Unlocking the Brain’s Learning Potential: Psychedelic Drugs and Critical Periods

Researchers at Johns Hopkins Medicine have made a groundbreaking discovery, revealing that psychedelic drugs have the remarkable ability to reopen “critical periods” in the brain. These critical periods are phases during brain development when mammals are highly receptive to environmental stimuli, enabling significant learning and adaptation. Published in the journal Nature on June 16, the study sheds light on the diverse effects of psychedelic substances and their potential applications in treating conditions such as stroke and deafness. Moreover, the research offers valuable insights into the molecular mechanisms influenced by these drugs.

For years, neuroscientists have sought ways to reopen critical periods, as they play a crucial role in availing mammals to environmental cues that shape brain development. The team at Johns Hopkins Medicine conducted a study in mice, revealing that psychedelic drugs share a common ability to reopen critical periods, albeit with varying durations. A single dose of these drugs can extend the critical period from two days to as long as four weeks.

The findings have profound implications, not only for understanding the workings of psychedelic drugs but also for expanding their potential therapeutic applications. While current studies focus on conditions like depression, addiction, and post-traumatic stress disorder, the researchers suggest that psychedelic drugs could be utilized in the treatment of a wider range of ailments, including stroke and deafness. The study also provides new insights into the molecular mechanisms affected by psychedelics.

Critical periods are known to facilitate various functions, such as birds learning to sing and humans acquiring new languages. Additionally, they aid in the relearning of motor skills after a stroke and establish the dominance of one eye over the other.

Dr. Gül Dölen, an associate professor of neuroscience at the Johns Hopkins University School of Medicine, explains, “There is a window of time when the mammalian brain is far more susceptible and open to learning from the environment. This window will close at some point, and then, the brain becomes much less open to new learning.”

Drawing on their expertise in studying social behavior, Dr. Dölen’s team focused on how psychedelic drugs reopen critical periods. In a previous study in 2019, they discovered that MDMA, a psychedelic drug associated with feelings of love and sociability, could open critical periods in mice. However, in the recent study, the researchers were surprised to find that other psychedelic drugs without prosocial properties also had the ability to reopen critical periods.

To explore this further, the research team investigated the reopening potential of five psychedelic drugs: ibogaine, ketamine, LSD, MDMA, and psilocybin. These substances, known for altering perceptions and fostering self-discovery, were tested on adult male mice using a well-established behavioral test. The mice were trained to associate a particular environment with social interaction or solitude. By observing the time spent in each environment after administering the psychedelic drug, the researchers could determine if the critical period had reopened, allowing the mice to learn the value of a social environment—a behavior typically acquired during their juvenile stage.

The results demonstrated that ketamine extended the critical period for social reward learning in mice for 48 hours, while psilocybin maintained an open state for two weeks. For mice administered MDMA, LSD, and ibogaine, the critical period remained open for two, three, and four weeks, respectively. Interestingly, the duration of the critical period appeared to correspond with the reported acute effects of each psychedelic drug among human users.

Dr. Dölen explains, “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.” She suggests that the open state of the critical period could be viewed as an opportunity for post-treatment integration, providing a period for healing and learning, similar to the recovery phase following open-heart surgery.

In addition to investigating the duration of critical periods, the researchers explored the impact of psychedelic drugs on molecular mechanisms. They examined the role of serotonin receptors in opening critical periods using mouse brain cells. The study revealed that while LSD and psilocybin utilized serotonin receptors, MDMA, ibogaine, and ketamine did not.

To delve deeper into molecular mechanisms, the research team turned their attention to ribonucleic acid (RNA), which indicates gene expression in cells and provides insight into protein production. They found differences in the expression of 65 protein-producing genes during and after the critical period was reopened. Notably, approximately 20% of these genes regulate proteins involved in maintaining or repairing the extracellular matrix—a supportive structure surrounding brain cells located in the nucleus accumbens, an area associated with social learning behaviors related to rewards.

The study received funding from various sources, including the Klingenstein-Simons Foundation, the Kavli Neuroscience Discovery Institute Distinguished Postdoctoral Fellowship, the Johns Hopkins Provost’s Postdoctoral Fellowship Program, and the National Institutes of Health (R01MH117127, R01HD098184, R01AG066768, R01AG072305, K99NS122085). The research involved the collaboration of multiple individuals from Johns Hopkins, including Romain Nardou, Edward Sawyer, Young Jun Song, Makenzie Wilkinson, Yasmin Padovan-Hernandez, Júnia Lara de Deus, Noelle Wright, Carine Lama, Sehr Faltin, Loyal Goff, and Genevieve Stein-O’Brien.

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More about psychedelic drugs

• Nature: Tripping Through Time: How Psychedelic Drugs Reopen the Brain’s Learning Window
• Johns Hopkins Medicine: Tripping Through Time: How Psychedelic Drugs Reopen the Brain’s Learning Window
• Johns Hopkins University School of Medicine: Psychedelic Drugs Reopen “Critical Periods” in Brain, Says Study