All right, so we'll go ahead and get started. So thank you everyone for attending today and welcome to today's webinar. My name is Benjamin Buchholz and I'm an Instructional Designer here at the American Psychiatric Association Department of Education, and I'm very pleased that you'll be joining us for today's webinar in the Emerging Topics webinar series, Psychedelics for Addiction, a Primer for Providers. Next slide, please. So today's webinar is part of a new APA initiative, the Emerging Topics webinar series. The goal of the series is to stay up to date on important topics and trends impacting psychiatry. These activities are free of charge for all members, and these webinars are presented by specialists across the field. And these webinars will explore a range of diverse and pertinent topics and offer a chance to interact with peers and subject matter experts. Next slide, please. Today's webinar is designated for 1.5 AMA PRA Category 1 Credits for Physicians. Credit for participating in today's webinar will be available for 60 days, so until July 31st of 2022. Next slide, please. Links from the presentation today will be available in the chat area of the attendee control panel, so please click that little message bubble icon below to open the chat function and then select the link to download the PDF version of the slides. Next slide. So throughout the presentation, please feel free to submit your questions by typing them into the Q&A area, also found in that attendee control panel, and we'll reserve 20 to 30 minutes at the end of the presentation for Q&A. Next slide. So now I'd like to introduce you to the faculty for today's webinar, Dr. Nathan Sackett. Dr. Sackett is an addiction psychiatrist and serves as an acting assistant professor at the University of Washington Department of Psychiatry. He's also the director of the Center for Novel Therapeutics in Addiction Psychiatry. And Dr. Sackett's expertise includes exploring novel therapeutics and treatments as well as psychedelic treatments for substance use disorders. And Dr. Sackett, thank you so much for being with us today, and I'll hand it over to you. Great. Thank you so much. It's a pleasure to be here, and I hope you guys find this talk useful. So in terms of disclosures, I do do some consulting for a ketamine-assisted psychotherapy clinic, but they don't fund any of my work in any capacity. So we're at an interesting point in time when it comes to psychedelics and psychiatry, where public interest in psychedelics has outpaced our understanding of their safe use. The media often portrays psychedelics as the next cure-all and often makes some wild claims about their possible application. That said, there's some compelling early data to suggest that perhaps psychedelics, when paired with psychotherapy, may be able to treat substance use disorders and addiction. So today, I hope that we can generally speak about the field and give some context. But I want to say at the onset, the data at this point for the use of psychedelics as a therapeutic intervention for addictions, while rich in history, is still quite young. It's really composed of a small number of epidemiologic studies, a handful of naturalistic and observational studies, and a few pilot studies and a couple of small clinical trials. In my clinical practice, I'm contacted almost daily by desperate patients and families who want to know if psychedelics could be helpful. I always tell people that at this time, we have many more questions than answers. That said, for some patients, it seems plausible that psychedelics, when paired with psychotherapy, could be helpful. For those patients, I try to engage with them and consider options, which are limited at this time. And we'll discuss some of these options at the end of today's talk. So to that end, I have three broad goals for today's talk. I want to help better understand the current place of where we are in the research and kind of place that into a larger context. Second, I want to try to explain some very basic differences about the major psychedelics that patients may come to you with questions about. And thirdly, I'd like to help you explain to patients the current state of their research. So to meet these goals, the talk is divided into three sections. We have a background, a primer in psychedelics, and a kind of where are we at now. And we'll go through this in the next hour. Okay, so first we need to talk a little bit about definitions. So the term psychedelic was first noted by Canadian psychiatrist Humphrey Osmond in 1957, which means mind manifesting, and was originally used to describe the effects of LSD. Since then, the term psychedelic has grown to include a huge range of compounds, which has led to some confusion. I think of the term psychedelic as an umbrella term that includes numerous different substances that often share common subjective experiences. Grinspoon and Balakar provide a good description of the subjective experience of psychedelics in their 1997 book. It states, it more or less reliably produced thought, mood, and perceptual changes otherwise rarely experienced except in dreams, contemplative, and religious exaltation. We also need to be clear about how we're defining addiction. I prefer the 2019 American Academy of Addiction Medicine definition, which states, addiction is a treatable chronic medical disease involving a complex interaction among brain circuits, the environment, and an individual's life experience. People with addictions or engaging behaviors that become compulsive and often continue despite harmful consequences. But we need to be a little bit more precise when we talk about psychedelics in terms of the general terminology that we use, and particularly if we're going to talk about them as having potential therapeutic use. If you look at the literature, generally psychedelics fall into multiple different taxonomies. There are three broad taxonomies that we're going to quickly review. The first is receptor affinity, the second is chemical structure, and the third are descriptive terms. When we talk about receptor affinity, we can refer to them as 5-HT2A agonists, which includes things like LSD, psilocybin, and DMT. We can talk about them as having mixed receptor affinity, which includes things like MDMA, MDA, and iboga, or we can talk about them as having NMDA antagonist qualities, which includes things like ketamine, dextromethorphan, and nitric oxide. When we talk about chemical structures, we divide substances into two broad groups. We divide them into endolamines and phenylethylamines, with endolamines further divided into tryptamines and ergolines. When we talk about tryptamines, we're often referring to psilocybin DMT and 5-MeO-DMT. When we're talking about ergolines, we're referring to LSD and LSA. And when we talk about phenylethylamines, we're talking about mescaline and MDMA. And finally, oftentimes people will use descriptive terminologies when talking about psychedelics. They may refer to something like a classic psychedelic, which broadly refers to things like LSD, psilocybin, and DMT, kind of serotonergic psychedelics. You may have heard the term empathogens, which generally refers to MDMA, or you may have heard the term of a disassociative psychedelic, which generally