Compound increases cognitive flexibility, creates favorable conditions for therapeutic interventions.

New research in a rodent model at OHSU shows that some positive effects of psilocybin, a naturally occurring compound found in “magic mushrooms,” may take effect immediately. Researchers say the findings bolster the case for people using psilocybin in conjunction with clinical treatment for conditions like depression and post-traumatic stress disorder.

Cognitive inflexibility is a hallmark of many psychiatric disorders, including major depressive disorder.

A team led by Bita Moghaddam, Ph.D., Ruth Matarazzo Professor of Behavioral Neuroscience, examined the effect of psilocybin on cognitive flexibility in rats by measuring animals’ ability to switch between previously learned strategies. They observed that psilocybin enhances cognitive flexibility. This finding suggests that the combination of psilocybin and clinician intervention, such as psychotherapy, may be effective in treating symptoms of mental illness because of the drug’s impact on cognitive flexibility.

The team observed that other psychedelics didn’t have the same effects as psilocybin.

Until now, the leading hypothesis had been that psilocybin works by causing changes to synapses and brain circuits in the days and weeks following its administration. The OHSU team found changes to brain function while rats were under the immediate influence of psilocybin. This new research suggests that psilocybin’s therapeutic effect may be in large part due to its immediate effects, which may influence timing regarding therapeutic approaches to using psilocybin in treating psychiatric conditions.

The study, published in February 2023 in the journal Neuropsychopharmacology, suggests that psilocybin may be particularly effective in treating depression not as a standalone pharmacological treatment, but rather in combination with clinical intervention. The team observed, however, that other psychedelics didn’t have the same effects as psilocybin. They are currently conducting further investigations into the differences between psilocybin and other psychedelics to better understand what makes psilocybin so special.”

Psilocybin as a therapy aid

“With the attention that psychedelics have received, it is important to note that a key component of psychedelic-assisted therapy is the controlled clinical environment in which it takes place,” said Alejandro Torrado Pacheco, Ph.D., postdoctoral scholar in the Moghaddam lab and first author of the paper. “Psilocybin can be seen as a therapy aid that makes patients more capable of responding positively to clinical intervention by improving their ability to venture outside of established thought patterns and views of themselves or the world.”

The research team sees this study as providing signposts for future research, both on its immediate pharmacological action as well as its longer-term effects.

“The work raises the possibility that by improving cognitive flexibility, psilocybin is actively combating cognitive deficits that are associated with poorer mental health, said Moghaddam.  “It provides a novel preclinical model to study its therapeutic potential.”

Studies in rodents can only reveal so much about human health and physiology, but the findings suggest that the effects of psilocybin on cognition, along with the timing of acute psilocybin, may be a key element in its beneficial action.

The research reported here was supported by the National Institute of Mental Health of the National Institutes of Health under award numbers  R01MH115027 and R01MH048404. Torrado Pacheco was supported by National Institute of Drug Abuse of the National Institutes of Health under award number T32DA007262. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

All research involving animal subjects at OHSU must be reviewed and approved by the university’s Institutional Animal Care and Use Committee (IACUC). The IACUC’s priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. The IACUC conducts a rigorous review of all animal research proposals to ensure they demonstrate scientific value and justify the use of live animals.