Welcome, everybody who's waiting. We're just going to allow some time for participants to trickle in before we start the formal session. We're looking forward to today's discussion with Dr. Stauffer. In the next couple of minutes, maybe we'll just spend a little time talking about his work with oxytocin, which I've always been fascinated with. His work seems to have pivoted a little bit, but can you tell us a little bit about what your past work with oxytocin was? Sure. I conducted several clinical trials with oxytocin for substance use disorders as an intervention. Actually, I discovered MDMA-assisted psychotherapy for PTSD in 2010 at a conference. It was presenting the first findings from that study. That was what led me into a research career so I could work with interventions like MDMA therapy and psilocybin therapy. Along the way, I started working with oxytocin because oxytocin is such a big component of MDMA, just because it was more accessible in the meantime. I think it really helped frame. I think the oxytocin field is still going through this idea of being a molecule that affects social behavior and social motivation. Just thinking through the ethics and the protocols of are we using it to facilitate a psychotherapy process or is it in and of itself an intervention like traditional psychopharm? I don't think we figured that out yet for any of this stuff, but that'll be part of the conversation today. Cool. I think that isolation ends up being a part of a lot of people's path on addiction and anything that we can do to encourage the propensity towards isolation certainly could benefit. Connections is certainly a part of the healing process. Yeah, and safe connection because a lot of times people have a really good reason for isolating or avoiding. A lot of times it ends up looking similar if not the same thing of doing PTSD work like MDMA therapy for PTSD. We're working on a psilocybin trial right now for methamphetamine use disorder that I'll talk about a little bit, but we've just noticed that pretty quickly the treatment intervention becomes more about the underlying trauma and PTSD than about focusing on the methamphetamine use. Interesting. What do you think, David? Should we get started? Yeah, I was going to say, yeah, that's a nice segue to get started. I think we've had ample time for a lot of people to trickle in. Looks like we have a big group, which is exciting today. Formally welcoming everybody, I'm Dr. David Stifler. On behalf of the American Academy of Addiction Psychiatry, welcoming you to today's webinar, which is the first of our second year hosting what we're calling the Advanced Addiction Psychotherapy Curriculum. This is a monthly series that focuses on evidence-based intensive psychotherapy training for addiction psychiatry fellows and faculty. This is hosted in partnership with Oregon Health and Science University and New York University. We're excited to be able to offer you these live trainings. They will be held the second Wednesday of each month from 530 to 7 p.m. Eastern time. Our next presentation will therefore be next month on Wednesday, September 13th. That presentation will be by Dr. Sam Wan, who will be discussing psychotherapy with male patients. You can always check the AAAP website for updates on other upcoming speakers to mark your calendars. A few housekeeping items before we begin. You're welcome to ask questions at any time during the presentation. You can use the chat box on your control panel, and we'll do our best to kind of get those questions asked as is appropriate live. And then you can also use the Q&A box to submit questions at any time, but we will probably save all of those for the end, because we have about 10 to 15 minutes where we can ask those questions at the end of the talk. And then finally, after the session, you can claim credit by logging on to your AAAP account and accessing this course and complete the evaluation and follow the prompts to claim CME credit. So I'll turn it over to you, Dr. Blazes. So thanks, everybody, for joining us. We appreciate your attention and interest in our series and this topic. We're very excited to be joined by Dr. Christoffer today. I've known him for quite some time, back from our time at UCSF, and I'm really grateful to know him now. We're both together at OHSU. He's a psychiatrist and an addiction medicine physician who primarily treats veterans and LGBTQ populations with PTSD and substance use disorders. He's the director of what's called the SNAP Lab, the Social Neuroscience and Psychotherapy Lab, which aims to maximize the benefits of psychotherapy through the adjunct use of social psychopharmacology, such as oxytocin, MDMA, and psilocybin. Dr. Christoffer has been in the investigator, study physician, and study therapist roles for several clinical trials of psychedelic-assisted psychotherapy and has served in curriculum development, teaching, supervision, and mentorship roles for several psychedelic-assisted psychotherapy certificate programs. So we're looking forward to your talk, and thanks for coming, Dr. Christoffer. Thank you so much, Dr. Blazes, Dr. Stifler. I feel very honored to be here. I'm grateful that you chose this as a topic to include in your series, and I guess with that, I'll just jump right in. So just a couple of disclosures. I am a paid supervisor and trainer of the psychotherapy piece of MDMA-assisted therapy, and it is working with MAPS PBC, which is essentially kind of a public benefit corporation serving as the drug development corporation for MDMA. So in a sense, I'm like a drug rep, but I'm not talking about the drug as much as just teaching therapists how to do MDMA therapy. And then for our clinical trials, just a note that we receive study drug from USONA. We receive our psilocybin from USONA and our MDMA from MAPS PBC. And then an important disclaimer. So I'm going to be focusing primarily on psilocybin, but this applies to basically all psychedelics, but psilocybin, MDMA, I'll reference some, are all Schedule I substances currently under the Controlled Substances Act. So their use right now is limited to research or very limited expanded access programs with strict oversight by the FDA, DEA, and IRPs. And psilocybin and MDMA currently have no FDA approved indication. So more research is required. MAPS PBC is about to submit their new drug application to the FDA for MDMA-assisted therapy for PTSD. And so if all goes according to plan, that could be FDA approved as early as second quarter of next year. So we're on the brink of some of these interventions being FDA approved, but they're not yet. Just keep that in mind as we go through. Learning objectives. So reviewing the history of psychedelic therapy, assessing existing literature, and discussing some of the ongoing research on the use of psychedelic-assisted therapy to treat substance use disorders specifically, and then talk a little bit about training, certification, and also just the modality overall of psychedelic therapy. So what is a psychedelic? So first of all, the group of classic psychedelics are primarily defined by their action on serotonin 2A receptors. Classic psychedelics include psilocybin from psilocybin-containing mushrooms. LSD, which is actually an ergot fungus derivative, but was discovered in a lab by Albert Hoffman. He's the one in the picture in the bottom right. Mescaline found in peyote and other cacti. DMT found in plants like ayahuasca. 5-MeO-DMT found in the Sonoran desert toad. Ibogaine, which is from the iboga shrub in Gabon on the west coast of Africa. And each of these has their own cultural history, and some of them predate modern recorded history, so it's just important to note that. And also that some of these sources like peyote, Sonoran desert toads, iboga shrub, have all been over harvested in recent years, and so there are some major preservation efforts in place. And for the most part, the active ingredients can be manufactured in a lab, and so there's been a big push to protect and preserve peyote cacti and just create mescaline synthetically in a lab. Other substances worth mentioning due to their effects on consciousness and sometimes are categorized as psychedelics include a class referred to as empathogens or intactogens. Intactogen meaning touching within. This includes MDMA or MDA. And also dissociatives have been used in the psychedelic therapy model, including the NMDA receptor antagonist ketamine, which is traditionally in medicine an anesthetic used to treat acute suicidality, depression, other mental health conditions, and can have more psychedelic properties at higher doses, PCP. And then I'll be focusing this talk primarily on psilocybin, mostly because it's, when it comes to psilocybin therapy for substance use