refers to ketamine. As it pertains to the potential therapeutic use, we're going to broadly discuss compounds that fall into each of these different categories. So next, we're going to talk a little bit about the history. We can't really understand our current research landscape without some understanding of how we got here. And the history of psychedelic research in the modern medical paradigm can be broadly divided into three waves. I generally think of the first wave as what we call, or what I call, the discovery wave, which occurred between 1897 and 1943. And it's defined largely by the use of mescaline and the synthesis of mescaline and other compounds. So in 1897, mescaline was synthesized. In 1901, iboga was first identified in the French Congo. In 1912, MDMA was synthesized by Merck. In 1913, there was the first publication of administered mescaline, both to physicians and healthy volunteers, and ended up resulting in the first qualitative paper of their experience. The second phase, or the second wave, is what I refer to as the experimentation wave. And this occurred between 1943 and 1970. 1943 is the infamous Bike Day. That's the day that Albert Hoffman, the chemist at Sandoz Pharmaceuticals, accidentally ingested LSD and biked home. In 1947, Sandoz Pharmacy is reported to say, or reported and began distributing Daylacid specifically to psychiatrists and trainees. And they're quoted by saying, by taking Daylacid himself, the psychiatrist is able to gain an insight into the world of ideas and sensations of mental patients. Daylacid can also be used to induce model psychosis of short duration in normal subjects, thus facilitating studies on the pathogenesis of mental disease. Then in the 1950s, 1954, William Shaw proposed the serotonin hypothesis. In 1958, Sandoz Pharmacy synthesized psilocybin and branded it as indocybin. And then in the 60s, in 1962, we had the Good Friday experiments done at Harvard by Timothy Leary. In 1963, the head twitch response was developed in animal models, which is the first behavioral pharmacological assay used in animal models as a surrogate for psychedelic activity. And then in 1970, we had the passing of the Controlled Substance Act, which essentially stopped all clinical trials on psychedelic compounds. Until the third wave, which can be generally termed kind of the neuroscience wave. The third wave really started back with, in 1985, the investigative new drug application was filed by MAPS for DMT. And then in 1994, was the first observational study by Rick Strassman at the University of New Mexico, giving DMT to 12 healthy volunteers. In 1997, the 5-HT2A receptor was first localized. In 2006, the first phase one psilocybin for end-of-life trial was published. And then in 2016, Michael Pollan's book was published, which really increased kind of general public awareness of psychedelics use in a therapeutic context. This was the same year that psilocybin study for the end-of-life distress by Ross was published. And then in 2018, both the USONA and Compass Pathways both were given breakthrough therapy designation for a phase two clinical trial using psilocybin for depression. And so that's led us to our current state. Thinking back about psychedelics and their history, it's interesting to note that psychedelics have long been used to treat addiction. In fact, in 1934, Bill Wilson, who was known as the founder of AA, was admitted to New York City's town hospital with his fourth attempt to recover from alcohol use disorder. And at that point, he was administered a mixture of henbane and belladonna, plants with a mixture of tropine alkaloids often classified as a psychedelic. It's during this experience that it's reported he had experience of a white light and feelings of great peace, which was interpreted as a spiritual experience. Now it's unclear what brought this on, as it was reported to only have lasted 20 minutes. But Bill Wilson would report reportedly avoid alcohol for the rest of his life and go on to develop AA with a mission to heal individuals with alcohol use disorder through spiritual awakening. And then in the 1950s, Humphrey Osmond, the Canadian psychiatrist who first used the word psychedelic, noted that patients with alcohol use disorder who experienced delirium tremens often had a transformational experience that would result in them stop, that they would stop drinking thereafter. And he wondered if LSD could induce a similar experience as DTs and thus began giving LSD to a variety of alcohol use patients. And this really led to the explosion of early studies that were often poorly designed and underpowered, but led to this awareness that LSD perhaps had some therapeutic utility. Bill Wilson later went on to do LSD a number of times with Dr. Sidney Cohen and philosopher Gerald Heard. During these experiences, Wilson notes a remarkable similarity between his white light experience and that of LSD. And it's interesting to note that Osmond, he first developed the format that's often used today, using preparatory sessions, guided sessions, and psychedelic integration sessions thereafter. And then over the last 20 years, there's been this renewed interest in the use of psychedelics to accelerate engagement of folks struggling with addiction in things like AA and 12-step facilitation. And the remainder of the talk is going to be reviewing some of these smaller studies. Okay. But wait, you're going to use drugs to treat drugs? This is a question that I often get. To address this, let's talk a little bit about drugs in general and then discuss some of their properties. When I am faced with this question, both from fellow researchers and from patients, I often point to a paper by Nutt and colleagues who conducted an interesting analysis in 2010 of various drugs in the UK using a technique called multi-criteria decisional analysis. Essentially, they took a range of experts and epidemiological data and identified a range of harms to users and harms to society. And they ranked this harm so we could better understand the effects that these substances have and kind of characterize these compounds by risk and harm. So when they talked about harm to users, they included nine measures, including things like physical harm, psychological harm, and social harm. And examples include drug-specific mortality, dependence, and loss of relationships. Harm to others included seven measures, including things like injury, crime, economic cost, and family adversity. And then they ranked each of these substances with harm measured on the y-axis converted to a 100-point scale and the specific substances on the x-axis. And you see here that in the blue is harm to users and in the red is harm to society. And here we see that alcohol is ranked to have the greatest burden of harm in total, scoring 72 out of 100, followed by heroin of a score of 55, crack on the score of 54, and methamphetamine of 33. Note the harm associated with ketamine is about 15, which is on par with benzodiazepines. And then LSD is seven, and psilocybin or mushrooms are six. I like this graph because it illustrates how drugs are not all the same and that legal status does not seem to follow harm. Additionally, most psychedelics are not considered to have high intrinsic addiction risk. There's a lot of studies