New Insights into Mechanisms Behind Therapeutic Effects of Psychedelics

A recent study in mice suggests that psychedelic drugs have the common ability to reopen critical periods of social learning in the brain, bringing scientists one step closer to understanding how the drugs work. According to researchers, the findings also indicate that psychedelic drugs could potentially treat more conditions than previously thought, such as stroke and deafness.

Scientists define the brain’s “critical periods” as highly influential periods of brain development during which mammals are more sensitive to signals in their surroundings. Research suggests that critical periods help mammals perform new functions, like learning a new language or relearning motor skills after a stroke.

The study, published in the journal Nature, aimed to explain the mechanisms behind the shared therapeutic effects of psychedelics. To do so, a team of researchers led by Gül Dölen, MD, PhD, associate professor of neuroscience at the John Hopkins University School of Medicine, observed the impact of different psychedelic drugs on the brain cells and the behavior of mice.

Using a well-established behavioral test, scientists analyzed how adult male mice responded to five drugs, ketamine, LSD, MDMA, and psilocybin. The mice were trained to develop associations between an environment where they experienced social interactions and another environment where they were alone. Researchers then observed the differences in the mice's behavior in the two settings after they were given the drugs. Through their behaviors, scientists determined whether the critical period was opened in the mice, allowing them to learn the values of a social environment as a juvenile would at an older age.

The study showed that different drugs opened the mice's critical periods longer than others. For instance, results suggest that ketamine opened the critical period of mice for 48 hours, while the open state for psilocybin lasted for two weeks. Researchers said the length of the opened state roughly coincided with the average length of acute effects reported by humans for each drug.

“This relationship gives us another clue that the duration of psychedelic drugs’ acute effects may be the reason why each drug may have longer or shorter effects on opening the critical period,” said Dölen.

When researchers analyzed the drug’s impact on molecular mechanisms, they found that LSD and psilocybin used the serotonin receptor to open the critical period, while MDMA, ibogaine, and ketamine did not.

Researchers also studied ribonucleic acid to identify what genes were expressed in the mice’s cells before and after the critical period was opened. According to the study, there were 65 differences in the expressions of protein-producing genes, 20 percent of which were involved in maintaining or repairing the extracellular matrix, an area associated with social learning behaviors responsive to awards.

“The open state of the critical period may be an opportunity for a post-treatment integration period to maintain the learning state, “said Dölen. “Too often, after having a procedure or treatment, people go back to their chaotic, busy lives that can be overwhelming. Clinicians may want to consider the time period after a psychedelic drug dose as a time to heal and learn, much like we do for open heart surgery.”