disorders, psilocybin has been utilized the most in modern day clinical trials, and so there's the most data. MDMA has one pilot trial with promising effects for alcohol use disorder, but very preliminary. And there's a long cultural history and more and more funding and more and more research being put toward ibogaine for opioid use disorder. But again, we'll focus primarily on psilocybin today. Just for some context, so psychedelics have a storied history from indigenous roots to political legal conflicts to use in various contexts that show promising health or well-being effects. But just to kind of look at the different categories, different lenses from which to view sort of the effects of psychedelics and how psychedelics affect culture. So going from left to right, toxicological discourse. So the idea that any effects of psychedelics are a reaction to a poison. I think in a lot of medicine, we still call these hallucinogens, indicating that they're mimicking psychosis. And then the orange box prohibition, the idea that psychedelics are dangerous, public threat, create criminals, that we have the DEA scheduling system. And so just looking here, Schedule 1, if you're not aware, Schedule 1 drug, the criteria to be in a Schedule 1 category is that there's no accepted medical use, there's high potential for abuse, and there's a lack of accepted safety even under medical supervision. And so research is the only setting where Schedule 1 substances are allowed to be used. And psilocybin was scheduled as a Schedule 1 with the Controlled Substances Act in the early 1970s. We've also seen the decriminalization movement, which emphasizes, kind of calls out the harms done by the war on drugs, and demonstrates some of the mismatch of scientific evidence and legal classification. The decriminalized nature movement specifically has sort of taken local and state jurisdictions and decriminalized primarily plant and fungi-based psychedelics. And decriminalization doesn't legalize use, but it deprioritizes law enforcement action for personal use. But this model continues to limit access to a supportive set and setting with trained facilitators for those hoping to address mental health conditions with people who are trained to do that. And the clinical research so far that I'll go through primarily focuses on psilocybin use within a psychotherapy protocol, not psilocybin on its own in an unsupervised or unregulated setting. Psychedelics as fun, just like recreational, hedonic freedom, cognitive liberty are kind of terms that you hear in this world. And this has some overlap with decriminalization. And then psychedelics as self-exploration, the betterment of well people, this has been referred to as microdosing psychedelics, sort of the meaning of psychedelic is mind manifesting, which was a term coined to express the idea that these substances alter conscious perception in a way that provides access to usually hidden aspects of the mind, so mind manifesting. But another approach that's being piloted in Oregon, Colorado, is legalization of supervised use of psilocybin mushroom products. And this is at certified service centers in the presence of a certified psilocybin facilitator. So you can't take the mushrooms home. These models are not designed to be clinical. There's no requirement for a diagnosis. Screening is minimal. Psilocybin facilitators actually are not allowed to be licensed healthcare professionals, or they're not allowed to use their professional licensure while they're doing psilocybin facilitation. So there has to be two separate businesses, essentially. But rather, it's set up to be a service, which is kind of up for interpretation. And I guess we'll see how that turns out in different iterations. Let's see. So this essentially bypasses the FDA drug development process. And so thinking of psychedelics as medicine, we have the drug development route to FDA approval, or medicalization. And this involves preclinical research, phase one safety studies, phase two and three studies for a specific indication. And that track takes many, many years and many, many millions of dollars. And as of today, the FDA has designated psilocybin therapy as a breakthrough therapy for major depressive disorder, treatment-resistant depression, and designated MDMA-assisted psychotherapy as a treatment for PTSD breakthrough therapy. And so MDMA therapy has finished phase three. Psilocybin therapy for depression is moving into phase three. And in these contexts, screening is much more rigorous. There's a long list of inclusion-exclusion criteria. I think an argument that comes up against the medical model is that it's overly restrictive and will lead to cost hikes from pharmaceutical development and medical systems. However, this is also the most likely route to result in insurance coverage. And then finally, the last two are more spiritual or religious contexts. And so entheogenic, enthean means eliciting the divine within. So using sort of sacraments to go inward and have spiritual experiences. And then animistic is more the gods without. So I believe that everything has a consciousness or everything has a soul. Some cultures refer to these as plant medicines. And so this is Maria Sabina, who was a psilocybin curandera in Mexico. So using psilocybin for healing purposes and also for spiritual and sacramental use. And she was the first to introduce psilocybin to the West, which I'll talk about a little bit later. The Aztecs referred to mushrooms as the flesh of the gods, which was first documented in the 15th century. And then this guy here, his name is Steve Urquhart, and he was in the Utah legislature and learned a lot about religious freedom laws, sort of fighting discrimination, that's sort of the misuse of religious freedom to to be able to discriminate. And then he later used that knowledge and founded the Divine Assembly, which is a psilocybin mushroom church and promotes direct access to the divine by using psilocybin mushrooms as a personal sacrament. So it's interesting that this isn't just sort of a historical or indigenous category that this is coming up today, even. And these categories aren't mutually exclusive, but it helps you see sort of the range of context, the range of protocols, the range of intention, how it's administered, experiences that are had. And we will, for the rest of the talk, primarily be focusing on the medical model of psilocybin-assisted therapy as an intervention. Here is just showing psilocybin in the scientific literature. You can see the little bump sort of in the 60s and then 1970 became a Schedule I substance. A lot of the research, actually all the research programs that were studying psilocybin at the time shut down and practices moved underground. So there wasn't as much published in the scientific literature. And then you see just in the last five to 10 years, this exponential increase in scientific publications related to psilocybin. Psilocybin, so I think there are over 200 mushrooms that contain psilocybin across several different genera with an estimated 144 psilocybin-containing psilocybe species, which is the most common and the most potent and so forth. And then there's a lot of research and the most potent and psilocybin-containing mushrooms can be found all over the world. Dosing-wise, this is sort of the range. Psilocybin can also be extracted from mushroom products, which is what will be happening in Oregon. And then all of the studies that I've worked on, all of the clinical trials so far have used synthetic laboratory-made psilocybin. And this is the dosing for that. It's dosed in milligrams. I had another thought that I was going to say, but I can't remember. So looking at this, this is pharmacokinetic studies, psilocybin, all the pharmacokinetic studies have required people to fast with the exception of drinking water for an average of two to four hours before psilocybin administration. So these timeframes will probably vary if there's food in the stomach or other variables. This is based on a fixed dose of 25 milligrams of psilocybin. So starting in the bottom left and moving toward the right, about 20 to 40 minutes in after oral ingestion, the participant or person ingesting begins to feel the effects of the psilocybin. And that also coincides with when psilocybin starts to become detectable in the plasma, which is the red line. Peak subjective effects happen between about an hour and an hour and a half after ingestion. Peak plasma levels occur about the same time, 80 to 105 minutes. And then you see a quick drop-off in plasma concentrations. The half-life range of psilocybin is one to three hours indicated in the green, though there is some minor variability. Then primary subjective effects are mostly gone within four to six