highlighting this, but there's a process called tachyphylaxis, or a rapid reduction in drug effect due to the downregulation of the 5-HT2A receptor, making it very unlikely or very difficult for someone to develop a physiologic dependence and tolerance on serotonergic psychedelics like LSD and psilocybin. This is well documented if you talk to patients who have tried to use psychedelics soon thereafter and that they often will report that there's no effects on the second day of them trying to use this. This is also illustrated in animal models. The first graph measures a thing called the head twitch response, which I mentioned earlier. It's a prototypical behavior observed in mice when they're administered 5-HT2A agonists. What the first graph shows is the effect of administering two doses of a very selective 5-HT2A agonist on the y-axis, and that's their behavioral response. On the first bar, we see the expected response, and then we re-administer the same dose at 60 and 90 minutes later, and there is a noted reduction in the head twitch response, despite the half-life only being 11 minutes. Then they repeated the same experience with the same dose given over 24, 48, and 72 hours. As you can see here, their behavioral response is significantly reduced, and this again parallels the experience of patients. Another reason the psychedelics are thought to not have high addiction potential is that they have very low activity with the dopamine reward pathway, and thus have very little reinforcing qualities. In fact, many times the psychedelic experience can be quite uncomfortable, and so it's thought that its reinforcing qualities are quite low. And then finally, when people ask me about using drugs to treat drugs, I like to explain the importance of set and setting. We're not just giving people drugs to use them recreationally, and the difference between psychedelic use for recreation and for therapeutic purpose is intent. So we're studying psychedelic-assisted psychotherapy, where patients are given therapy to prepare for the experience, discuss intention and goals, and then they're given the psychedelic in a highly controlled environment, often under direct supervision of one to two therapists, and then they have therapy thereafter to help them integrate the experience and to create some context and make the experience meaningful. And this form has really been the standard format that goes on in clinical trials today, and it looks something like this. And oftentimes the logistics of administering it, it's in a clinic room that's, you know, tried to look more comfortable. People are given eye shades and music, and therapists are generally at their side to ensure safety. Okay, now we're going to shift gears a little bit and talk a little bit about some of these major compounds in very broad terms. But first, before we do that, I do want to highlight a couple of interesting observational studies. So there's some interesting data that's come from epidemiologic data sets and some naturalistic studies over the last couple of years that basically highlight this relationship that psychedelic use seems to reduce the risk of problematic substance use. Now, obviously, these are all observational, so we can only speak to the association, but they help us think about the possible interaction between psychedelics and substance use broadly. So this graph is from Passano and colleagues published in 2000, and I can't recall exactly when this was, 2017, where they essentially looked at a national survey drug use data from 2008 to 2013, where they collected 44,000 adults who reported opiate use disorder. Then they took that data set and they looked at the subset of patients who also use psychedelics, of which there were 18,000. And the finding there was that of the people who use psychedelics, there was a 27% reduced risk of past year opiate dependence and a 40% reduced risk of past year opiate abuse. It's also notable that cannabis was associated with a 55% reduced risk of past year opiate abuse. So that seems to suggest there may be some possible noise or some interaction between 5-HT, 2A agonism, and opiate use disorder. In 2019, Garcia-Romeo and colleagues conducted an observational study of naturalistic psychedelic use and alcohol use using a survey design where they looked at 343 adults with alcohol use disorder with an average of seven years of problematic drinking. Most of them took either LSD or psilocybin. There was no control based on the study design. And they looked at alcohol intake before and after psychedelic use. And what we see here is here are the rates of alcohol use prior to psychedelic use and here are the rates after. And we see a general trend towards reduced alcohol use after psychedelic use, with that reduction being more pronounced with increased severity of alcohol use disorder. Now, obviously, there are significant limitations given there is high probability of recall bias and reporting bias. But again, it provides some interesting suggestion that there may be some interaction there. Okay, now let's talk a little bit about some specific compounds. We're first going to talk about LSD, which is probably the most widely publicized psychedelic over the years. So LSD, it's a semi-synthetic derivative of lysergic acid. It's found in the parasitic rye fungus C. purpurea. It's termed LSD-25 because it's the 25th compound developed in a systematic study of amides related to lysergic acid. So lysergic acid is the natural compound. It's the backbone for all ergot alkaloids. And the diethylamide group is added in the lab, resulting in a semi-synthetic product or LSD. It was branded, as I said earlier, from 1947 to 1963 for research purposes. And it was branded as Daylacid by Sandos. And it's, you know, as I said earlier, it's worth noting that Daylacid was given to medical professionals at that time. And part of their distribution practice was they had to publish results. So that led to an explosion of case reports and case series and generally kind of poor quality studies throughout that time, which was a necessary part of getting access to LSD. And it's estimated that about 40,000 psychiatrists and trainees between 1947 and 1963 received LSD. In terms of the dose and the route, doses range normally from about 200 micrograms to 800 micrograms. It's most often orally administered. It's often found in a liquid form, which is then applied to paper, which is seen here as blotter. Now, in terms of safety, there are no reported overdose cases from the LSD specifically from like a toxicology perspective. In 1974, there was a case series of eight people who accidentally overdosed on what they thought was cocaine. And it ended up being crystallized LSD. It's estimated that they had about 1,000 doses a piece and they all presented hyperthermic agitated tachycardic and three went into respiratory failure, but all lived and were discharged 48 hours later. In terms of the pharmacokinetics, this was derived from a number of phase one healthy volunteer studies that were done in the late 90s and early 2000s, where they administered between 100 and 250 micrograms of LSD. And what they found is that the average onset was about 30 to 45 minutes. The peak effect was one to two and a half hours with a duration of effect