Introduction Part I: Psychedelic Neuroscience in a Nutshell

Written By Michael Angyus

Introduction

Welcome curious friends to Psychedelic Neuroscience, where we summarize and contextualize the advancing ideas of psychedelic research to learn about brain, mind, and soul. Psychedelics provide a unique opportunity to study perception, meaning, and mysticism through a modern scientific lens. I’ve watched my generation grow up with science taking the center stage in our explanations of the universe, often pushing religion and spirituality to the side, but science does not yet provide a deep enough understanding of the human mind to take their place in our daily search for meaning. The goal of this podcast is to explore how science and spirituality can coexist, feeling out the limitations of science while also utilizing it to support our pursuit of a meaningful life. Psychedelics are the perfect tools to explore this intersection, because on the scientific end they are a class of molecular structures that target receptors in the brain, but on the other end, they are producing meaningful, spiritual, and healing experiences. Join me as I attempt to harmonize science and spirit.

During my masters in neuroscience at Imperial College London, I was privileged to work with some of the best researchers in the world focused on the mechanisms of psychedelics in the brain. Since I joined the field, I’ve gone through a steep learning curve trying to understand the literature, and I was compelled to organize this information in a way that could be useful for people like me who wanted to learn more about the exciting work that I believe is going to have a far-reaching impact on our culture. Therefore, this podcast is a place for curious minds to dive into the neuroscience of psychedelics, whether esteemed researcher or common lay person, the topics discussed will impact the way you think about brain, mind, and soul.

The structure of the podcast will be a hybrid between scripted episodes and interviews with experts of the field. For scripted episodes, I will be reviewing the literature on a certain topic and organizing the ideas in a comprehendible manner. You can find these scripts on my website, psychedelicneuroscience.org. These scripts give you a chance to double check my interpretations of the cited literature, as well as give you a chance to read the episode if you prefer that to listening. Each scripted episode will be paired with an interview episode with a scientist who studies the topic discussed. This way we can have an introduction to the topic before expanding on the details with an expert.

The first four episodes will be an introductory series that bring together key aspects of the field from the molecule up to the mystery to create a foundation from which we can contextualize the more specific topics of future episodes. Episode one (today’s episode) will be a brief overview of the entire field. The next three episodes will work from molecule up to mystery in a little more detail. Episode two will start at the molecule with a summary of the cellular and molecular work, episode three moves up a level into the world of brain imaging, covering the work that has contributed to the main theoretical models of psychedelic action, and finally, episode four moves into the mystery where I widen the focus to discuss how the unique subjective phenomena related to psychedelics has implications for individual development as well as why these experiences might be perceived as spiritual. After this 4-part series, you will be ready to join me as I dive into unique research topics of the field. Welcome to Psychedelic Neuroscience!

 

The basics

Psychedelic neuroscience intersects multiple levels of study including cellular and molecular, neuroimaging, and subjective. Obviously, these fields overlap and interact with each other, but I felt splitting them could be a nice way to introduce clarity to a field of research with overwhelming reach. This multiplicity is part of what makes psychedelic research so special; rarely can an area of science originate from one molecule and encompass the expansive questions of meaning and self. Trying to bridge such distant worlds will be difficult, very difficult, but with open minds and careful discussion, I think it’s possible for us to harmonize science and spirit.

While psychedelic experiences are known to vary widely, researchers have tried to find some consistent subjective effects that may help us find a common underlying mechanisms behind the diverse range of experiences. One commonality of the psychedelic experience is the apparent increase in sensory information that floods the persons conscious awareness. The contents of this so-called flood are often described as hallucinations because they differ so greatly from normal waking consciousness. Not only are senses such as sight, sound, taste, smell, and touch distorted, but thoughts, and more importantly the emotions associated with thoughts, are highly distorted under high doses of psychedelics. The nature of these alterations diverges between users, but you can imagine that altered senses would disrupt someone’s connection to reality and altered thoughts and emotions would disrupt their connection to themselves. The resulting experience is often highly introspective, directing the individual’s attention toward their sense of self and their relationship to the world. This freedom from usual thinking induced by the flooding of the senses can be frightening, but it can also produce valuable insights that mediate positive change. Scales to assess psychedelic induced insights have shown that they are related to positive outcomes in emotional breakthrough and changes in well-being (Peill et al. 2022). Additionally, most participants in clinical trials rank the experience as highly meaningful to them, a ranking that endures at long-term follow-ups months and even years later (Griffiths et al. 2008). However, the outcomes of psychedelic experiences are not always positive. The use of the word ‘flooding’ rightfully alludes to the intensity and turbulence of psychedelic experiences, and this chaotic and hallucinatory nature led early researchers to use them as a model of psychosis (Faillaice, 1966), even assigning the drug class the alternative title ‘psychotomimetic’ (Nichols & Walter, 2021). While the research has advanced to include significant positive effects on well-being and mental illness (van Elk & Yaden, 2022), it is imperative that we don’t neglect the dangers of these drugs.