hours after ingestion. The drug is relatively eliminated by five to eight hours with complete excretion by about 24 hours. Usually our sessions, when we use this in psychotherapy clinical trials, sessions are usually about six to eight hours. It says here four to six, but I think usually if we're doing it for a clinical indication, sessions are a little bit longer. Psilocybin is a pro-drug, so it's converted to its active metabolite psilocin via dephosphorylation, removal of the phosphate group, mostly by the acidic environment of the stomach. But this happens pretty quickly once you actually pick the mushrooms. Mushrooms tend to turn blue. The blue discoloration is actually the psilocin molecules aggregating together. When two psilocin molecules come together, they actually look very similar to the blue dye that colors like blue jeans. That's why mushrooms turn blue when you pick them. Then bioavailability is about 50 percent. Talk a little bit about metabolism. About 80 percent of psilocin is metabolized by liver glucuronidation. These are the primary two enzymes. Then they turn the small lipophilic molecules. That's why psilocin is able to cross the blood-brain barrier into water-soluble excretable metabolites. Psilocin turns into the inactive secondary metabolites, psilocin O-glucuronide. That's cleared to the kidneys with minimal amounts of unconjugated psilocin. Because the secondary metabolites inactive, there's no need to adjust the dose for people with mild to moderate kidney impairment. Then the remaining 20 percent is excreted through bile into the stool with other pathways. Psilocin is an agonist or a partial agonist at serotonin receptors. It's important to note that psilocybin has functional selectivity, so it activates different biological reactions downstream pathways than serotonin does when it hits the same receptors. Because it's a direct agonist, there's actually very low risk of serotonin toxicity, whereas MDMA, for example, works to release and prevent reuptake of existing serotonin. That can potentially lead to serotonin toxicity, especially if people are taking a MAOI inhibitor at the same time. But this isn't as much of a risk for psilocybin based on the data that we have. Catanserine is mostly a research molecule. It's a selective serotonin 2A antagonist. Research has shown that catanserine blocks the psychoactive or subjective effects of psilocybin. We assume that the psychoactive effects of psilocybin are related to its activity at the serotonin 2A receptors. But psilocybin and psilocin act on other serotonin receptor subtypes, also dopaminergic and other receptors to a lesser degree. But we understand less what the effects of those are. Serotonin 2A receptors also are distributed throughout the body, throughout the GI tract, blood vessels, peripheral nervous system, blood platelets, but most of our scientific inquiry has been focused on central nervous system and effects on consciousness. But there's, I think, a lot more to be explored with these molecules. Let's move more into risks. First, we're just going to take a look at this. You might be familiar with this. This is an older version. I need to update this slide, but this is CDC data. Overdose deaths between 1999 and 2020. This includes prescription medications. You can see the synthetic opioid is mostly fentanyl that makes up that blue line that goes up above the rest. What we don't see on here is psychedelics. Looking at the DEA website, this is what they say about the overdose effects of psychedelics. Deaths exclusively from acute overdose of LSD, magic mushrooms, and mescaline are extremely rare. Deaths generally occur due to suicide, accidents, and dangerous behavior, or due to the person inadvertently eating poisonous plant material. I bring this up just because of the amount of stigma. Looking, this is again from data from the 2019 US Poison Control Center involving psilocybin without any other substances. Presumably, probably mushroom use in unsupervised settings. There was a total of 266 cases that year, 112 of them ended up presenting to an emergency room. One case was considered severe, meaning an effect that was considered life-threatening, such as repeated seizures or dangerous cardiac or respiratory effects. There were zero deaths associated with psilocybin in this context. There are people now, as psilocybin becomes more and more available, tracking things like this and tracking ER visits. But this is what it looked like before wider decriminalization or legalization of supervised use. It is important to know that psilocybin can increase heart rate and blood pressure. So any cardiovascular and neurovascular risk factors that were pre-existing may become an issue with prolonged increase in heart rate and blood pressure. But just for comparison, this is Tylenol, which you can buy over the counter. Over 30,000 cases of Tylenol ingestion were reported to poison control. Most of the cases warranted presentation to a healthcare setting. 985 of them were considered life-threatening and 101 ended in death. So looking at more population-level data, this is the National Survey on Drug Use and Health that SAMHSA does every year with around 70,000 people, includes people from all 50 states and Washington, DC. And I'm gonna include data for people 12 years and older. And I put this together just because I was curious, but looking at, so the whole circle is, the relative size of the different circles is the number of people who used alcohol in the past year. So 12 years and older who used alcohol, over 177 million. And then 16% of those met criteria for an alcohol use disorder. Marijuana, about 50 million people, almost 30% marijuana use disorder. Cigarettes, one of the few that were more than half of the people who used a cigarette had met criteria for a tobacco use disorder. Opioids. And then taking that opioid circle, I'm gonna magnify that here. And then the next category is hallucinogens. And so the way that they asked about hallucinogens is they lumped together and they specifically asked about LSD, PCP, peyote, mescaline, psilocybin, MDMA, ketamine, DMT, AMT, 5-MeO, DIPT, and then salvia divinorum. And then they had any other sort of hallucinogen or designer hallucinogen. And so it's a lot of drugs. Some of them have more abuse potential. Others are thought to not have sort of addictive potential, although they can all have abuse potential. Yet only 5% of these users met criteria for a use disorder. And then moving forward, just looking at cocaine, meth, heroin, fewer people use them, but for meth and heroin, particularly higher incidence of use disorder. So just as a comparator. And then this, there've been a few studies like this. These are two European studies where they essentially assembled panels of experts and created categories and criteria for harm, harm to others and harm to self, and then rated the different substances based on what they thought its risks of harm were. And you can see psilocybin mushrooms were rated last in all of these. All of these in pink here are all schedule one substances. So you can see kind of the mismatch of what the experts considered were the harms versus what the legal classification is. Alcohol and tobacco, not even controlled by the DEA scheduling system. And then moving from harm to potential benefits. So using the same national survey data, this is a paper that looked at national survey data between 2008, 2012, almost 200,000 respondents, 18 and over. And they distinguished between individuals with a history of psilocybin use ever in their lifetime, which was about 4% of that survey. So about 4% of that sample and individuals with no history of any psychedelic use. And they found that having ever used psilocybin in any setting for any reason was associated with significantly reduced odds of experiencing psychological distress in the past month, suicidal thinking, planning and attempt in the past year. And so this sort of starts to ask the question, not of harm, but of potential benefit. And there have been a few other studies like this published showing history of psychedelic use correlated with, I think, decreased blood pressure, some other physical effects. There have been some using prison data showing that people who had a history of psychedelics, and this is all correlation, not causation, but people who had a history of psychedelic use had less violent crimes, shorter sentences. And so moving into sort of looking at psychedelics throughout history in more of an anthropological lens, there have been several sort of anthropology assessments and qualitative studies of indigenous groups that demonstrate that classic psychedelics have helped treat addiction to other substances. This is an image from a Bwiti ritual involving