from nine to 12 hours and a half-life of about 175 minutes. Now, in terms of the subjective effects, what you see here is what's called a radar plot. And what this highlights is there are kind of three primary measures used in psychedelic research to categorize the acute effects of a psychedelic. There's the altered state of consciousness scale, there's the hallucinogenic rating scale and the mystical experience questionnaire. All are self-report like-hearted scales that have been used for some time now to describe subjective experience. And so here you see a radar plot of the major elements of the subjective experience of LSD with 11 of the outcome measures used in the altered state of consciousness scale. And what you see with LSD is that you have a higher score of audio-visual synesthesia, some imagery and some complex imagery, and which is pretty typical and you hear that from patients as well. In terms of its general mechanism, it's a 5-HT2A agonist. It's demonstrated, this has been well-demonstrated when you co-administer it with catanserin, a 5-HT2A antagonist, it limits the effects. LSD is also known to have some dopamine interaction, particularly D1 and D2, but its primary effect is thought to be related to 5-HT2A. Okay, so let's talk a little bit about some of the evidence-based for LSD use in substance use. So there's a number of small clinical trials that have looked at LSD for alcohol use disorder that were done throughout the 60s as mentioned earlier. And many of these studies were of poor quality. Krebs and colleagues in 2012 completed a meta-analysis of trials and examined six randomized trials of LSD for alcohol dependence that reported outcomes. These studies were all male inpatient alcoholics. They were, all the participants were employed and they had a single dose of LSD. Otherwise they were quite heterogeneous with sample size varying from 20 to 176. So the intervention group was 325 people who received LSD ranging in dose from 200 to 800 micrograms with 211 folks being in placebo. And placebo in the meta-analysis included low dose LSD of about 50 micrograms to using ephedrine to amphetamine. There was a significant variation and the primary outcome was abstinence at one month. And what you see here is the odds ratio essentially was double the LSD compared to placebo group which is pretty alarming. Now, obviously the limitations are this is a meta-analysis. So there's significant publication bias but still interesting nonetheless. There was also a small handful of studies that looked at the use of LSD for opiate use disorder. This is a graph from a study done in 1973 by Savage and McCabe, where they looked at 74 folks with opiate use disorder who were on parole or probation in the state of Maryland. They basically took that group of 74 and cut them in half. 37 were randomized to an experimental condition of six weeks in a residential facility. There was no therapy there, it was just basically housing. And given a single dose of LSD of three to 450 micrograms. And then they were given 24 hours of psychedelic psychotherapy over five weeks versus a control which was general outpatient care where they had weekly group therapy for 12 months. And then the outcome of measure were daily urine analysis for the first six weeks and then at three, six, nine, and 12 months. And what they found is that the experimental condition essentially there was a significant higher percentage were abstinent at 12 months in the experimental condition versus the placebo condition. There was nine out of 36 were abstinent in the experimental condition, whereas two out of 37 in the placebo condition. It's of note that a participant died in the experimental condition during that trial. Now, the big limitation of this study is obviously the LSD group had stable housing. So you could make the inference that, that was a pretty important variable, but nonetheless, this kind of highlights some of these early studies that were done. So in terms of current studies on LSD as it relates to substance use disorder, there are currently none listed or that I'm aware of. There are nine phase one trials currently listed on clinicaltrials.gov, but none for substance use specifically. And many speculate that LSD has been difficult to use in a clinical application really because it still has a lot of negative press and associations from the 60s and 70s, where there was a lot of pretty wild claims during the kind of counterculture movement and the war on drugs. But I do suspect that we will probably see some studies with LSD for substance use disorder in the near future. Okay, now moving on to psilocybin. So psilocybin is 4-phosphoryloxy-NN-dimethyltryptamine. It's a substitute indolealkeline. It's derived from the genus psilocybe, a mushroom found all over the world. The mushrooms are small and brown, and they're known for a bluish tone, which is thought due to the psilocybin oxidizing after tissue injury. In terms of its brand and class, it was branded as indocybin, and it was synthesized by Sandos between 1958 and 1965. Its class is a serotonergic psychedelic and a tryptamine. And dosing in terms of clinical trials generally use 25 milligrams of psilocin, which is the prodrug, or 20 to 30 milligrams per 70 kilograms, which is equivalent roughly of about three and a half grams of dried mushroom currently. In terms of the safety of psilocybin, it's known to be fairly safe. There's one case report of a person who had a cardiac transplant who had a cardiac event after using psilocybin. This was published in 2012. But apart from that, from a toxicology perspective, it is quite safe. Now, there are, of course, dangers associated with its use, mainly due to set and setting and people making bad choices while under the influence. And then, of course, pharmacologically, there is some sympathetic activation, so it can lead to a little tachycardia, tachypnea, and some headache for some people. From a pharmacokinetics perspective, the onset of action, it generally takes about an hour. Its peak is at about two hours, and the duration is about six hours, which most think this is probably why psilocybin is more utilized in a clinical perspective because it's just more manageable. And then it's absorbed via the GI system, and it has a variable half-life depending on formulation and GIPH as well. In terms of the subjective effects, again, you see here a radar plot of the 11 dimensions of the altered state of consciousness scale. The blue line demonstrates patients after taking 30 milligrams per 70 kilogram. As you see here, there's a greater score of the experience of unity, the spiritual experience, insightfulness, and disembodiment. There's, so you see greater numbers over here with psilocybin, whereas with LSD, you saw kind of a little bit more robust numbers over here, which is just interesting to note. From a mechanistic perspective, again, it's serotonergic. It's thought to interact with the 5-HT2A receptor, but it also interacts with 2C, with some moderate binding to 1A and 1B. There is also some receptor affinity to alpha-2A, 2B, and dopamine to D3 specifically, but most of its mechanism is thought to be serotonergically mediated. So psilocybin, you know, it's been studied for a range of indications, including depression, end-of-life