MDMA Reopens Child-like “Critical Periods”

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Psychedelics have been used for thousands of years in both cultural and medicinal settings. Over the past few years, a renaissance in psychedelic research has provided new insights into psychedelic drugs as a treatment for serious mental health conditions, such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), when combined with psychotherapy.

The biological mechanisms behind these therapeutic advancements are still poorly understood at present. But some aspects are being uncovered.

In a recent Analytical Cannabis webinar, Gül Dölen, an associate professor of neuroscience at Johns Hopkins University, explained one such recent discovery. Her presentation delved into research from her lab that shone a light on how the effectiveness of MDMA-assisted psychotherapy may be linked to the psychedelic’s ability to reopen a “critical period” in the brain for social reward learning.

What is a critical period?

As the brain develops in infancy and through childhood, it has to adapt to vast amounts of external information and stimuli. To make sense of these stimuli, the young brain will go through certain “critical periods” of learning, which can create a significant impact on later behavior as the brain matures.

“Critical periods are periods of time, usually during development, where the brain is extremely sensitive to the outside world and the ecologically relevant cues that it needs to learn from,” Dölen explained. “And this sensitivity to the world is coupled to a heightened period of malleability and plasticity that allows synaptic circuit and behavioral modifications to occur.”

The term critical period was first coined by the zoologist Konrad Lorenz to describe the first 24-48 hours after snow geese hatch and imprint onto the first moving object they saw as a mother figure. This is ordinarily their actual mother, but during Lorenz’s research, it was himself. If no suitable mother figure is shown to the geese until after this critical period, they will fail to form a strong attachment.

“Scientists have long recognized that our inability to cure certain diseases comes from the fact that, by the time we get around to identifying the disease process or making a treatment available for the disease process, the relevant critical period is closed,” Dölen said.

“Once the critical period is closed, even if the disorder process that is responsible for the disease is reversed or ameliorated, because the brain is no longer able to reorganize itself and induce these synaptic and circuit modifications, that rebalancing is ineffective.”

This is most famously seen in cases where people are born with bilateral cataracts, Dölen added. If the cataracts are not removed until adulthood, then the person will still remain blind as the brain’s visual system is not able to adapt to this new, corrected visual space. If there were a way for scientists to reopen these critical periods, then it could open the door to new treatments for conditions involving the brain and its plasticity.

Oxytocin and serotonin control critical periods for social reward learning

The Dölen lab at Johns Hopkins University is interested in the brain mechanisms that control social behavior, and so the team has postulated that there could be some critical period for social reward learning involved in this process. To test this, the lab used a social conditioned place preference assay with laboratory mice at different age gaps to determine if social reward learning is conditioned by a critical period in mice.

The mice were raised in a home cage with a neutral bedding material inside of it. Pre-trial, the mouse subject was placed into a new cage with two areas, each containing a novel bedding material for the cage, and the time the mouse spent in each area was measured. The mouse would then be subject to social conditioning by being introduced to a cage with other mice that also contained one of the two novel bedding choices. They would then undergo isolated conditioning by spending time alone in a cage with the second bedding choice. Post-trial, the mouse was reintroduced to the split-area cage and the amount of time spent in each half was remeasured to assess the effects of the social conditioning.

“The social reward learning – the ability to learn from these social cues – peaked around postnatal day 35 to 42. Then it declines, and by mature adulthood it’s closed,” said Dölen.

With a critical period identified, the focus turned to the brain mechanisms that might regulate this social reward learning behavior in juveniles. From her postdoctoral training, Dölen was aware that synaptic plasticity induced by the hormone oxytocin might be a candidate for this. And so the team used an electrophysiology experiment to invoke synaptic responses from brain slices taken from the lab mice and compared the synaptic plasticity of the mice at different ages.

They found that the application of oxytocin in the juvenile mice brain slices induced robust plasticity, but that this plasticity was not observed when the same experiment was done on adult mice brains.

This suggests that the magnitude of oxytocin-induced synaptic plasticity in the nucleus accumbens is developmentally downregulated and corresponds to the developmental downregulation of the behavioral plasticity that we saw,” Dölen explained.

“Interestingly, we have also shown that serotonin and oxytocin are working in coordination to encode this social reward learning, but serotonin plasticity is not developmentally downregulated. So what this tells us is that while the two mechanisms work together, they are regulated differently across development.”

Reopening the critical period with MDMA

With this new insight into oxytocin playing a role in the opening and closing of the social reward learning critical period, theoretically, it would then be possible for researchers to leverage this knowledge and reopen such critical periods for therapeutic benefit. However, oxytocin cannot directly cross the blood-brain barrier, making it an unreliable therapeutic avenue for further development.

“So, we decided to turn our attention to MDMA,” Dölen said. “We knew that it had these prosocial effects, and we thought, ‘Wouldn’t it be interesting if somehow this prosocial psychedelic could trigger the reopening of the critical period?’”

“We knew that MDMA, from previous literature, binds to the serotonin transporter, and when it does […] it reverses the direction of the transporter. So, instead of taking up the serotonin from the synapse, it’s actually injecting it into the synapse. And so you’re getting this massive influx of serotonin in response to MDMA.”

“But there was also anecdotal evidence and some circumstantial evidence that MDMA might be triggering oxytocin neurons to release oxytocin.”

And so the researchers repeated the mouse experiment, but this time they gave the mice a single dose of MDMA up to 48 hours before the place preference assay began.

They found that the MDMA dose did indeed reopen the critical period for social reward learning in the adult mice, beginning around 6 to 48 hours after the dose. The reopening of the critical period lasted at least two weeks, up to around 4 weeks before returning to baseline.

“We were really excited about these results, because we knew about the human clinical trials that have been looking at MDMA-assisted psychotherapy for the treatment of PTSD,” Dölen said. “To our knowledge, this is the first time anybody has been able to match a sub-acute or chronic effect of MDMA to the behavioral readout that we’re using.”

According to Dölen, this idea of MDMA reopening critical periods in the brain accounts for many of the observations coming out of MDMA-assisted psychotherapy trials, observations that other theories simply cannot explain.

“MDMA’s therapeutic effects are context-dependent,” explained Dölen. “If you take MDMA and go to a rave party, you don’t come back automatically cured of PTSD, or addiction, or depression. You have to have used MDMA in a therapeutic setting.”

“This context-dependence of MDMA’s therapeutic effects does not hold for the proposal that maybe MDMA is working as sort of a next-generation anxiolytic. Whatever anxiolytic properties MDMA has or not, these are context independent. Whereas the MDMA-dependent reopening of the critical period for social reward learning is dependent on giving the MDMA in the social context. I think that this is very interesting, and it differentiates this explanation from other explanations.”

Building on their discoveries in the area of MDMA and critical periods, Dölen’s team recently initiated the PHATHOM project (Psychedelic Healing: Adjunct Therapy Harnessing Opened Malleability). This initiative aims to investigate the hypothesis that psychedelic drugs as a wider drug class can reopen other distinct critical periods in the brain and that these effects can be further harnessed for therapeutic benefit.

Originally posted at Analytical Cannabis

Photo by Nastya Dulhiier on Unsplash


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