the iboga shrub, the bark from the iboga shrub in Gabon. And they've used iboga in healing ceremonies and spiritual rites of passage, personal development, physical healing for longer than we have recorded history. But in 1962, a guy from the US named Howard Lotsoff went to Africa and brought iboga home after he reported that it treated his addiction to heroin. And then in 1967, it became a Schedule I substance, but it's now used legally in some places in the world in a clinic setting to treat opioid addiction, also to treat some stimulant addiction. And there's more research coming out on the use of ibogaine primarily for opioid use disorder. And then some spiritual groups use natural psychedelics as sacraments to support recovery from addiction. So the Santa Domi Church, which uses ayahuasca as a sacrament and the Native American Church, which uses peyote as a sacrament, both legally practicing in the United States and with observational evidence of recovery from alcohol and other substance use disorders that's sustained as part of a community when used as part of a community. And then this is an addiction treatment center in Peru that uses traditional ceremony, community building techniques in combination with ayahuasca. And they also have published observation data of their effects. So more to learn, but just, these are kind of the seeds of how these plant medicines have been used throughout history prior to sort of Western medical model. And then a little bit more history. So in 1953, this is when psilocybin mushrooms were first introduced to Western society. And so here again is Maria Sabina, the Mazatec curandera. And she allowed Westerners, including the guy here is Robert Gordon Wasson and his wife, who was a mycologist, to participate in a healing ritual using psilocybin mushrooms. And so prior to this, it's believed that psilocybin mushrooms were used for millennia by indigenous societies, but he brought some home with him and sort of introduced their psychedelic effects to a wider Western audience for the first time in this 1957 Life Magazine article called Seeking the Magic Mushroom. He also sent some of these mushrooms to Albert Hoffman, who discovered LSD. He was a Swiss chemist. And in 1959, he synthesized psilocybin from the mushrooms and determined that this was sort of the active component. And he was working for Sandoz Pharmaceuticals at the time, and they actually marketed and sold pure psilocybin to researchers. And so in the 60s, this was administered to hundreds of patients around the world in various clinical research contexts. And the research at the time found that it was helpful for the treatment of different substance use disorders, primarily alcohol use disorder and depression. There were multiple international conferences on psychedelic therapy at the time. And then in 1970, the Controlled Substances Act categorized psilocybin as schedule one, and those research programs shut down. However, today, clinical research has been back for a couple of decades. In most clinical trials, we administer the synthetic capsule, but we also know that psilocybin mushrooms are coming into the picture in places like Oregon and Colorado. Another thing, I guess, to mention is that the DEA has approved the use of psilocybin mushrooms. Now, Sue Sisley has approval to do research with psilocybin mushrooms in addition to synthetic psilocybin. Just going a little bit into the evolution, because I think this is pertinent to how it's used in a psychotherapy context. So remembering the psilocin acts on several serotonin receptors. Serotonin receptors are evolutionarily old and actually conserved from single cell organisms, which don't have a nervous system. But all the way forward through history to the serotonin receptors we know exist today on neurons and other cells. But it's hypothesized that psilocybin originally evolved to act on serotonin receptors within bugs to prevent them from eating mushrooms. The stoned ape theory is sort of this theory that came from Terence McKenna in the 60s that psilocybin had some role in the development of consciousness as we know it. Robin Carhart-Harris and Ari Brower have more of a scientific frame for this. Like they developed the theory of pivotal mental states, which they define as hyperplastic mental states that facilitate rapid and deep learning and mediate psychological transformation. So these are pivotal mental states can happen spontaneously and that they have served over time an important evolutionary function to aid in psychological transformation in the face of environmental threats or perceived environmental threats or pressure. So when a transformation would be needed to increase chances of survival. And they note that stress alone can lead to increased release of serotonin. And most interestingly to up-regulation of serotonin to A receptors, which we know are primarily responsible for the subjective effects of psychedelics. So stress on its own can prime the nervous system for a pivotal mental state, even without a psychedelic drug. And serotonergic psychedelics then may be associated with a neural system that evolved to mediate rapid and deep learning. This is a PET image taken by having research subjects in just a small amount of radioactive substance that targets the serotonin to A receptors. And I thought it was really interesting that sort of the to A receptor distribution is very similar to where the default mode network is. There's been a lot of research on the default mode network in psychedelics. Default mode network is separate brain areas that are highly interconnected during rest when someone's sort of focused inward, not on the outside world. So an example of resting state functional connectivity. And activity in the default mode network decreases when you start to focus on external tasks or external things. And studies have shown that hyper connectivity or increased activity in the default mode network in people with certain types of depression is possibly linked to depression symptoms like increased rumination, lack of motivation and the classic psychedelics like psilocybin have been found to decrease activity in the default mode network. Which research has shown can last for at least a week after taking psilocybin and maybe one of the mechanisms behind its ability to treat depression. Just an image of the downstream signaling pathway for what happens once a cell or in a cell once the serotonin to A receptors are activated, very complex and different again for serotonin versus psilocybin. But serotonin acts as a neuromodulator and it alters glutamate, GABA, but overall serotonin to A activation tends to lead to more glutamate than GABA. So it increases the likelihood of neuronal firing, making neurons more reactive than usual to stimuli. And this is one of my favorite images from this psilocybin literature. This is a homological scaffolds created by imaging, which is basically a mathematical method for measuring aspects of the brain that are communicating with each other. So different sub regions and how they link. And you see on the left brain connectivity with placebo and on the right brain connectivity with psilocybin. So we see a decreased resting state functional connectivity in the default mode network, but overall increased connectivity in the brain with psilocybin. Some scientists have hypothesized that maybe this is why we get some of the synesthesia from psilocybin. People with schizophrenia and bipolar one disorder have traditionally been excluded from psychedelic research out of fear that this hyperconnected state might trigger a psychotic or a manic episode. But early mid 20th century researchers actually used LSD to try to treat schizophrenia. And so that's an interesting sort of model that might be coming back. I saw a study approved of MDMA-assisted therapy for schizophrenia at UCLA that's gonna be starting up. But this is from a study in the 1950s with LSD. It's a series of drawings of the researcher by the study participant during the different phases of LSD. Earlier on in LSD research, they saw it as a model to mimic and better understand psychosis. And so that's why we call it hallucinogen or psychotomimetic. This is from a nature paper published by a group in Italy last year. And basically it looks at neural interconnectivity reduced overall in people with schizophrenia compared to healthy controls, whereas interconnectivity is increased overall in the psychedelic state. So in people with schizophrenia, they have disrupted myelin sheaths surrounding the neurons and that leads to delays in neural processing. Psychedelics on the other hand, alter the time of arrival of neural signals. But we still get changes in information processing. So in both disconnection and