Multiple Psychedelic Drugs Can Reopen the Critical Period for Socializing in Mice

During development, our brains go through periods of sensitivity, where adaptation and change in response to our environment are easier to achieve. These “critical periods” help the developing brain learn how to socialize, perform particular tasks and even establish which of our eyes becomes dominant in our vision.

But mental health disorders are thought to be characterized by periods of ruminative and inflexible thinking, patterns that form deep cognitive chasms. Could we re-open these critical periods to allow seismic changes in the “stuck” brain’s landscape, and help those struggling with psychiatric problems to escape these mental fissures?

Party drugs and critical periods

The Dölen lab at Johns Hopkins University investigates whether psychedelic drugs could be critical to that effort. A new study conducted at the lab in mice suggests that multiple psychedelic drugs are capable of reopening critical periods for durations stretching from just a couple of days through to a full month.

The findings, published in journal Nature, provide a novel way of thinking about how psychedelic drugs alter the brain, say the authors. They suggest that the broad range of critical periods – which exist not just for socialization and thinking but for our movement and senses – could make it possible for drugs that reopen these periods to treat non-psychiatric conditions and disabilities such as stroke and deafness.

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

This isn’t the team’s first foray into the social critical learning period. A 2019 study from the lab showed that the often-used party drug, MDMA – which has achieved recreational popularity due to the feelings of warmth and empathy it produces in users – can open a social critical period in mice. They have additionally shown that the molecular mechanism that reopens these critical periods is evolutionarily ancient. MDMA even puts octopuses – which diverged from other animals 270 million years ago – in the mood for socializing.

The new study’s findings have surprised the team, showing that even drugs like ketamine – not renowned for making recreational users into logorrheic motormouths – can reopen social periods.

Making mice more social

Dölen and colleagues looked at the reopening potential of five psychedelics – ibogaine, LSD, MDMA, psilocybin and ketamine. Dosing mice with the drugs, the researchers tested the compounds’ ability to reopen critical periods using a classic behavioral test where adult male mice were taught to link certain environments to either being alone or socializing. The researchers measured how much time the rodents spent in the two settings before and after drug administration.

The results, say the authors, suggest that the social learning window reopens for 48 hours in mice given ketamine. After psilocybin, the reopening period extends to two weeks. The figure for MDMA, LSD and ibogaine is two, three and four weeks respectively.

These lengths of time appear to parallel the average period that people report effects from the drugs lasting, say the authors.

“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,” says Dölen.

She adds, “The open state of the critical period may be an opportunity for a post-treatment integration period to maintain the learning state.” Post-treatment integration is usually a session of talk therapy that is incorporated into the protocol of many psychedelic studies.

“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.”

Reading genes key to social mechanisms

The researchers also took a deep dive into how psychedelic drugs impact molecular mechanisms. In mouse brain cells, the team looked at regions of brain cells where psychedelic drugs bind, called receptors. The results suggested that docking points, which also act as receptors for the neurotransmitter serotonin, are key to how LSD and psilocybin reopen critical periods, but not for MDMA, ketamine and ibogaine.

The exact mechanisms that these drugs use to reopen critical learning periods still needs to be decoded, but the researchers noted that expression – a process by which DNA data is converted to another molecule, RNA, for later translation into the proteins that makes up our cells – was altered among 65 genes before and after critical period reopening. Roughly a fifth of those genes were linked to a kind of cellular scaffolding called the extracellular matrix. The researchers suggest that changes to this scaffolding induced by psychedelic gene expression may make it easier for the brain to reorganize. This, they suggest, could be the molecular basis of critical period reopening.

Reference: Nardou R, Sawyer E, Song YJ, et al. Psychedelics reopen the social reward learning critical period. Nature. 2023:1-9. doi: 10.1038/s41586-023-06204-3

This article is a rework of a press release issued by Johns Hopkins University. Material has been edited for length and content.