Psychedelics and Brain Networks

Hi, and welcome to the Psycho Pharmacology Institute podcast. I'm your host, Dr. Richard Sieber, and this is the place for a reshare clinical perils to keep you updated in the field. Let's start with the case. A 45-year-old executive comes to your office with treatment-resistant depression. She's tried multiple SSRIs, SNRIs, and even augmentation strategies with lithium and airy-pipersol. Nothing is provided lasting relief from her persistent rumination and negative self-talk. She asks you about psilocybin therapy, and she's been reading about it a lot lately. How might you respond? Today we'll discuss the use of psychedelic drugs and their profound effects on brain networks. Did you know that psychedelics don't just create temporary altered states of consciousness, but actually promote cellular neuroplasticity? Cell compounds affect the default mode network, a brain network most active during wakeful rest, and engaged in self-directed thought. When this network becomes dysfunctional, we see rumination, anxiety, and a sense of feeling trapped in negative thought patterns. Psychedelics seemed to temporarily disrupt this very network, creating what researchers describe as "Ego to Solution." Joining us today to discuss psychedelics in brain networks is Dr. Franklin King, who serves as director of training and education at the Massachusetts General Hospital Center for the Neuroscience of Psychedelics, and holds a faculty appointment as clinical instructor of psychiatry at Harvard Medical School. Before we dive in, remember that the Psychopharmacology Institute stands out for its commitment to industry-free funding, providing you with reliable, unbiased, and evidence-based educational content, free from pharmaceutical company influence. And now let's explore psychedelics and their influence on brain networks with Dr. King. So let's talk about what we know about the effects on the brain with psychedelics. But before talking about the brain, I want to talk about psychedelics and the mystical experience. So the mystical experience has been defined as these cardinal attributes, which I've listed here, internal unity, external unity, transcendence of time and space, ineffability, sense of sacredness or awe, noetic quality, and deeply felt positive mood. So this was not a measure that was designed to measure psychedelics. This is the mystical experience questionnaire in the attributes and factors that it looks at. This was designed to measure more broadly these mystical states that can be very difficult to describe that can occur not just from psychedelics, but in settings of deep meditation, ecstatic dance, religious conversion experiences, all of these things. The therapeutic effects of psychedelics have been correlated with the degree to which the person had a mystical experience, and this is measured in the mystical experience questionnaire, which I mentioned two segments ago. So the higher the score on the mystical experience questionnaire, the greater the clinical improvement. One of the major areas of focus of the group at Johns Hopkins on the left here, you're seeing how the MEQ correlated with reductions in craving. This was a smoking cessation study, so there were given psilocybin and people who had higher scores on the MEQ ended up having lower cravings in the setting of that study. On the right, this was a study looking at anxiety and depression associated with terminal cancer and other Johns Hopkins study, and this is showing that mystical experience on the session days predicts reductions in anxiety five weeks post-silocybin. This is a tricky concept, I think, for most of us in medicine because medicine is highly secular, and things like mystical experience, maybe they don't sound religious, but they sound potentially non-secular. Abutting this is just the fact that people, not just mystical experiences, but they often report having spiritual experiences in their own words. And this is a study of healthy volunteers, another Johns Hopkins study, showing a very large percentage of participants reported that their psilocybin session was in the top five most spiritual experiences of their lives. And I should have mentioned that this was a study of people who were religious practitioners. They had to have a daily religious or spiritual practice. So for them to say this indicates, I think, something very significant that's happening here. But I want to switch into the Petri dish. So as I mentioned, psychedelics promote neuroplasticity. So this is a very interesting study published in 2018, showing individual neurons exposed to three different psychedelics as well as a control. So the VEH just stands for vehicular control, it's the inert substance. DOI is a long-acting psychedelic that I haven't mentioned, it's only used in research. But what you can see is that there is a major change, or major presence at least in this, but this was a pre- and post study, in the growth of dendritic spines. So I believe the yellow or gold coloring there is actually a marker for synaptic proteins. And so you can see that there's a growth from all three psychedelics following exposure that was not seen in the controls. So zooming out of the Petri dish into more network level aspects of the brain. When we talk about networks, we're talking about different anatomical regions that often are not contiguous geographically with each other in the brain, but they are wired together to perform specific tasks. And one of these networks is the default mode network, which in normal states, the default mode network is involved with our narrative sense of self. It's on when we're daydreaming, when we're engaged in internally directed thought, is when the default mode network is most active. And unsurprisingly, this is a network that's been implicated in a variety of psychopathological conditions. So we know that it's more active or dysfunctional in rumination, which of course is repetitive and negative self-directed thoughts. Abnormal activation patterns are seen in anxiety disorders. There's decreased global integrity of the default mode network, which has been correlated with PTSD severity. And it's also implicated in reduction in executive function and substance use, so decreased attention to the consequences of relapsing, obeying the impulse of craving, et cetera. What's interesting about the default mode network is that this network, which is involved in our sense of self, is precisely one of the major networks that's been shown in many different studies to become disrupted under the influence of psychedelics. And so there's studies of psilocybin, as well as LSD and ayahuasca, that all show default mode network activity disruption during the acute effects. And that some of these studies have even correlated the magnitude of default mode network disruption with the intensity of