hyperconnection, entropy of the system increases. But one sort of newer novel potential mechanism that has had a lot of attention is increase in neuroplasticity. So you can see with schizophrenia, there's an increase in synaptic pruning, but with psychedelic states, there's an increase in neurite growth, dendritic arborization, spine density, synaptogenesis. So greater neuroplasticity that appears to open within a few hours of ingesting the psychedelic and may last more than a few days. But the neuroplastic changes made during this window of increased plasticity might survive for longer, much longer. So just to kind of summarize what I just said. So activation of 2A receptors by cellulose thought to increase extracellular levels of glutamate. Glutamate activates AMPA receptors, which then activates, which leads to fast neural transmission. And we still don't have an understanding of further downstream effects, whether it's BDNF or other growth factors that can increase neuroplasticity. So this is still an active area of research. And then the debate, I think this is the final thing I'll say kind of about the neuroscience piece, but the debate of whether or not the subjective effects are important continues. In 2021, NIH and NIDA had a big psychedelic workshop to educate leadership about psychedelics and psychedelic assisted therapy research. At the end of that workshop, they released this RFA on business innovation research to develop new psychoplastogenic compounds from scratch that do not have psychedelic properties. So a drug that has neuroplasticity effects, but no subjective psychedelic effects is what they got from the workshop. The essential question basically is, are the underlying neurobiological mechanisms sufficient to see the full and enduring beneficial effects we've seen in psychedelic therapy trials? Some researchers argue, yes, that we can have lasting therapeutic benefits from increased neuroplasticity alone. And that can get rid of some of the time consuming and costly psychotherapy sessions. Other researchers like Roland Griffiths from the Hopkins Center for Psychedelics, who's been conducting clinical trials with psychedelics longer than most people in the modern era, argues that the subjective effects are necessary to reach full therapeutic benefits. And we don't actually have any data yet to understand non-psychedelic psychoplastogens effects and the importance of context and set and setting if you're increasing neuroplasticity without any support or contextual therapy. What would that look like? We don't actually yet know. So that gets into sort of, again, where the term psychedelic comes from, mind manifesting. This is a quote from Stan Grof that I really like, psychedelics used responsibly and with proper caution would be for psychiatry, what the microscope is for biology and medicine, or the telescope is for astronomy. And so Stan Grof was a Czech psychiatrist who did a lot of LSD therapy research in the 1950s. And I think this is a good analogy. This is a quote from Humphrey Osmond, to fall in hell or soar angelic, you need a pinch of psychedelic. And he's the person who's famous for coining the term psychedelic. And I think as far as the neuroscience of the unconscious, we don't yet have a good grasp on that in general. So I always just like to mention that what we do know about the neuroscience of psychedelics is probably a very small slice of what's actually happening. I don't know if we have the tools to really fully understand what's going on during these sessions. So just holding the mystery too of what's going on, not everything can yet be explained. There's a lot of work to do. And I think a lot of the work with the psychotherapy is sort of holding onto the mystery and maybe not knowing what's going on as we're moving into these treatments. And so mystical experiences are something that you might hear in relation to psychedelic therapy. Mystical experiences are ancient phenomena. It can happen spontaneously. They can happen in conjunction with spiritual practice, meditation, or through the use of psychedelics. And William James defined sort of mystical experiences and common core themes across cultures and religions for a more modern audience in 1902 with his book, The Varieties of Religious Experience. And the Hopkins group developed and validated the mystical experience questionnaire based on William James' work to measure the quality and strength of mystical experiences during psilocybin sessions. The questionnaire now is 30 questions. It has six domains, including unity. So an experience of both internal, external unity. So a strong sense that everything is connected. Noetic quality, the feeling of having intuitive knowledge of some ultimate truth, a sense of sacredness or awe, deeply felt positive mood, transcendence of time and space, and ineffability or difficulty describing the experience in words. And Hopkins really was the first place to start up psychedelic therapy again. And in 2006, they did a study in healthy adults giving them high dose psilocybin. 61% reported meeting their criteria for a complete mystical experience. And then more than two thirds at 14 month follow-up rated the psilocybin experience to be among the top five most personally meaningful and among the top five most spiritually significant experiences of their lives. And then what's more, they continue to use the mystical experience questionnaire and other labs use the mystical experience questionnaire. And across studies and across indications, so depression, anxiety, alcohol use disorder, smoking cessation, the strength of the self-reported mystical experience during the psilocybin experience correlates significantly with therapeutic outcomes for the different studies. Over decades of research and also the work that continued underground after schedule one in really informed sort of the model that we use today. And people like Stan Grof and other early psychedelic researchers from the fifties and sixties also learned a lot from indigenous practices. But we've kind of distilled a lot of researchers now doing psilocybin assisted therapy work believe that the positive outcomes are a result of the interaction of these things. So there's the drug, the set, which refers to the mindset of the participants and the therapists including their intentions. And then the setting is the physical setting or the therapeutic environment, which is typically different from recreational use and also different from other clinical environments. This picture here is from one of the MAPS studies. This is Bruce and Marcella who are MDMA therapists. They've set up in their clinic a couch which they kind of turn into more of like a bed type thing. And their whole office is more of like a cozy living room environment rather than a clinical space. And then support. So support during from the therapist, but also support of the family systems or other social systems that the individual might be in during the entire protocol. It's hard to sometimes explain sort of what happens in these sessions, but I hear a lot of really great metaphors. And one of the metaphors used particularly for treating PTSD with psychedelics is that our bodies have an innate capacity to heal. One of the sort of tenants of psychedelic therapy is inner focus, interdirected focus on an inner self. Interdirected focus on an innate healing capacity. So our body knows what we need in order to heal just like when we break a bone. Or we might go to the ER and get a cast or even screws to set the bone, but the bone and our immune system and our bodies do the healing themselves. And so with psychedelic therapy, we're essentially removing obstacles, removing distractions. And during the psychedelic dosing sessions, we really sort of put the trust on the inner healing intelligence. And so you see this participant has eye shades on and headphones. Usually there's music used, that playlists are sort of designed to support the arc of the psychedelic experience and the process. And the therapists are not really doing like talk therapy during a dosing session, specifically, especially with psilocybin. They're more just there to support if the person needs support, make sure that they're drinking water, getting to the bathroom okay. But usually four to six hours can go by without a lot of conversation. We also encourage people to allow the process to be non-linear. And sometimes it doesn't make sense to them until the next day. Sometimes it doesn't ever make sense to them what happened, but they just feel better. And so just kind of letting them unravel in whatever way makes sense for them. And so now I'm gonna go into some of the research studies that used psilocybin assisted therapy for substance use disorders. I think it's