anxiety, and OCD. Related to substance use, there's really two small pilot studies to date that show some interesting evidence. The first is on tobacco use, and the second is on alcohol use. So the first study was done by Matt Johnson and colleagues at Johns Hopkins in 2014, and it's a pilot study where they took 15 smokers who smoked more than 10 cigarettes a day who had previous failed attempts, and they recruited from the general public. And what they did as an intervention is they enrolled them in CBT, and then they gave them psilocybin at week five, seven, and 13 of a 15-week course of CBT. And their comparator was a CBT-only group, and their main outcome was urinary codotine levels, which is a metabolite of nicotine. And then they looked at exhaled CO2 at intake weekly and six months after that. And so what you see here is actually from a follow-up study that Johnson did in 2017 that continued to track outcomes up to 30 months after. And what you see here is the number of cigarettes on the Y-axis and on the X-axis is the time of measure. So here's the intake they were smoking. And then at 10 weeks, they had, I'm sorry, at one year, they had, of those 15, they had a 67% abstinent rate. So 10 of 15 had quit. And then at 30 months, they had a 60% abstinent rate, or nine out of 15. And interestingly, 13 out of 15 participants rated the psilocybin experience to be one of the most meaningful experience of their life. Interestingly, on this other graph, what they tracked was this change in codotine level or a proxy for smoking. And their score here for their, one of their subjective experience measures, the mystical experience questionnaire. And essentially what this demonstrated was that the greater the intensity of the experience, the greater the reduction in nicotine use, which is a theme that is seen in a lot of these studies. The next study was done in 2015 by Michael Bogenscholtz's group. It was an open label psilocybin study for alcohol dependence where he looked at 10 alcoholics who had pretty severe alcohol use disorder. And he administered two doses of psilocybin separated by four weeks. And he coupled that with 12 weeks of motivational enhancement therapy. And there was no comparator here. And essentially what this graph shows is if, on the y-axis is the measurement of drinking amount, and this is time on the x-axis, essentially there was a significant drop off after week four, which is when they received their first psilocybin dose. And the reduction in alcohol remained significant for the remainder of the study through week 36. And again, just like with the tobacco study, the degree of mystical experience predicted the response. Now, obviously the limitations, there was no comparator, it was open label, very small study. But both of these studies have led to larger follow-up studies due to these promising early findings. So on that note, so currently psilocybin, there's a tremendous amount of studies. There's about 69 active psilocybin trials going on right now with nine of them for substance use disorders. So as I mentioned earlier, Matt Johnson, he had the first U01 grant in over 50 years to do a follow-up study on his tobacco study. And then Michael Bogenschultz at NYU has a trial looking at alcohol use disorder to kind of follow up on that prior trial. And additionally, there are actually three other psilocybin trials for alcohol use disorder, one at the VA in Connecticut, one at the University of Zurich, and another one at Johns Hopkins looking at MDD plus AUD. And then there are two trials of psilocybin for opioid use disorder, one at Johns Hopkins and one at the University of Wisconsin. They're both looking at the concurrent use of psilocybin with one's looking at psilocybin for methadone users. And the other one is looking at psilocybin plus buprenorphine and then there are two trials looking at psilocybin for meth use disorder, one at OHSU and one at the University of Wisconsin. Okay, next, ketamine. And I know I'm speaking fast, but I got a lot of stuff to go through. So I apologize if I'm speaking fast. So ketamine, so structurally, ketamine is 2,2-chlorophenyl-2-methylamino-cyclohexanone. It's a fencyclidine derivative first synthesized in 1962 to create a less hallucinogenic compound than fencyclidine for anesthesia. It was first used clinically in 1970 and now it's widely used for general anesthesia, for pain management, and recently for depression. Clinically, it's composed of two different enantiomers. It's brand and class. So it's a schedule three anesthetic. It's termed a disassociative anesthetic. It's branded as Spravato, which is the S enantiomer of ketamine and that's FDA approved for treatment-resistant depression and branded as Ketelar, which is the racemic mixture seen here. In terms of the dose and route, it really varies by indication, but for psychedelic application, it generally is modeled after depressive doses. So for in the depression studies, they gave ketamine at doses of 0.5 mg per kg. And so that's often become the standard. In a lot of psychedelic applications for ketamine, they use it intramuscularly and they give one to 1.3 milligrams per kilogram. You can also give it orally three to 400 milligrams. In terms of safety, ketamine has a long track record. It's pretty darn safe. It doesn't interfere with the respiratory drive. And so it's often safely used in emergencies. There was recently a meta-analysis of psychiatric trials who have explored ketamine use and found the hemodynamic changes was an increase in systolic blood pressure by 12 points, eight points of diastolic blood pressure and an increase in heart rate of six beats per minute. So pretty safe. In terms of the pharmacokinetics, it really varies by route. It's most studied, like I said earlier, by IV. And so via IV, the onset is quite immediate. And for IM, it can be a couple minutes delayed. And the duration of effects really varies. And again, it depends on the route of administration. But of note, the bioavailability, intramuscularly, it's thought to be about 93%. And orally, it's thought to be about 20%. It has a pretty short half-life of 10 to 15 minutes and it's metabolized via the SIP system. In terms of the subjective experience, it's often described as a dissociative anesthetic. It does share some of the features of the classic psychedelics. And it was compared to DMT in a 1998 study that essentially showed that it was fairly similar to DMT in certain ways and had a linear dose response between 50 and 200 nanograms per deciliter. In terms of the mechanism of action, it's categorized. There are both glutamate-independent mechanisms and glutamate-dependent mechanisms. The glutamate-independent mechanisms, it does have some receptor affinity to mu-delta and kappa. It also interacts with GABA and inhibits 5-H serotonin, norepinephrine, and DOPA reuptake. And then it has some glutamate-dependent activity, which is predominantly at the NMDA receptor. So in terms of studies, there's actually an interesting body of research that emerged out of Russia. Kropinsky and colleagues in 2002 conducted a randomized crossover design of 70 adults with opioid disorder. And they divided this group into a low dose versus a high dose. Their low dose was 0.2 mg per kg IM versus a high dose of 2 mg