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Reopening Critical Periods with Ketamine – Part 1 of 2

I strongly believe that ketamine therapy is more effective when combined with psychotherapy. But why?

Last September, I introduced the concept of critical periods from Dr Dölen's research from May 2023. In this two-part post, I will go into greater detail behind critical periods by highlighting key points from a virtual Q&A with Gül Dölen MD PhD who joined Jayne Gumpel LCSW and Carl Spitzer MD of Big Tent Ketamine or BTK. (BTK is a Google Group discussion board with over 3,000 health care professionals who exchange advice, ideas, training opportunities, and support in the spirit of advancing ketamine therapy.)

Throughout the engaging 90-minute Zoom meeting, Dr Dölen summarized findings from her research on critical learning periods using mice and the implications for psychedelic-assisted therapy including ketamine therapy. Like past guest lectures hosted by BTK, this was a special opportunity to get a close look into the minds of one of the most prominent researchers of psychedelics.

Social Reward Learning

Dr Dölen started by introducing the concept of social reward learning. Social reward learning refers to how key behaviors are shaped by our social interactions. Dr Dölen used the example of someone having a fond memory associated with green shaggy carpet stemming from positive experiences at a beloved grandmother’s house with similar decor. This imagery illustrates how social reward learning is an unconscious process of associating environmental elements with emotional social experiences. In other words, social learning is a highly effective way to assimilate new information and experiences.

Dr Dölen explained that this may be why teenagers are more susceptible to peer pressure than adults. However, as we mature, our capacity for social reward learning diminishes. As adults, we feel less peer pressure because the critical period—for social reward learning in this case—has closed. While this may help us make better decisions as we age, it also means that diseases and disorders of social impairment like post-traumatic stress disorder or PTSD may be harder to treat when entrenched at a younger age.

Photo of active eco volunteers people cleaning beach from plastic trash
Social reward learning may explain how we form lifelong thoughts and behaviors before adulthood

Origins of critical periods

Dr Dölen mentioned that Konrad Lorenz first described a critical period related to social behavior in snow geese. In 1935, Lorenz saw that geese hatchlings would follow him if he interacted with them but only within the first 48 hours of hatching. He showed that this specific window of time was when certain learning or developmental processes are most effective.

Since Lorenz's discovery, critical periods have become an area of great scientific research with thousands of articles and three Nobel Prizes. Dr Dölen noted that many other critical periods have been identified across different areas of development. These include language acquisition, where children learn languages effortlessly and without an accent, and various sensory systems like vision and somatosensory perception.

Reopening social reward learning critical periods with MDMA

A major question asked by neuroscientists like Dr Dölen was whether it’s possible to reopen the critical period for social reward learning. If so, might we be able to change maladaptive thoughts and behaviors which are correlated with depression, PTSD, and anxiety?

The first clue arrived in 2013. That year, Dr Dölen and her colleagues published a paper in Nature called "Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin." This research emphasized the role of serotonin, a neurotransmitter also known as 5-hydroxytryptamine or 5-HT, as a reward molecule. Rather than merely interacting with dopamine, which many assumed was the primary reward molecule, they found that serotonin combines with oxytocin, another neurotransmitter, to encode social behaviors. In other words, serotonin explains the basis for social reward learning.

The next clue came from a paper published in 2019 titled "Oxytocin-dependent reopening of a social reward learning critical period with MDMA." Led by one of Dr Dölen’s postdoctoral research fellows, Romain Nardou, this research showed that the critical period for social reward learning occurs during adolescence. This is unlike other types of reward learning like those implicated in substance use disorders. For example, one can become dependent on narcotics at any age.

Interestingly, researchers also showed that this window could be temporarily reopened with a single dose of MDMA. Why MDMA? MDMA or 3,4-methylendioxymethamphetamine was known to cause an excess release of serotonin which was shown earlier to help encode social behavior. Dr Dölen also noted that there was reliable, if not anecdotal, evidence that MDMA had strong prosocial characteristics since the days of Ann and Alexander Shulgin. If anything could reopen a critical period for social reward learning, it would be a powerful social psychedelic like MDMA.

A quick recap

  • Conditions like PTSD make social interactions challenging and are especially difficult to treat once the critical period for social reward learning has closed.
  • In 2013, Dr Dölen and her team demonstrated that social reward learning requires oxytocin to interact with serotonin, not dopamine.
  • Later in 2019, research led by Romain Nardou showed that the critical period for social reward learning closes by adulthood. They also indicated that this critical period could be temporarily reopened with MDMA.

Context dependence

To better understand how MDMA reopened the critical period for social reward learning, researchers administered MDMA to mice in both social and isolated settings. (In the social context, mice were placed in a cage with their social group, while for the isolation context, mice were housed individually.) They found that MDMA only reopened the critical period for social reward learning when mice were surrounded by other mice. When administered to mice in isolation, MDMA did not reopen the critical period.

For us humans, this means that MDMA is a more effective therapy when used as an adjunct to psychotherapy, not as a standalone treatment. Dr Dölen pointed out that using MDMA in a non-therapeutic setting, like at a rave, is unlikely to produce therapeutic benefits for conditions like PTSD. Effective treatment requires bringing up relevant traumatic memories or emotions in a controlled, therapeutic environment. Dr Dölen noted that this was the first time that anyone demonstrated that a medicine’s therapeutic effects may depend on the context.

The left side shows the tranquil psychotherapy room with muted colors, while the right side presents a more subdued nightclub scene
Psychedelics like MDMA and ketamine may reopen critical periods for social reward learning but only in the right settings. [Image created by OpenAI's DALL-E, generated at the request of Innerbloom Ketamine Therapy.]

Other Psychedelics

Based on the findings from Dr Dölen and her colleagues over the last decade, MDMA reopens a critical period for social reward learning in the proper context. With a powerful tool like MDMA to reopen this critical period, interventions like talk therapy, couples therapy, and group therapy may be more effective at reshaping memories and learning. They would last longer too. But what about other psychedelics like ketamine?

Next week, I’ll post the second part to this two-part post on reopening critical periods with ketamine. In my follow-up, I will summarize Dr Dölen’s latest research from 2023 and highlight key points from the discussion related to critical period durations, ketamine therapy timing, and other important considerations when using psychedelics for therapy.

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