Cerebrum Winter 2021

“People often come out of a psychedelic experience and say ever experienced—that the experience led to cre

since many of these substances, like the naturally occurring peyote and mescaline, have been used in spiritual practices for centuries. But, like Nutt, he believes the biggest mystery remains what psychedelic drugs do in the brain that lead to such powerful perceptual and cognitive effects. Animal work suggests these drugs stimulate serotonin 2A receptors (5-HT2As), resulting in the growth of dendritic branches and an increase in synaptic connections. Neuroimaging work across several laboratories suggests that their use also has a profound “disorganizing” effect on brain networks, including the default mode network, sometimes referred to as the brain’s resting state network. “There’s something about the 5-HT2A that helps to structure brain activity—and psilocybin disrupts normal patterns of activity in brain networks,” says Nutt. “When we saw it, it all made perfect sense. We could explain hallucinations by a disruption in the coordination of the visual system. We could explain the out-of-body experiences by the disruption of the default mode network. By looking at how these networks were altered, we really could explain almost all of things people report experiencing through these insights into brain function.” Carhart-Harris says such studies can also offer greater insights into how the brain is organized normally. As these large-scale networks “temporarily disintegrate” in response to the drugs, scientists can learn more about how the brain facilitates normal cognition, including consciousness. Christof Koch , chief scientist of the MindScope Program at the Allen Institute for Brain Sciences, and a leading expert in consciousness, agrees. He hopes to use psychedelics in living brain tissue samples to see changes in the cells. “New explorations of higher states of consciousness are usually only accessible if your participant has engaged in 20 years of meditation or prayer—and very few people get there,” says Koch. “But psychedelics offer the opportunity to study these changes in the cells reliably at the molecular level. It may help us understand what is required from a neurobiological standpoint to achieve different states of consciousness.” For his part, Seth hopes to use psychedelics to better understand perception. Sensory distortions are a hallmark response to these drugs, and the extraordinary vividness of such distortions may provide new insights into how the perceptual system works. His work with Carhart-Harris has shown that the disorganization of networks caused by psychedelics has a high degree of randomness—and that information flow decreases between brain regions that normally communicate with one another. “The take-home, basically, from these studies is that there is a large change in the global properties of brain dynamics which reflect increased disorganization and a lack of structure,” Seth explains. “The brain areas are becoming more random in their activity and speaking to each other less. The more we

can understand about this, the more insights we could gain into what has gone wrong in psychosis or other psychiatric conditions that result in hallucinations or other perceptual defects.” The study of psychedelics may offer a window into other fascinating phenomena as well. For example, the Johns Hopkins group recently published a study looking at feelings of interacting while using DMT with a compelling presence of another form of consciousness, such as a spiritual entity like God, an angel, a ghost, or even an alien. “These experiences are rated as extremely significant by those who have them and result in enduring positive effects regarding their attitudes about life and self, mood, and social reliably elicit these kinds of autonomous entity experiences that yield these kinds of positive effects means they could show promise as a potential adjunct to traditional therapies for mood and behavior problems.” Promise as a Therapeutic Some of the earliest work on psychedelics, in fact, hinted at their promise for treating depression. Certainly, people often report increased well-being and improved mood after a recreational psychedelic experience—but unlike other euphoria- relationships,” says Ethan Hurwitz , a doctoral student at the University of California San Diego and a member of the Johns Hopkins Center for Psychedelics and Consciousness Research who worked on this study. “The fact that DMT can important to look at psychedelics’ potential as a therapeutic. “Typical antidepressants don’t work for everyone,” he says. “And psychedelics have these powerful mental health benefits which probably work by very different mechanisms than drugs like selective serotonin reuptake inhibitors (SSRIs).” Certainly, the basic science work suggests that is the case. Nutt and colleagues demonstrated that psilocybin reduced activity in the subgenual cingulate cortex, a region of the brain implicated in depression. “This region is one of the driving nodes of depression,” Nutt explains. “And other work has shown that a necessary feature of antidepressant therapies is the ability to switch down activity in this area. When you couple that with the profound changes in the default mode—and there is evidence that overconnectivity in this network leads to depressive ruminations—you see why these drugs may have therapeutic effects.” Several studies have now shown just that. Recently, the Johns Hopkins group published the first randomized controlled trial of psilocybin-assisted therapy—the drug is administered in causing drugs, those feelings can last for days or even weeks after “a trip.” Charles Raison , a psychiatrist at the University of Wisconsin Madison, says, given the personal and societal costs of treatment-resistant depression, it is

28 DANA FOUNDATION CEREBRUM | Winter 2021

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