per kg IM. And they paired this with existential psychotherapy for 10 hours prior and five hours after. And their primary outcome was opiate use as measured by urine toxicology for monthly for 24 months, as well as self-report and family report. And what we see here, so the high dose group demonstrated greater rates of abstinence at each month, at each time point, and it remained significant for almost the entire duration of the 24-month follow-up. Limitations of the study, there's no control, and the participants were all enrolled from an inpatient setting. So they were abstinent, and that was confirmed prior to the study. But still, I think this is an interesting demonstration of the higher dose seemed to have more effect that sustained over a two-year period. Kropinsky then later explored if there was any utility in increasing the number of ketamine doses. And so here what he did is he compared a cohort of 59 adults with opioid use disorder and he divided them into two arms. There was an arm that received a single dose of 2 mg per kg as in the prior study of IM ketamine with some general therapy versus a group that had three intramuscular ketamine plus manualized therapy. And the primary outcome was abstinence over of heroin at one year. And here's a Kaplan-Meier curve that demonstrates the results. And essentially, although it's hard for me to read these, but at one year, there was a 50% abstinent rate at the high-dose ketamine group compared to a 22.2% of the low-dose ketamine, suggesting that multiple doses seem to have more potential impact. Now, obviously, too, there was no placebo here. So, you know, take those with a grain of salt. Krupinski in 1997 did a two-arm case control prospective trial in Russia for alcohol use disorder and ketamine where he enrolled 111 treatment-seeking adults and he compared that to a control of 100 folks. And what he did is he took the active group and he gave them IM ketamine at 2.5 mg per kg at a single time point. And he paired that with therapy versus a control group who just received usual care. And here, their outcome of primary interest was abstinence at one year, and that was collected monthly. And the results indicate an abstinent rate at one year of 65.8% in the active arm versus 24 in the control arm. Now, the limitation of this study, the patients were enrolled from a hospital where they had three months of abstinence. And the, yeah, and the patients weren't randomized either. So obviously there was some bias there. So picking up from some of this work, Dakwar at Columbia did some work in 2019 where he looked at the effects of ketamine, of IV ketamine with mindfulness-based therapy for cocaine use disorder. So here what he did is he randomized 55 adults with cocaine use disorder and the intervention group received five weeks of mindfulness-based intervention and IV ketamine at half a milligram per kilogram versus a control group who received the mindfulness-based intervention with midazolam as an active control and the outcome were cocaine use via urine drug screen and self-report as well as time to relapse. And here we see at two weeks after the infusion we see 48.2 percent of the active group were abstinent from cocaine seen here in the green line with a significant reduction of cocaine use for the duration of the study compared to 10.7 of the control group seen in the orange line. Now the big limitation of this study was the you know very short follow-up but still given our limitations to treat cocaine use disorder I think this study has some interesting possibilities. Now Dakwar in 2020 conducted a study using IV ketamine for alcohol use disorder and here he conducted a two-arm midazolam controlled pilot study of 40 adults and the intervention group received ketamine IV ketamine at 0.71 milligrams per kilogram plus motivational enhancement therapy over five weeks and he compared this to a midazolam control group with with the same manualized therapy and their outcome was abstinence rates proportion of heavy drinking days and time to return to drinking and what there what he found was that the ketamine arm showed greater time to relapse stable heavy drinking days compared to the midazolam group and he calculated a number needed to treat of four and so and then of course the limitation here was also a short follow-up time of 21 days there was a relatively high dropout rates and you know the ongoing issue with difficulty with the blinding which is a challenge in all of these studies that seems to perpetually be a challenge. Okay so more recently in 2021 no in 2022 Grabinski published a study a phase two double-blind placebo controlled trial examining the use of ketamine for relapse prevention of alcohol so what their group did is they took 97 adults with severe AUD who had recently detoxed and he stratified them into four conditions. So there was essentially a condition of ketamine infusion of 0.8 milligrams per kilogram plus therapy versus ketamine plus what they're calling alcohol education which is kind of the placebo to the therapy versus a saline infusion plus manualized therapy versus a saline infusion plus this alcohol education and there was 22 to 25 people in each of these groups and he he did this over 10 visits spread out over six months and their primary outcome were the self-report percentage days absent it's at six months after the first infusion with a number of secondary outcomes like things like mood like the BDI the HAMD as well as measures of nicotine dependence and measures of cravings and so what we see here is that their greatest days of abstinence were in the ketamine plus psychotherapy group and the statistical separation only occurred between the two extremes between the placebo and psychoeducation which is kind of placebo placebo versus intervention intervention and then the standard error bars crossed in the in the middle two but nonetheless that seems to be a somewhat significant change that they found which might indicate that ketamine may have some place for relapse prevention moving forward. Okay so where are we at now so there's over 200 active clinical trials right now in ketamine there are only two for substance use disorders one for alcohol use disorder and one for opiate use disorder so the one for the opiate use disorder is essentially it's at the Medical University of South Carolina and they're exploring ketamine assisted psychotherapy for concurrent depression for people who are absent from opiates and then there's an AUD trial going on where they're looking at CAP or ketamine assisted psychotherapy plus naltrexone for people with MDD and AUD at the VA Connecticut healthcare system. Now ketamine is you know the only legally available psychedelic right now and so it's currently being used in a range of different methods at this kind of sub-anesthetic level to treat mood disorders anxiety PTSD and substance use disorder and there's a huge range but often IV clinics will give a half a milligram per kilogram infusions with the most common indication still being depression and there's relatively short effect and so often clinics give multiple IV infusions and some give lozenges that's becoming increasingly popular but there's a huge diversity of clinical practices and there's a bunch of different organizations