidity, like depression, PTSD, and potentially even Alzheimer’s disease.
How Psychedelics Change the Brain Long After Use
The study builds on previous research showing psychedelics can trigger structural changes in the prefrontal cortex, the brain region responsible for high-level cognitive functions like decision-making and behavioral flexibility. This new research, however, demonstrates actual behavioral benefits persisting long after the mind-altering effects of the drug have worn off.
To test cognitive flexibility, researchers used a specialized device that dispensed food pellets when mice correctly followed a sequence of nose pokes. First, the mice learned to poke a left hole, followed by a right hole, to receive a reward. After six days of practice, researchers reversed the pattern, now requiring mice to poke right first, then left.
This reversal task mimics the kind of adaptation humans need when circumstances change in life. The mice given 25CN-NBOH 15-20 days earlier performed significantly better at adapting to the new rule than those given a saline solution.
Mental Flexibility After Psychedelic Treatment
Researchers used multiple metrics to measure results: “poke efficiency” (the proportion of food pellets dispensed relative to total pokes), percentage of correct trials, and total rewards earned. Across all metrics, the psychedelic-treated mice outperformed the control group during the reversal phase.
These cognitive benefits appeared in both male and female mice, suggesting the effect isn’t sex-dependent, a crucial consideration for potential use in human trials.
The researchers were careful to distinguish these long-term benefits from the immediate, mind-altering effects typically associated with psychedelics. Their experiment specifically examined effects 2-3 weeks after a single dose, well after any acute drug effects had disappeared.
This timing is key, as previous studies examining the acute effects of psychedelics on cognitive tasks have shown mixed or even negative results. When tested immediately after administration, some psychedelics can temporarily impair cognitive functions. But this new research suggests the lasting neuroplastic changes triggered by psychedelics may produce beneficial cognitive effects that emerge only after the drug has cleared the system.
Potential Human Therapies
These results align with emerging human research suggesting psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder. However, the researchers note that human studies to date have used repeated measurements with the same participants, making it difficult to separate drug effects from increased familiarity with the tasks.
The psychedelic used in the study, called 25CN-NBOH, is specially designed to target one brain receptor—known as the serotonin 2A receptor—that’s believed to play a key role in how psychedelics affect brain plasticity. It binds to this receptor 50 to 100 times more strongly than to similar ones, making it a powerful tool for studying how these drugs work in the brain.
Cognitive flexibility deficits appear in numerous disorders, including depression, PTSD, and neurodegenerative conditions like Alzheimer’s disease. Current treatments for these conditions often fall short in addressing cognitive symptoms.
Beyond the Trip: Lasting Brain Benefits
If these findings translate to humans, it could mean that a single dose of a psychedelic compound might help people become more adaptable and less cognitively rigid for weeks afterward, potentially opening new avenues for treating conditions characterized by inflexible thinking.
Psychedelics could potentially be used for long-term cognitive benefits, well beyond their effects during a trip. The ability to enhance the brain’s adaptability with a single dose of medication could totally change treatment approaches for several brain conditions that lack effective treatment paths.
Paper Summary
Methodology
Researchers administered either 25CN-NBOH (a selective serotonin 2A receptor agonist) or saline to adult male and female mice through intraperitoneal injection. After a waiting period of one day and light food restriction for two days, mice underwent five days of training with a feeding device. For the actual experiment, mice first learned a “forward” sequence (left poke followed by right poke within 30 seconds to receive a food reward) over six days of 4-hour sessions. Then researchers reversed the rule, requiring mice to poke right first, then left, for another six days. The experiment measured three key metrics: poke efficiency (pellets dispensed relative to total pokes), percentage of correct trials, and cumulative reward pellets earned. Researchers analyzed performance during both the forward learning phase (9-15 days after drug administration) and reversal phase (15-21 days after administration).
Results
Both groups of mice learned the initial forward task at similar rates, with no significant differences in poke efficiency or percentage of correct trials. However, the 25CN-NBOH-treated mice obtained more total reward pellets during this phase. During the reversal phase (15-20 days after injection), the psychedelic-treated mice showed significantly better adaptation to the new rule. They demonstrated higher poke efficiency, higher percentages of correct trials, and earned more reward pellets compared to saline controls. These improvements occurred in both male and female mice, though male mice generally performed slightly better in both treatment groups. Statistical analysis confirmed these findings were robust and significant.
Limitations
The study only examined one specific psychedelic compound and one dosage level. The researchers note that future studies should investigate different psychedelics, doses, and administration schedules. While the task measured cognitive flexibility in mice, it remains unknown whether the effects would translate to humans or to other types of cognitive flexibility beyond reversal learning. The study did not use knockout mice lacking serotonin 2A receptors, which would have further clarified the specific receptor mechanisms involved. Additionally, the researchers note that estrous cycle can influence cognitive flexibility in female rodents, though their experimental design encompassed multiple cycles.
Funding and Disclosures
The research was supported by several National Institutes of Health grants (R01MH129282, P50NS123067, T32DA007268) and the University of Michigan Eisenberg Family Depression Center Eisenberg Scholar Award. The authors declared no competing financial interests in the study.
Publication Information
The study titled “Single-dose psychedelic enhances cognitive flexibility and reversal learning in mice weeks after administration” was authored by Elizabeth J. Brouns, Tyler G. Ekins, and Omar J. Ahmed from the University of Michigan. It was published in the journal Psychedelics on April 22, 2025.
And who paid for this research? Another simple way to get the masses to dumb down and controllable. Just like the pushing of Marijuana- which is now proving to be horrible for you.
I am a medical anthropologist researcher and author, and I study the human brain. Giving mind-altering substances to mice is animal cruelty, and tells us nothing about humans except that they can be cruel to animals.
Poor mice! First, they get a needle in the abdomen to inject the drug, which makes them “trip”. My guess is that a human would have a “bad trip” after receiving a needle to the abdomen. Of course, it’s hard to get into the minds of mice to know what they are thinking and feeling, which is why it’s also hard to interpret the new learning plasticity under the influence of this drug. Were they also more anxious? Were they more hyper? Were they hungrier, making them work harder to get the food pellets? What else was going on in their heads after being dosed with hallucinogen and then being forced to learn how to poke their noses to get a reward? How long did the trip last, especially given the weeks-long impact of the injection? Was the increased reward of pellets a result of better cognitive plasticity, or a result of the munchies and compulsive behavior, in which case these mice would theoretically gain weight under the drug and be hard to live with for other mice.
The title of this article ignores the species-specific nature of this cruel experiment. “Single Psychedelic Dose Shows Cognitive Boost Lasting Week” should end with “in Mice”. And it is not cognitive boost that is seen; the changed behavior could have been the result of pathological behavior caused by the hallucinogen.
This study illustrates the importance of ending animal research. See my article, Of Mice and Men: The Problem with Studying Mice to Learn about Men. https://www.academia.edu/127948044/Of_Mice_and_Men_The_Problems_with_Studying_Mice_to_Learn_about_Men
Animal research is cruel, evil, and barbaric. Animals should have the right to live in peace on this earth, but because they lack a voice to speak up for themselves they are subjected to pure torture. It’s heartbreaking.