important just to talk about some of the limitations. Some of these are online surveys and a lot of the pilot trials, clinical trials are open label. So everybody knew that they were getting psilocybin. For the RCTs, it's still, it's really difficult to blind a psilocybin trial. If you're having psilocybin versus an inactive placebo, people usually know. Even if researchers have tried to find an active placebo, which people have used different iterations of different things or tiered dosing, people still usually know. And so you have expectancy effects and essentially like unblinding. And then I mentioned some ongoing studies. Those aren't yet complete. Okay, so this is the typical protocol of psychedelic assisted psychotherapy. So there are a number of preparatory sessions, average of three, but can be more or less, depending on the study protocol. And these sessions are intended to build rapport. So you're going into a deep process with your therapists. You wanna make sure that you have some therapeutic alliance built before you go into that just to maximize the effects. And then for the therapist to provide psychoeducation around the non-ordinary state of consciousness, trying to not set expectations, but just make sure that they know what they're getting into, informed consent. And then methods for how to therapeutically maximize the effects of the psilocybin dosing sessions. We also encourage participants to set intentions for the dosing session. This can be as simple as, I wanna stop using alcohol, or I wanna understand sort of blocks to having more self-compassion and that they state their intention at the beginning of the session and then kind of forget about it. And then we can bring it back again afterward or during the following integration sessions. Dosing sessions. So these are typically several weeks apart and these are day-long sessions. They usually come in around 9 a.m. in the morning, get settled in, and we usually administer the psilocybin by 9.30. And then again, the acute effects typically are four to six hours, and then the session ends seven to eight hours in. We encourage people to come in with beginner's mind, sort of staying present with what's coming up. I've never been in a session where nothing came up, so there's always a lot of material usually to work with. And just moving into and through experiences as they come up, even challenging experiences and challenging emotions rather than trying to move away from them or get rid of them or avoid them. I talked a little bit about the interdirected approach. I've never seen two psilocybin sessions that were even remotely the same. That's just such a wide variety when you really just allow the participant to drive the experience. We encourage the interdirected approach because people can have such vivid visions or symbols come up, messages. People have pretty intense transpersonal experiences. They can have experiences of talking to deceased loved ones and resolving issues that they didn't think were possible to resolve. And there's slight differences between managing someone in a psilocybin session versus MDMA versus ketamine, but the Venn diagram is pretty overlapping. So if I were to be watching a video of a session, I don't know if I would be able to really tell if it was psilocybin or MDMA or ketamine. And the general principles are the same. MDMA may be a little bit more active for the therapist and you may need more specific training in trauma, but general principles are the same. How are we doing on time? I'm forgetting what we- Another 10 to 15 minutes. Okay. Gosh, I talked a lot. And there are quite a few questions also just so that time will be useful. Okay. I'm gonna just really quickly go through some of these studies just so you can see. And I'll send out these slides too so you can read the other stuff, but these are the clinical trials that we've done in the past. And we've done a lot of clinical trials and you can read the other stuff, but these are the clinical trials. So you can see the sort of the model of the therapy for alcohol use disorder study. They use motivational enhancement therapy and you can see the reductions in percent of drinking days, percent of heavy drinking days. This was an open label trial with 10 people. This was a larger randomized controlled trial. They used a high dose diphenhydramine as the control. You can see similar reductions in drinking days, heavy drinking days, and you can see the psychotherapy protocol. Tobacco cessation at six months, 80%, around 80% had continued to quit tobacco. This was in a CBT framework. 12 months, about two thirds still were abstinent from tobacco, more trials coming. Stimulant use disorder. So this is a study of psilocybin therapy for cocaine use disorder. Peter Hendricks, the University of Alabama. And this is a little bit of a backwards chart. So you want the line to go up. This is abstinence. And the red line, this is the first 10 completed participants. The red line got psilocybin, the black line got diphenhydramine as an active placebo. And so you can see there's greater rates of abstinence. He's about to publish the results of the FULS trial, which I think is 40 participants. This says 30 here, but I think it's 40. And then our trial, this is our protocol for psilocybin therapy for methamphetamine use disorder. And it takes place within a residential treatment program at the Veterans Recovery House of the Portland VA. And you can see we have four PrEP and then four integration after each psilocybin. We wrote a little bit about our thinking about this and there are other groups. There are at least three or four other groups around the world who are looking at psilocybin for methamphetamine use disorder. So we're trying to coordinate and plan together so we can put our data together. This is a really great paper from Katrin Preller's lab, just about the potential mechanisms for psilocybin therapy and substance use disorders. And then I'll stop there and see what questions we have. Well, actually you could continue for a few more minutes. I meant to say that 10 to 15 more minutes of your discussion. Oh, I see. Yeah, so if you don't mind going back and finishing up some of this stuff. Yeah, so let's see. So once, what do I have to say about this? I think we talked about a lot of this already, neuroplasticity, a lot of the things that you see substance use disorders doing, like reducing neuroplasticity, deficits in learning, altering brain connectivity in a way that reduces cognitive flexibility. You see the opposite effects from the sort of therapeutic implications of psychedelics. So increasing neuroplasticity, increasing brain connectivity, increasing cognitive flexibility. And so this is just a nice paper putting together sort of the background in science from some of these possible mechanisms. But again, we really don't quite have the full picture. These are just kind of, I don't know, hypotheses at this point. It's hard to be reductionist when it comes to the effects of psychedelics. Just a moment to sort of comment on the psychotherapy frame. People have used different things. The tobacco cessation study used CBT for tobacco cessation. The alcohol use disorder studies with methamphetamine use disorder, the crack cocaine study all kind of used a framework of motivational enhancement therapy. And for me, this is a really helpful model. Already being an addiction psychiatrist and understanding and knowing motivational interviewing really helped me with the sort of non-directive, you know, client-centered is kind of a good accompaniment to this non-directed, inter-directed approach. I think using motivational interviewing skills can be really helpful in the context of psilocybin therapy. Rolling with resistance is something that is also sort of a key component of psychedelic therapy, resolving ambivalence, all these things. Other types of therapy that have become sort of good pairings with psychedelic therapy are acceptance and commitment therapy, internal family systems, has been really helpful just because of the sort of multiplicity and transpersonal nature that can come up, but to be able to talk about different parts using the system that IFS has, has been really helpful. And then just a little bit about the history of 12 steps in psychedelics. So this is from a paper, David Yadin, Peter Hendricks, just thinking through how psychedelics might be integrated into a 12-step model. You know, the first step of a 12-step program is admitting one's powerlessness over the drug, but I've always found it interesting that all the other steps are not about the substance, they're about surrendering, they're about connection, social repair, and eventually self-transcendence. And actually the lore is that Bill