that have emerged in the last couple of years to try to position them so arguably to position themselves in the kind of psychedelic renaissance and so you'll probably get patients asking you about these different organizations and honestly they're all so new that I don't have any direct experience with a lot of them so it's hard for me to comment on that. Okay moving on so the next substance I want to talk about is ibogaine. Ibogaine may arise for your opiate users who have heard of it. Ibogaine it's an indole alkaloid from the root bark of the iboga shrub. It's native to West Africa. It was isolated by the French in 1900. It's 10 methoxy ibogamine and it was branded as lamberine in France between 1939 and 1966. That was initially used for I think headaches. In terms of its class it's an indole alkaloid with mixed receptor affinity. Its dosing is very odd at low doses of five milligrams per kilogram. It has minor kind of kind of it's a more of a stimulant. At 10 milligrams per kilogram it leads to some visual distortions that can last for a couple of hours and at larger doses at 10 to 25 milligrams per kilogram these are kind of called the flooding doses. These are often what are used for substance use disorders. Now in terms of safety ibogaine can cause a lot of different acute side effects nausea, headache. The nausea is often motion dependent. It can lead to some ataxia which can lead for which can go on for a number of hours. But I think the thing that's most important to note is that ibogaine has been associated with some significant mortality that has really stopped or slowed down their research in this area. So Alpert and colleagues reviewed a case series of 19 deaths associated with ibogaine and 12 of them had known cardiac conditions. But much of the toxicity of ibogaine is thought due to its receptor interaction with what's called the ether agogo channel. It inhibits this calcium channel that interferes with QTC and essentially what you see here is this is the ether agogo channel under normal conditions where potassium can flow out from the intracellular space to the extracellular space. Ibogaine inhibits that leading to an increase of intracellular potassium prolonging the QTC and putting people at greater risk for arrhythmias. There's also some hypothesis that there is some CYP2D6 polymorphisms that may also alter the metabolism of ibogaine increasing the potential cardiac risk for some of the patients. In terms of its pharmacokinetics it is quite variable but generally the onset's about an hour its peak is like two to two and a half hours. Its duration is remarkably long from 24 to 48 hours and has a very long half-life and you know in terms of the subjective effects they're also quite unique. They are often described as a kind of a dream-like leading to what is termed kind of this autobiographic visuals that leads to very strong emotional response and like I said can last up to 24 hours. Its mechanism of action is not well understood. It has agonist it does act on the 5-HT2A receptor but it but weekly it's it interacts with 5-HT3 and there's some agonism at the at the serotonin transporter. It also has some agonism at NMDA and some muscarinic receptor as well as some partial agonism at mu kappa and sigma opiate receptors but essentially because of these deaths a lot of these studies were stopped. But I want to review a couple of them because I do think there's a market for this and patients will certainly and have asked me about pursuing this so I think it's helpful to know. So Noller and colleagues in 2018 did an observational study of 14 patients in New Zealand so it should be noted that Ibogaine is legal in some countries including New Zealand, South Africa and there's a number of other places that I can't recall but in New Zealand it's it's it can be prescribed and so there they did this observational study where they they took people who were in withdrawal and they gave them an initial dose with a booster dose and they measured mood, withdrawal symptoms, ongoing use over time and what they essentially found was that there was reduced depressive symptoms at 12 months and six of the 11 folks who remained enrolled in the study were opiate negative. And again you know observational study so it's obviously a big limitation but still six out of 11 you know having seen opiate users that's still somewhat impressive results. There's another study that was done by Brown and Alper out of UC San Diego where they it was an observational study of 30 opiate use disordered patients and what they did is they it was a similar model where they gave people who were in opiate withdrawal a initial dose and then a booster a couple of hours later. This was purely observational so there was no comparator and they looked at the SOWS score, the acute withdrawal score, and then the addiction severity index at follow-up at 1, 3, 6, 9, and 12 months and I'm sorry this chart I know is very hard to read but the main point here is that at 50% at one month and yeah there was there was a significant reduction and at one in three months there was a significant reduction in use. And then there was also a reduction in other substance use as well and again this limitation it's a very small small trial but you know 50% at one month I mean just as a comparator if you look at buprenorphine studies there was a study done where they tapered people off buprenorphine and 28 days later there was a 17% of that population was urine negative at one month so 50% is still quite impressive but again it's a very small sample size. Okay there was a phase one safety study of 14 opiate users published in 2022 where they gave ibogaine of 10 milligrams per kilogram and essentially they were looking at they were trying to better better understand the cardiac effects and I think what's notable here and what stood out to me is that seven of the 14 participants had elevated QGC of greater than 500 and you know they all returned to normal but I think that speaks to the potential cardiac concerns that ibogaine brings to mind. Okay so currently you know there are no studies right now that I'm aware of of using ibogaine in the U.S. for for substance use disorder but there are a number of private clinics throughout the globe that report using ibogaine as part of their therapeutic modality. Here's a clinic I think in Spain that charges 5,000 euros and it includes one ibogaine treatment and there are private clinics in Mexico and oh and I'm sorry I misspoke there are actually three clinical trials with ibogaine but none of them are in the U.S. There's one in Spain that's a phase one trial examining ibogaine used to detox off methadone with an N of 20. There's one in the U.K. a phase two trial enrolling 116 people and then in Brazil there's a small pilot study of 12 but there's nothing here in the U.S. Okay lastly just real quick the next psychedelic which I'm sure patients if they have not already they will be asking you about is MDMA. So what is MDMA? So it's 3, 4-methylenedioxymethamphetamine also known as MDMA. It's classified as a phenylethylamine due to its structure its core structure which is shared with methamphetamine DOI and mescaline. It's widely associated with kind of the party scene. It's been used recreationally for many years and its