 

The bold vision of neuroscience

Neuroscientists have integrated recurrent, measurable themes of the subjective experience with molecular, cellular, and neuroimaging data to develop mechanistic theories of how psychedelics work. Proposing neural mechanisms that bind molecule to experience is a bold undertaking, one which is only just beginning. However, I feel psychedelics are uniquely poised to elucidate the connections between brain, mind, and soul. Neuroscientists have pursued this task for centuries, and the following quote by Thomas Willis simultaneously portrays the beauty in our pursuit, as well as the importance of our modesty.

 

“To explicate the uses of the brain seems as difficult a task as to paint the soul, of which it is commonly said, that it understands all things but itself.”

                                                                        -Thomas Willis, 1621-1675

 

Thomas Willis was a physician and neuroscientist in the 1600’s, living in Oxford right in the middle of the scientific revolution. He and his team of chemists and physicians collaborated on problems of the body and brain, and one of their impactful discoveries was the idea of fermentations in the body. In modern language we would call this biochemistry, but Willis’s group helped transform the understanding of the body from a mechanical collection of pumps and pulleys to something of dynamic chemical transformation. I’m telling this story for two reasons: The first is that I want to make it clear that our scientific understanding is constantly changing in very drastic ways. We need to be cautious when confidently explaining how something works, especially with something as complex as the brain. The other reason is that this story demonstrates our transition from a centrally religious culture to a centrally scientific culture. I read about Thomas Willis in a book called “Soul Made Flesh” by Carl Zimmer, which details how Willis’s work, and the scientific revolution more broadly, has shifted the core explanations of the world from spiritual to scientific. We have continued to take aspects of conscious experience and explain them using increasingly detailed models of neural activity. To me, it’s incredibly exciting to find a conceptual explanation for how the brain is orchestrating consciousness, but I think many people are wrong in thinking these scientific explanations have to reduce the experience. Even if a spiritual experience is conceptually understood as a manifestation by the brain, just the same as any other experience, it doesn’t negate the need to develop spiritual tools that can help us connect to, describe, and interact with our world in a different way, a way that can be applied in situations where science falls short. With this understanding of the limitations of science, let’s move forward with theories of how psychedelics might be working within the brain.

 

Three leading models of acute psychedelic action

While there are numerous theories of psychedelic action, I will focus on three that have received significant attention by the field (Doss et al., 2022), each roughly mapping to a different psychedelic research center.

The first model of psychedelic action was developed by Franz Vollenweider at the University of Zurich in Switzerland. Dubbed the cortico-striatal thalamo-cortical loop model (CSTC), this theory was first proposed in 2001 (Geyer & Vollenweider, 2001), later revised in 2008 (Vollenweider & Geyer, 2008), and again in a recent review (Vollenweider & Preller, 2020). This final revision was published in Nature Reviews Neuroscience which I feel indicates both the acceptance of psychedelic research in mainstream neuroscience, and the improved mechanistic acuity that has accompanied and assisted this evolution.

Nerves from each of your sensory organs pass through the thalamus (which sits atop the brain stem at the center of your brain). Information from these nerves is further processed by the cortex (the 6 layered sheet of cells outermost of the brain, uniquely large in humans, and attributed to complex and higher-level processing (Müller-Dahlhaus & Ziemann, 2015)). CSTC centrally posits that sensory flooding is caused by disrupted thalamic gating, which normally depends on top-down cortical inputs for regulation. This results in altered sensory processing by the cortex.

The next theory of psychedelic action was put forward by Robin Carhart-Harris and Karl Friston in 2019, titled relaxed beliefs under psychedelics (REBUS) (Carhart-Harris & Friston, 2019). Both from Universities in London (Carhart-Harris then the head of the Imperial College London Centre for Psychedelic Research, Friston at University College London), these researchers formulated REBUS as a marriage of their previous work. Friston models the brain as a hierarchically organized prediction machine, generating top-down predictions which are compared with bottom-up sensory information to iteratively produce an optimal model. The confidence associated with top-down and bottom-up information can affect whether bottom-up information is ignored, or whether it is used to update the model. REBUS proposes that psychedelics relax the confidence of top-down predictions, causing the brain to be more sensitive to bottom-up stimuli. This explains the flooding of sensory information, the subjective chaotic state, and the enduring changes in perspective that can follow psychedelic experiences.

The third model I will discuss is the cortico-claustro-cortical theory (CCC), presented recently by Doss et al. (2022) who are associated with the Johns Hopkins Center for Psychedelics and Consciousness Research. This theory resembles the CSTC in that it is a circuit level perspective, rather than the more abstract informational perspective of REBUS. The claustrum is a slim strip of cells that sit between the cortex (specifically the insula) and midbrain (specifically the putamen). It is considered to be the most densely connected region to both cortical and subcortical regions of the brain (Brown et al., 2017; Chau et al., 2015). The CCC posits that the claustrum is a central orchestrator of sensory processing into a unified consciousness, and that this capacity is disrupted by psychedelic drugs.

