Tim Ferriss - Dr. Gül Dölen

1) Dr. Gül Dölen explains philosophy of mind and theory of mind, which are topics that have drawn attention from philosophers with various perspectives. She describes theory of mind as the neurobiological process of anticipating what someone else might be thinking and understanding the world from their point of view, which is used for activities like playing poker, lying or tricking people. Dölen explains how individuals with autism often struggle with theory of mind, while psychopaths can use it to manipulate others.

2) Gül discusses how octopuses hunting behavior can be seen as a theory of mind-like behavior despite octopuses being mostly asocials pecies. She talks about how this behavior can provide insight into the evolution of theory of mind and suggests that it may have emerged from hunting behavior rather than social behavior as previously thought.

3) Gül discusses her past research on Fragile X, the first identified cause of autism, and the use of psychedelic interventions to restore biochemical imbalances that contribute to the condition. While past clinical trials with drugs failed to cure the disease, she believes that combining the psychedelic treatment with biochemical interventions during the critical period of development could reopen the relevant critical periods so that the patient can learn from their social environment in the normal way under the conditions of the restored biochemical imbalance.

4) Gül discusses the heritability score of autism, which was found to be around 0.96, making it very highly heritable. The definition of autism has expanded to include a spectrum of disorders, which led to a drop in heritability estimates. Dr. Dölen focuses on genes like FMR1, which regulates 25 percent of all autism genes, as a good starting point to understand autism. While genetic screening for autism probability as an outcome in offspring may be possible, FMR1 is still rare enough that it's not worth doing screening tests unless there's a family history of Fragile X.

5) Gül discusses critical periods and the concept of imprinting behavior in animals, particularly snow geese. Critical periods are sensitive times in an animal's development that is open to experiences that leave lasting impressions, such as the ability to learn a language more easily as a child. Dölen's lab also researched social reward learning in mice and found that there is a critical period in which animals learn from their social environment more strongly as adolescents than adults. The idea of critical periods helps explain why it is difficult to treat brain disorders in adults because the brain is no longer flexible and able to learn.

6) Gül explains her team's investigation into the possibility of a "master key" for unlocking critical periods in the brain. They started with the idea that MDMA may reopen the social critical period due to its pro-social properties. However, they found that all psychedelics, including LSD and ibogaine, reopened this critical period for social reward learning, despite not being primarily pro-social. This led to the idea that psychedelics are a master key for unlocking critical periods in the brain, evidenced by the similar molecular mechanisms involved in the closure of critical periods for vision, somatic sensation, and motor function.

7) Gül discusses the possibility of using psychedelics as a "master key for unlocking lots of different critical periods, "including visual, touch, and motor critical periods. She uses the example of bilateral cataracts to explain the concept of critical periods and the potential for psychedelics to restore vision by reopening critical periods. Likewise, pairing mGluR therapy with psychedelics may help restore the ability to learn from the social environment in people with autism by targeting the genetic impairment that causes the condition and reopening the social critical period for learning social interaction.

8) Gül discusses the possibility of psychedelics reopening critical periods and providing a mechanistic handle for understanding big philosophical questions about consciousness and altered states of consciousness. She also talks about the limitations of circuit mapping in understanding complex behavioral functions and the need for generalizable principles and rules governing circuit-level rearrangements. Finally, she challenges the idea that psychedelics can only be understood in humans and suggests expanding research to other animals.

9) Gül shares her thoughts on the idea that studying the effects of psychedelics can only be truly understood in humans due to their behaviorally complex actions. She pushes back on this idea and suggests that as we gain a better understanding of what the drugs are doing in mice, we may be able to develop concepts that generalize. She also cautions against using the term plasticity in relation to psychedelics, as it can be confusing and have different meanings to different people. Instead, she believes the idea of metaplasticity, or the regulation of plasticity, is a more appropriate concept to apply when studying the effects of psychedelics.

10) Gül explains the difference between hyperplasticityand metaplasticity, two terms that can be easily confused with each other.While hyperplasticity is associated with drugs that are highly addictive,metaplasticity is the property that enables psychedelics to induce plasticity.Metaplasticity allows for a change of plasticity over time and occurs due tomolecular factors, resulting in the ability to induce plasticity declining asone grows older. NMDA receptors, which detect when two neurons are firing atthe same time, are implicated in metaplasticity and are important for encodingmemories, but ketamine and PCP can interfere with this process.