subjective experience. So one way of looking at this is that this may be the neuro anatomical or neural circuitry level basis for this experience of ego dissolution, right, because this is a network that's involved in our sense of self, it is involved in the sort of gating between internally directed thought and externally directed thought, which is precisely what becomes experientially disrupted under the influence of psychedelics. And there's a lot of downstream implications for what this might mean, disrupting this network could lead to reduce self-referential thinking and improved executive function. So being able to get out of negative thought ruts about the self, being able to lift oneself out of a self-absorbed internally directed state to be more efficiently focused on external tasks and goals and allow other networks involved in those to become more active and functional, right, including in substance use disorders, having a reduced self-focus in regards to craving may be a mechanism by which we could treat those. So a little bit more about this moving over to the cloud strum, it's deep within the cortex, it's this long thin sheet of neurons that sort of buried underneath our neocortex. The role of the cloud strum is that it supports the co activation of widespread cortical regions participating in networks necessary for cognitive control. So the cloud strum as well as the salience network is thought to be involved in switching between internally directed thoughts via the default mode network and external task-oriented processing networks, like the task-positive networks. So initiation and stabilization of executive and task-based networks by a top-down control action is one of the major functions of the cloud strum. And interestingly the cloud strum is one of the territories of the brain that is most densely loaded with 5HT2A receptors. The study conducted at Johns Hopkins showed that psilocybin caused significant changes in the cloud strum's connectivity both to default mode network internally directed thought as well as task-positive networks externally directed thought. So the idea is that psilocybin may be inducing a more dynamic or variable activity pattern in the cloud strum, which is disrupting its ability to coordinate the switching on and off of different networks of the brain that generally are functioning in discrete fashion with the default mode network, being activated when we're involved in internally directed thought. Usually what happens is networks involved in attention or executive function or tasks with the external world, those are going to be turned off. And so if we are disrupting the ability of coordinating the antagonism between these different networks, this may be one of the mechanisms by which there is this profound change in the feeling of consciousness, again, with this disruption of the felt difference between the internal and the external world. The reason I mentioned neuroplasticity is that all of this at the cellular level may be leading to a neuroplastic state, and so by disrupting all of these networks, it's thought that there may be this transient state of neuroplasticity that, given the right therapeutic context, may actually lead to improved patterns of thought to changes in deeply held thoughts such as negative constructs of the self, perhaps negative sensitivity to things like external distress, somatization, all of the things that we see in many different disorders of psychiatry, and that these might actually be able to be shifted. However, as I'll mention in subsequent slides, this would require a therapeutic setting for this to occur, that for most people this wouldn't happen in isolation. There needs to be a therapeutic context to take advantage of this neuroplastic state in order to affect any change in what is going on in the brain. So the key points here are that the degree to which study subjects have had a mystical experience as measured by the MEQ has been positively correlated with the therapeutic effects, and numerous clinical trials. The default mode network is a network of the brain normally associated with our narrative sense of self, and abnormal default mode network activity has been found in numerous psychiatric conditions. This network has also been shown to be disrupted by psychedelics and is likely a key mechanism by which psychedelics exert therapeutic change. Psychedelics may also disrupt the cloustrom, which is a small region of the brain responsible for synchronizing and controlling activity of different brain networks, including the default mode network. Disruption of the cloustrom may be another key mechanism by which psychedelics induce a more dynamic brain state. That was Dr. Franklin King discussing how psychedelics influence brain networks and their potential therapeutic mechanisms in psychiatry. So back to our patient with treatment-resistant depression. What might be our approach? First, we might acknowledge that while psychedelic-assisted psychotherapy represents an exciting frontier in psychiatric treatment, it's not yet easily accessible in most states outside of clinical trials. We might explain that we're seeing remarkable results precisely because these substances work differently from traditional antidepressants. The key insight from today's episode is that therapeutic benefits correlate with the intensity of mystical experience, profound moments of unity, transcendence, and ineffability. In the data are clear, patients who score higher on the mystical experience questionnaire show greater clinical improvements. We also learn that psychedelics target the 5-HT2A receptor, promoting dendritic spine growth, and creating new synaptic connections. At the network level, they disrupt the default mode network, that internal narrator constantly generating self-referential thoughts and ruminations. They also affect the cloustrom, a thin sheet of neurons that coordinates switching between different brain networks. This creates a window of neuroplasticity, but here's the crucial point. This window leads to therapeutic change within the right therapeutic context. It's not just the psychedelic alone, but the combination of neuroplasticity and skilled therapeutic guidance that produces lasting change. For our patient, we'd probably discuss referral to sinners conducting FDA-approved clinical trials or once available licensed psychedelic therapy programs with proper preparation, guided sessions, and integration support, if clinically indicated. Remember that if you're a silver or gold member of the Psychopharmacology Institute, you can earn CME credits for the video lecture and access exclusive content not covered in this podcast feed. And that's all for today. I'd like to thank you very much for joining me for today's episode. This is Dr. Richard Seiber, and I look forward to seeing you in our next episode. Bye now.