 REBUS, CSTC, and CCC attempt to explain the common subjective features of the psychedelic experience using different analytical levels (computational vs circuit level) or emphasizing different neural pathways (thalamic gating vs claustral orchestration). These theories highlight three leaders in psychedelic research: University of Zurich, Imperial College of London, and Johns Hopkins University. While these three players have largely shaped the foundations of the field we see today, there are many other dedicated labs not mentioned here, and new official psychedelic research centers continue to emerge as the field grows. I’ve begun with the basic introduction of these theories necessary to move forward with this review but will dive deeper into the data that supports them throughout the introductory series, particularly when discussing neuroimaging. First, we will touch on how the general mechanisms discussed relate to evidence for transdiagnostic treatments of psychiatric disorders (Zeifman et al., 2022).

 

How might these models relate to therapeutic effects?

            A major contributor to the ‘psychedelic renaissance’ was the release of Michael Pollan’s “How to Change Your Mind”. This book discussed the recent revival of psychedelic research in the context of its scientific and political history of the 50’s and 60’s. The title “How to Change Your Mind” touches on a core effect of psychedelics. Whether changing entrenched mental states like depression or simply transforming into a better (or worse) version of yourself, psychedelics enable minds to change. The evidence for psychedelic induced neuroplasticity, the ability of the brain to change its structure and function, stretches across multiple levels of psychedelic research (Kwan et al., 2022). Many researchers agree that this neuroplasticity is playing a major role in therapeutic change, but why would the brain be organized so that one molecule could facilitate such great change?

            Ari Brouwer and Robin Carhart-Harris have suggested that psychedelics take advantage of a fundamental system in the brain evolved to deal with extreme stress. They claim that under conditions in which current behaviors are dangerously unsuccessful, the brain is able to enter a Pivotal Mental State (PiMS) (Brouwer & Carhart-Harris, 2021). This shocks the brain into a massive remodeling, with rapid disintegration of old maladaptive models making room for new, potentially fruitful ones to take over. A commonly reported experience of psychedelics is ego death (Nour et al., 2016), in which the user loses their sense of self. This may be a subjective correlate of the widespread death of prior models. Further, psychedelics have also been known to incur seemingly spontaneous insight (Peill et al., 2022), which may reflect the rapid integration of new models. It makes sense to me that psychedelics are doing deep work within the brain to restructure a person’s mind, but is there something inherently meaningful or spiritual about this process?

80% of participants in a John Hopkin’s study ranked their psychedelic experience in the top 5 most meaningful experiences of their life, even over a year after the trial (Griffiths et al. 2008). Many participants described these experiences as “mystical” (Barrett et al., 2015), and high scores on a “mystical experience questionnaire” were correlated with positive treatment outcomes. Additionally, Psychedelics have been integral to spiritual practices within indigenous communities around the globe and throughout history (George et al, 2020), suggesting that a spiritual quality is engrained in the psychedelic experience in a way that transcends culture. Additionally, it suggests that the spirituality associated with psychedelics plays a role in their efficacy for treatment. While we can only speculate on the link between neuroscience and soul, this connection between spirituality, neuroplasticity, and meaningful change is deeply intriguing to me. That a single molecule can catalyze such processes enables thorough investigation of their relationships for the first time. Further, we can start to understand how these experiences might relate to a positive and meaningful experience of life.

Spirituality isn’t the only wholistic aspect of mental health that psychedelics are helping us recognize. Another example is the importance of genuine relationships. Positive outcomes from clinical trials and naturalistic use of psychedelics have been shown to be more likely if there is a positive relationship between the user and the people in their environment, whether that be the therapist (Murphy et al., 2021), or people present in a retreat setting (Kettner et al., 2021). Psychedelics may therefore also provide an opportunity for us to recognize the importance and utility of community in healing and well-being.

Psychedelics are showing great promise for their ability to treat mental illness in clinical trials (Zeifman et al., 2022), but what’s really exciting is their potential to transform the way mental illness is viewed and treated in our culture. While the pharmacological approach of psychedelic drugs fits the western medical system, the experiences that these drugs produce are demonstrating the importance of spirituality and community for emotional health. While the brain is a biochemical system, it is also a person who is embedded within a community, and psychedelics present an excellent opportunity to include these elements in our treatment approach. With this biopsychosocial perspective, we can better inform our pursuit of a meaningful life.

             While I’ve only scratched the surface of psychedelic neuroscience, you should now have an idea of the power psychedelics hold in our quest to connect brain, mind, and soul. This was the first episode of the introduction series, where I’m giving you an overview of the field from the molecule up to the mystery. The next episode will be on cellular and molecular mechanisms of psychedelics. Thanks for tuning in to Psychedelic Neuroscience. See you next time.

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Michael Angyus
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Introduction Part II: Cellular and Molecular Mechanisms of Psychedelics