Psychedelics May Reopen Locked Learning Opportunities

A shared feature of psychedelics may be their ability to unlock temporary time spans of growth called “critical periods,” according to new research from Johns Hopkins University. 

A critical period is a window in development where an animal has their only chance to learn a behavior. For instance, within their first 48 hours of life, snow geese will learn to associate whatever object is in their immediate field of vision as their parent. Whether this is their true mother, a human, or a model airplane, once this window has passed, the association sticks for life.

The research, published last week in the journal Nature, showed that injecting LSD, MDMA, ibogaine, ketamine, or psilocybin into adult mice re-opened their youthful critical period for learning socially rewarding experiences after the immediate effect of the drug subsided. 

Acknowledging the potential differences between rodents and humans, the researchers found that how long the critical period remained open in mice was proportional to the duration of psychedelics’ effects in people – for days after with ketamine, and for weeks after with ibogaine. 

Researchers previously showed that MDMA could prompt the re-opening of critical periods. The new research reveals that this same action can also be initiated by ibogaine, ketamine, LSD, and psilocybin. 

Gül Dölen, a neuroscientist whose lab at the Center for Psychedelic and Consciousness Research at Johns Hopkins University conducted the current study as well as the previous MDMA research, suspects psychedelics “are the master key for unlocking lots of different critical periods.”

“There’s an adage you can’t teach an old dog new tricks,” she adds about the current study. “And when we gave psychedelics, what we found is that we can teach old mice new tricks.”

A Different Type of Plasticity

Plasticity is the ability for the nervous system to change. Researchers generally agree, however, that heightened plasticity does not adequately describe how psychedelics work. For instance, they note that drugs such as cocaine or fentanyl promote plasticity in the brain’s reward centers, which is part of their long-lasting addictive power.

The authors in this study use the term “metaplasticity,” or the plasticity of plasticity, to describe the effect of psychedelics in re-opening critical periods. The recent research published in Nature is among the first experiments to suggest, with multiple lines of evidence, that metaplasticity may be at the root of how psychedelics work.

Robin Carhart-Harris, the Ralph Metzner Distinguished Professor of Neurology, Psychiatry and Behavioral Sciences at the University of California San Francisco, wrote by email that while the team’s research methods are “sophisticated and impressive,” their inclusion of ketamine and ibogaine under the umbrella of the term ‘psychedelic’ may be inappropriate. He also agrees with the team that a different term than plasticity, such as metaplasticity, is warranted to describe their findings, but “whether this is strictly the right term to use can also be questioned.” Metaplasticity may be a redundant term to describe the critical period re-openings shown in this study, he argues.

This is not the only study, however, to describe metaplasticity as a potential key mechanism of psychedelics. Earlier this month, a study published in Nature Neuroscience suggests that LSD could create critical period-like plasticity in the visual cortex. This may allow mice with what researchers call an imbalanced “ocular dominance,” or lazy-eye, to restabilize their eyes.

“I think metaplasticity is potentially one of several really important mechanisms by which psychedelics could be producing various types of therapeutic effects,” says David Olson, Director of the Institute for Psychedelics and Neurotherapeutics at University of California-Davis, who was not involved in the study. “But I highly doubt that psychedelics are the only types of compounds that can do this. And I doubt that metaplasticity is the only mechanism by which these compounds produce therapeutic effects.”

Olson noted that non-psychedelic compounds such as Prozac have also been shown to induce critical period-like plasticity in the visual cortex, but at a slower speed.

Analyzing Gene Expression

Dölen’s team also discovered that the brains of mice who were given psychedelics had higher amounts of “Pac-Man”-like enzymes called matrix metalloproteinases, which clear away the space between neural synapses. The researchers speculate that in adulthood, this space around neurons, called the extracellular matrix, becomes bogged down with molecules that impede plasticity. The scientists believe that psychedelics may create a fresh biological slate that allows neurons to reconfigure themselves more easily.

“What we think is happening is that when you give the psychedelic, it chews up the extracellular matrix, and that dissolution of the extracellular matrix makes the synapses malleable again,” says Dölen.

Analyzing the brains of mice exposed to these compounds, the researchers detected the expression of 65 different genes, 20% of which were associated with regulating the extracellular matrix. They believe this suggests that the extracellular matrix plays a key role in how to reopen critical periods, and opens the possibility for a deeper understanding of the potential therapeutic effects of psychedelics.

A Paradigm Shift

In the history of the field, researchers hypothesized that the 5HT2a serotonin receptor could be fundamental to the action of psychedelics. But this theory has been challenged by the fact that substances such as ibogaine and ketamine do not exert their main effects through this receptor, raising questions about what defines a psychedelic. Recently, researchers released a proposed consensus statement to argue that only compounds that act on 5HT2a receptors and exert psilocybin or LSD-like effects should be called psychedelics.

However, in their report, Dölen’s team argues that what defines a psychedelic is not its action on 5HT2a receptors, but its ability to re-open critical periods. “Our first piece of evidence to support that was that all of the psychedelics do it, whether they’re dissociative psychedelics, hallucinogenic psychedelics, oneirogenic psychedelics, or empathogenic psychedelics – they all do it.”

Dölen speculates that “what it feels like to re-open all your critical periods is just what it feels like to be in an altered state of consciousness.”

When attempting to describe what defines a psychedelic, the consensus statement excludes compounds such as ibogaine from this category and also ketamine which is not considered a classic psychedelic. There is disagreement among researchers on how to create new terms to describe psychedelic-like compounds and question whether this category should be more inclusive as Dölen’s team argues.

Dölen’s research group also studied cocaine in this experiment, which did not have the effect of reopening critical periods in mice, meaning the effect was shared only by the compounds used in her study that have historically been considered psychedelic or psychedelic-like.

According to Dölen, there are huge implications of being able to re-open critical periods. The therapeutic potential of psychedelics may extend beyond psychotherapeutic conditions such as depression or PTSD and could include conditions once thought incurable, such as deafness, stroke, or lazy-eye.

“This paradigm shift, really, in how we imagine psychedelics are having these therapeutic effects, not only offers a better explanation for the ones we’re already trying to cure, but opens up the door for a bunch of other diseases that we didn’t even think of,” said Dölen.