Wilson, who founded AA, had his own self-transcended experience while he was receiving an experimental treatment for alcohol use disorder that included plants known to have hallucinogenic properties, belladonna and henbane. And this was his fourth attempt to quit using alcohol. And after that experience, he remained alcohol-free for the rest of his life. He was inspired to found Alcoholics Anonymous. And interestingly, I can't remember how many years later, two decades later, he took LSD, reported a similar experience to his initial sort of self-transcended experience that inspired him to start AA. And so he tried to advocate for the use of LSD in Alcoholics Anonymous, but already AA was an abstinence-based program, and he was essentially, you know, the idea was suppressed by his own organization. But that being said, there is a group that has formed called Psychedelics in Recovery, which is a 12-step program like AA or NA, but it's for people, you know, run by the community, peer-led, doesn't cost anything, interested in incorporating psychedelics into their recovery using a 12-step program. And I'll end with that. And a lot of the things that I skipped were just like survey studies that Hopkins did, just to kind of summarize those quickly. They would put out surveys and get hundreds of responses of people who felt that they had been able to quit smoking, quit drinking, reduce their other substance use, opioid stimulants, after a psychedelic experience. So a lot of it was like retrospective surveys of people sort of rating what their substance use was before a psychedelic experience and what their substance use was after a psychedelic experience. All right. Well, thank you, Dr. Stauffer. So let's jump right into questions. David, do you want to start off? Sure. First, I'll kind of lump together some pharmacologic questions. Any effects of psilocybin beyond the serotonin agonist properties? And should we have any concern or offer any cautions to people or patients who are on 5-HT2A active drugs like SGAs who also want to use psilocybin? Yeah. I mean, I think for the first question, we don't know. There's so much to learn and explore. I think we've really, you know, we focused on sort of the obvious subjective effects and being the serotonin 2A, but we don't know what the effects of psilocybin are beyond that. And also with mushrooms, there are other potentially psychoactive agents that are not psilocybin that have yet to be really very well explored. And then, yes, I mean, I don't know if they're necessarily cautions, but like if someone is taking a, you know, an antipsychotic that blocks 2A receptors, then the psychedelic is less likely to work or may not work at all. And I wrote a systematic review of basically all the trials to date looking at pairing like SSRIs, SNRIs, and other psychiatric drugs with MDMA or psilocybin. And there's not a lot for psilocybin. There's not a lot of like good quality data. But Johns Hopkins just published the results of a large survey where they just asked people in general, you know, were you on psychiatric drugs when you use psychedelics and what were the effects? And I think they also asked people who had recently titrated off before they use psychedelics. And they estimate based on this survey data that the sort of window for people being on long-term SSRIs to titrate off before a psychedelic without it blunting the psychedelic effects is about three to six months. So another question, how do you discuss with patients the difference of the potential benefits and risks between psilocybin-assisted psychotherapy and recreational use of psilocybin? Yeah, I mean, sorry, I'm just looking at the question again. I get this question a lot sort of in the context of, I work at the VA and I hear from providers working with veterans who, you know, want to access psychedelic therapy because it's in the news everywhere or they get on a list for one of these programs that brings veterans outside of the country to do psychedelics and the list is hundreds of people along. And so they just decide, you know, I'm going to just do this on my own. And so I take like a harm reduction approach with that. There are harm reduction resources you can give. The Zendo Project has a pretty good manual for harm reduction points to think about with psychedelic use. The Fireside Project is a free psychedelic support line where people can call either during or after a psychedelic experience. But in general, I think the main thing is, you know, the source where they're getting the drug from, you never know based on what it is, what it might be. I think it's a little bit more safe for something like psilocybin mushrooms. And then just not having a trained or even, you know, supportive person present during the experience can also introduce risks. I was just putting in the title of that paper that you just mentioned about the attenuation of the effects of psilocybin with antidepressants. So the link came up with a paywall, but I put the title in in case anybody wants to check that one. Chris, I missed the last question. Sure. I could go next. So there was a question about, you know, saying there's lots of interesting psychopharmacology. How do you deal with psychopharmacology and how do you deal with interesting psychopharmacology? How do these various psychedelics interact with psychosocial interventions? How do psychedelics promote spirituality? Has anybody used psychedelics in doing 12-step facilitation? And how have participants changed in terms of their spirituality after treatment with psychedelics? And do changes in spirituality persist and for how long? And just to add to that question, I think the word spirituality is kind of like has a, is taboo within the scientific community. And I think one of the interesting things about psychedelics is the fact that, you know, that there's a direct correlation between the degree of mystical experience and the success of the treatment. So one of the interesting things is maybe bringing the word spirituality back to being acceptable within the medical community. Yeah. And, you know, one of my friends up here, Granqvist, just won the William James Award at the APA conference. So I think some of that is happening. Just understanding the importance of, you know, these experiences and to the human condition. Hopkins is about to publish a really interesting study using psilocybin with religious leaders from different religions and the impact it had on how they interact with their congregation and, you know, how they think. But in the study that I mentioned where people had reported their psilocybin experiences being among the top five spiritually significant experiences of their lives, the follow-up was 14 months later and was still really high. But then when you kind of bring it down to more of a case-by-case level, you know, you see a whole range of things. I worked with a participant in the psilocybin for methamphetamine study who essentially for several hours straight had multiple conversations with dead loved ones and had made all of these repairs and had this really profound experience. And we have a chaplain who works with closely with us for people who have experiences like this. So we're not just, you know, the scientists like asking them to fill out a form that they have somebody to process with who's trained also in psychedelic therapy. So we asked if he wanted to talk to the chaplain and he said, no, I don't want to talk to the chaplain. I'm still an atheist. I don't like that. It didn't change the way that I think about my beliefs. So I thought that was interesting. We have a question. Any advice you can give for residents who are interested in becoming psychedelic therapists, like which trainings to do or when and how to get started? Yeah, I think it's good to have some clinical experience. So if you can do it later in your residency right now, I think the gold standard is getting training for MDMA therapy because you are a little bit more active. People are more lucid. You can do a little bit more therapeutic work within the sessions. And so there's just deeper training on like the, you know, how transference and counter transference are dialed up, you know, the rupture and repair amplified. So things that you really need to be prepared for. And if you're trained for MDMA therapy, I think it makes it a lot easier to do psilocybin therapy or ketamine therapy. Right now, there aren't really like we're in kind of the Wild West of psychedelic certification programs. Oregon has several programs that have been approved by Oregon Health Authority. So if you go to the Oregon Health Authority website to look at the different programs, you can read about the different programs and they all have sort of different cultures