11) Dölen discusses the potential use of psychedelics in treating allergies. She presents the idea that psychedelics can reopen the critical period for learned threats, which could enable people to unlearn the association between certain triggers and allergies. While she likes this idea, Dr. Dölen cautions that more research is needed before people should attempt to use psychedelics to cure their allergies.

12) Gül discusses the boundaries for defining classical psychedelics and the necessity of the serotonin 2A receptor for their therapeutic properties. She explains that while there is evidence for antidepressant properties in psychedelics, it's up for debate whether the receptor is required. Her lab has been focused on understanding the commonality across all psychedelic receptors, and they've found that regulation of the extracellular matrix is responsible for the final common pathway that happens. The working model is that psychedelics bind to their receptor, signal to the cell to hit the reset button, call in all receptors, and degrade the extracellular matrix that is holding the synapse together, allowing for the reintegration of more sensitive receptors that are able to induce plasticity. She briefly mentions kappa-opioid agonists and their potential therapeutic applications but notes that they are not very pleasurable.

13) Gül explains the difference between ionotropic and metabotropic receptors and how LSD binds to the serotonin 2A receptor to prolong its effects by triggering the beta-arrestin pathway. She also expresses her disappointment in discovering that while beta-arrestin serves as a mechanism for some psychedelics, it is not the universal mechanism for all of them. Later on, she shares a funny story about Alexander Shulgin and explains how she aligns with him in his dedication to self-experimentation.

14) Gül explains how psychedelics have been a fascination for neuroscientists for their potential to alter the brain's perception and interpretation of reality. However, while scientists like Sasha Shulgin come from a tradition of experimenting on themselves, the "noetic property" created by psychedelics poses a challenge for scientists to maintain skepticism and objectivity. Dölen also touches on the short window of time for physical therapy to be most effective after a stroke, but the reason for this remains unknown.

15) Gül discusses the potential use of psychedelics in reopening critical periods, such as the critical period of motor recovery following a stroke. With a collaboration with a neurologist at Johns Hopkins who has developed a rodent model for this critical period, they are working to see if psychedelics can help patients with debilitating, lasting impairments from stroke. She emphasizes the importance of never stopping learning and questioning, even if traditional cultures have been using psychedelics for healing purposes for a long time.

16) Gül discusses the importance of understanding the context of psychedelic drug use, including the rituals and practices that have been developed around them. She argues that these elements may be important to their therapeutic effects and cannot be simply imported into medicinal practices without understanding how they work. She also discusses the shift towards pairing drugs with psychotherapy and the importance of the right context for different diseases. In the future, she suggests that treatment with psychedelics will rely on identifying the right context for each disease, which may involve unconventional practices.

17) Gül discusses the dosing issue and the potential of long-acting psychedelics in reopening critical periods. She explains that their studies indicate a narrow dose response for reopening critical periods, and that increasing the dose does not necessarily increase the duration of the critical period open state. She suggests that the most benefit from long-acting psychedelics, as they can reopen motor critical periods for as long as possible, and that they could be used more like surgery rather than next-generation anxiolytics or antidepressants.

18) Dölen discusses the importance of goal-directed versus goal-undirected learning when it comes to motor rehabilitation. She explains how children's play-like behavior of learning motor patterns is much more effective than directed therapy. She then touches on the fun aspect of science, which was important to her during her time at Bears Lab at MIT. Although she initially struggled with obtaining funding in academia, she finally got a break with her pioneering experiments on octopuses on MDMA.

19) Gül shares how she struggled to obtain her first NIH grant and how her creativity was curtailed by rejections from peers. Not wanting to be discouraged, she decided to pursue a marine neuroscienceexperiment involving octopuses on MDMA. Although it wasn't a huge risk for her at the time, it bought her great joy and revived her sense of play andcuriosity. As she continues her work, she acknowledges that taking risks is important but may become more difficult as scientists become more establishedand feel they have more to lose.

20) Dölen recommends three books that she has gifted the most to other people. The first is "Invisible Women" by Caroline Criado Perez, a book about feminism and how ignoring data about women's body sizes and travel patterns ends up costing society at large. "The Dawn of Everything" by David Graeber, a new history of humanity, is her second recommendation, which also has a chapter on psychedelic uses in other cultures, while "The Immortality Key" by Brian Muraresku is her third pick, a book that talks about the recreation of the elixirs of Midas and the use of psychedelics in ancient cultures among other fascinating stories.