Single psychedelic dose boosts long-term cognitive flexibility in mice

This kind of cognitive flexibility is impaired in many psychiatric and neurological conditions.

“Psychedelic compounds are being tested in ongoing clinical trials attempting to treat depression and PTSD,” said Omar Ahmed, U-M associate professor of psychology and senior author of the newly published study.

“These conditions, as well as Alzheimer’s disease, are often accompanied by decreased cognitive flexibility. We find that a single psychedelic dose can boost flexible learning over several weeks in mice, highlighting the ability of these compounds to induce long-lasting and functionally important changes to the brain.”

The team discovered that one dose of the psychedelic compound 25CN-NBOH helped mice think more flexibly and do better in behavioral tests even weeks after drug administration.

This research, which appeared in the journal Psychedelics, highlights why clinical trials of psychedelic drugs may benefit people living with depression or PTSD.

Clinical trial designs for depression use only one or two doses. Our results show, in mouse models, that even a single dose of a psychedelic can result in lasting benefits. We studied flexible learning up to three weeks after the single dose and saw improvements. The benefits may last even longer.”

Elizabeth Brouns, U-M psychology master’s student and study’s first author

The present study utilized rodent models, but the results are likely to translate well to humans.

“The mice nervous system is an excellent model system to understand how psychedelic drugs function. Neurons in the prefrontal cortex of mice, as well as of humans, express serotonin 2a receptors, which are the primary target of psychedelic drugs. These serotonin 2a receptors are also considered to be responsible for the therapeutic benefits of psychedelic treatments,” according to study co-author Tyler Ekins, U-M postdoctoral fellow in psychology.

The tests involved injecting mice with either the psychedelic compound or a control placebo injection. The mice were introduced to an automated training device called the FED3, which gave them food pellets as rewards for poking their noses into distinct holes in the correct sequence.

After the mice became proficient at remembering this sequence over several days, the rules of the task were suddenly reversed, requiring the mice to learn to now visit the holes in the opposite sequence. Both male and female mice treated with the psychedelic learned this new rule more quickly than mice given control injections, even three weeks after the psychedelic was first administered.

This automated task design, developed by the team, marks an advance in how scientists study flexible learning over long durations. Designed to streamline the evaluation of cognitive adaptability, this innovation opens the door to more efficient and precise research into the effects of psychedelic compounds on the brain, requiring only infrequent human intervention, the researchers noted.

Despite the findings, Ahmed cautions that many questions remain. Psychedelic medicine is still in its infancy but progressing quickly, he said.

“A lot of fundamental, basic science and translational research is needed to ensure that clinical trials utilize optimal versions and doses of psychedelic drugs,” Ahmed said.

For example, the current study focused on the long-term effects of a single psychedelic dose. One key question is what happens with two, three or even 20 doses taken over several months. Is every additional dose increasingly beneficial for flexible learning, or is there a plateau effect or even 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, he said.