and different focuses. But that might be a good place to start. But we don't know kind of post FDA approval if any of that will mean anything. CIS, the California Institute of Integral Studies, has the, as far as I know, the longest running above ground program for psychedelic facilitators and researchers. And that's a year long program. I think the applications are due in December. And I know a lot of people who have done that who have found it really helpful. So here in Oregon, it's now legal to give psychedelics in the setting of, I don't know if it's called therapy or not, but it's already happening here. Can you help us understand the difference between what you're doing and what's actually happening in the community here in Oregon? Yeah. So in the community in Oregon, to be a psilocybin facilitator, you need to have graduated high school, you need to be older than 18 years old, and you need to take an Oregon approved psilocybin facilitator course. And I'm not remembering how many hours that is, but it's something like 120 hours. And you have to do some sort of practicum where you're at a site, you know, being observed or working alongside someone, I think for 40 hours. And so that is sort of the minimum requirements to be a psilocybin facilitator. In Oregon, again, it's not a medical model, it's not psilocybin therapy. And actually people are not allowed to practice therapy. If they're a licensed therapist and they're doing psilocybin facilitation, they're not allowed to say that they're doing therapy with people. They're just either sitting for someone on psilocybin or they're doing therapy with them afterward in their therapy practice, which should be separate. So that's a little bit, you know, to distinguish it. There's no requirement for a diagnosis. So anybody could go in and if they meet the kind of minimum requirements, they can have a psilocybin experience. But there's no guarantee that it, you know, would be in a therapeutic setting. I've heard people talk about, you know, using this model, the psilocybin services model to like, I don't know, set up like the, like a psilocybin bar, you know, like where you would go to a bar and drink alcohol, you would go to a place and take psilocybin and it would be supervised by someone. But it's not that you would have to be doing therapy. I've heard someone say they wanted to open a microdosing golf company. So I think we're going to see all sorts of things in this company. So I think we're going to see all sorts of things in this model. Whereas in sort of FDA guided clinical trials, it's more focused on an indication, you know, like PTSD or alcohol use disorder. And usually at least we work in pairs, we work in therapy pairs in the clinical trials. And one, at least one of the people in the pairs has to be a licensed professional. So either a psychotherapist or a physician. And I think it's safe to say that the rigorousness that you go through and the clinical trials go through is significantly different than what's actually happening out there. Like oftentimes they're done in groups with maybe not even any preparatory sessions or follow-up sessions. Is that correct? That's right. Yeah. Yeah. And then the screening too, for the clinical trials is just really rigorous. Like I think our screening is like eight hours long for our psilocybin trial and includes like really in-depth psychiatric evaluations, medical, physical exam, labs, EKG. And one last question about that is that I suspect that if you are a physician or if you are a licensed practitioner and you end up doing, being a facilitator, it's easy to say, oh yeah, I'm just turning off that part of me and not using it. But I would suspect you might be at risk medical legally. What are your thoughts on that? I mean, nobody knows yet. I know people have reached out to like the Oregon Medical Board or the Board of Psychology to ask them, are you going to investigate people if they become psilocybin facilitators? And I don't think any of them have taken a stance yet. So it's kind of a gray area. There's definitely at least a little bit of risk at this point because we don't quite know how it's all going to turn out. I know you mentioned the default mode network. There were a couple of questions on it. It looks like maybe just to kind of review how psilocybin, involvement of psilocybin versus what it's like in a depressed patient. And then somebody also asked just to maybe elaborate on default mode network, neural connections, function, and how psilocybin helps in psychiatry as it applies to the default mode network role. Yeah. So default mode network is reduced with psilocybin. I did pick one. Are you planning to send like the PDF of the slides? Because there are a couple of citations on the page where I talked about the default mode network. And it's maybe easier to follow along in a paper because it does start to get pretty complex sort of these tracks. But in general, yeah, psilocybin reduces the activation of the default mode network, but increases connectivity overall. So based on your observations thus far, how much of an effect will these treatments have on refractory depression and PTSD, small, large, medium, truly revolutionary or another good tool in the toolbox? That's a really good question. I think I definitely lean toward more another good tool in the toolbox. And I think there are important risks. I think one of the slides that I skipped past is about risks. And so thinking about people in the hospital when they ask me about this, usually what they're thinking about is physiological risks with the increase in heart rate and blood pressure, seizures. They're thinking about, is this going to cause a psychotic episode? What if someone has a challenging experience or a bad trip? But I think a really important risk category is relational risk, especially if we're opening up critical periods of relational development. Something that I've seen is people will have these really profound experiences internally with eyeshades on, and then they'll take the eyeshades off and you're the first person that they see. And they sort of attribute this transformational healing that they just had to you. And so if you're not sort of tuned into your own counter-transference in your own attachment dynamics, it can be really easy to fall into an enactment. And so that's why I think psychotherapy skills are really important in this, because I think when we see things like boundary transgressions or boundary violations in the psychedelic therapy container, it's not always like conscious or intentional. And so being aware of those things is really important. Well, I'll just finish up with one last question. So what's your thoughts on the fact that, I think for pretty much all the trials out there, isn't coming off of all of their psychiatric medicines kind of a prerequisite? Have you noticed some difficulties with that? And do you think that there's a place for people to maybe stay on some of their psychiatric medications? Because it can be challenging. Right. I think that's an important question. We have had people who were unable to titrate off the medications and were not able to continue in the study. I do know that some people are starting to do those studies, like see if we just increase the dose of psilocybin for someone who's on an SSRI, does that help us get the same benefits while also not having to titrate off of their SSRI? So I think more research is coming, but we don't quite yet know. So yeah, the tradition so far has been to just take everybody off of any serotonergic medications. That also includes mood stabilizers and antipsychotics that don't have, right, pretty much all psychiatric medications. Yes, for the most part. Yeah. Well, I'm trying to think, we allow people to stay on hydroxyzine and trazodone if they're using them PRN, and then we just have a window, no trazodone within 48 hours before a psilocybin session, but through the rest of the study, they're able to use it. All right. Well, again, thank you so much, Dr. Stauffer. We really appreciate you spending time with us and sharing your wisdom. This is such an important topic, and we will make sure that we share the slides with everyone, hopefully, and look forward to next month. We're going to start the first of our series in gender-related psychotherapy issues with Dr. Sam Wan, also, who I got to know when I was at UCSF, so we're looking forward to that. And thank you, everybody, for your attention. Thank you so much for having me. Thanks again. See you next month, everyone. Bye.

psychedelics

psilocybin

substance use disorders

psychedelic therapy

psychological distress

reducing symptoms

risks

pharmacokinetics

prevalence

brain connectivity

neuroplasticity

mystical experiences