dosing in a research environment is generally 75 to 125 milligrams orally. You know from a safety and adverse event perspective it's really hard to characterize because there's a number of stories of people using it illicitly and having bad outcomes. You know because it's related to amphetamines you know tachycardia, palpitations, diaphoresis, insomnia and in more severe cases leading to rhabdomyolysis, hypothermia, hyponatremia, and renal failure and death. But I will say that a lot of this data comes from um samples that it's unknown if it's pure MDMA or not. They're often it's well documented that there are a lot of contaminants in in you know illegal manufactured MDMA. So it's it's hard to know how much stock to put in some of these case reports. There is though I think some concern that it does have some 5-HT2B activity which can cause some valvular disease at higher doses. From a safety perspective in the clinical trials most of the clinical trials to date are being done via maps to treat PTSD and it's been remarkably safe pharmacologically in that setting. And the kinetics data you know the onset is about a half hour it peaks in about an hour and a half its duration is about four or five hours with a half-life of eight to nine hours. The subjective effects of MDMA are unique in here again we see this radar plot and we see the 11 dimensions of altered state of consciousness and we see that MDMA induces less imagery and synesthesia you know if LSD is down here and psilocybin is over here MDMA is largely in this kind of blissful state arena. And therapeutically you know people often say it increases this sense of introspection, this bond between the patient and provider and so it has long been used in the psychotherapeutic model and seen to have some benefit in that setting. In terms of its mechanism of action it interacts directly with a monamine transporter as well as with adrenergic, serotonergic, histaminergic, and muscarinic receptors. And in terms of its application for substance use disorders, CESA and colleagues published this interesting study recently in 2021 where they looked at MDMA for alcohol use disorder and so this was a phase one pilot study and what they essentially did is they did two studies. First they took 14 adults who underwent detox and then they tracked them just kind of naturalistic they just observed them and to look at their relapse rates and then they took a second group of 14 and they gave them the intervention was two MDMA therapy sessions over a 10-week period and then they tracked them over time. And so what we see here is well first in this small study MDMA was well tolerated there was no adverse events but what we see is a pretty significant difference between the findings of so the red was the was the kind of naturalistic study of the first cohort of 14 and you see that at a little over nine months about 75% of the people were drinking again whereas 21% in the MDMA group were drinking. So again it's you know this is a limitation there was no direct placebo it was very small but seems to suggest that there might be some therapeutic value there and I'm confident we will see more trials of that very soon although you know in terms of the current studies there are 21 active studies right now listed on clinicaltrials.gov mainly for PTSD. There's one for addiction it's only it's at the University of New Mexico they're they're looking at 15 women with OUD and PTSD and you know it should be noted here that there's strong evidence to suggest that MDMA will be rescheduled in 2023 for PTSD so I'm sure we'll be seeing a lot more of this. Okay so quick summary I know I'm running out of time so first LSD so it's been shown to be helpful for alcohol use disorder although there are no studies currently underway for its application in substance use disorder. It does have a long duration of effect so it's generally seen as less desirable from a clinical application perspective. Psilocybin there's some early data that suggests a possible use for tobacco use disorder and alcohol use disorder with nine active studies for various substance use disorders that are currently registered. Ketamine has some studies to show that it may have some effect for opioid use disorder alcohol use disorder and maybe cocaine use disorder with two active studies going on one for alcohol use and one for opiate use and then ibogaine has some observational studies that suggest it may have some value for opiate use disorder although there are some safety concerns that have really limited our study of this. And then MDMA there's only one study going on for its application for opiate use disorder and PTSD but I suspect there's going to be more studies coming along as MDMA becomes more utilized. Okay so quickly to wrap things up so let's talk a little bit about the mechanism because I think that's important and when I think about mechanism I think there are two unique things there's kind of the biologic mechanism and there's the psychologic mechanism. So first just very broadly when we talk about the mechanism of psychedelics you know as I've said earlier we really focus on the 5-HT2A receptor with some thought and attention to the 2B, 2C, and 1A receptor. So the 2A receptor is expressed on multiple cortical and subcortical regions with significant concentration in cortical perimetal neurons in layer 5 and they're found on apical dendrites and the activation of these result in enhanced excitability and result in a complex downstream activation of B proteins and eventual neurotransmitter release and it's this eventual downstream effect that's thought to perhaps lead to this dendritic growth which may be the kind of physiologic correlate that explains some of the therapeutic benefit that is often termed neuroplasticity. But put differently you know dendritic growth can be the effects of increased learning and that happens in all different ways but I think it has some unique application here. So this is some data from an animal study that I think is quite compelling. Essentially they took mice and they taught them some behavior and they measured their ability to learn here on the y-axis and then they over time and so this is age on the x-axis and what we see is that the ability to learn in these animals peaks early in life and then reduces as the animal ages an experience that I think we can all relate to right younger folks my children can learn instruments and language and their brains are much more adaptable than mine and so we call this this kind of neuroplastic phase. However in the same study they then gave the older mice some MDMA and what they saw was that their ability to learn dramatically improved and so this theory posits that if these substances can help kind of reopen this critical learning period in our patients then we have a substantial opportunity to help our patients engage in treatments for trauma or for addiction and probably for a range of other things as well. A simpler model or another model states that that psychedelics when put in a therapeutic container of psychotherapy can result in an experience where patients can see themselves in a different context, in a different way. And for many, they describe the ability to sit with these extremes feelings and to begin to overcome their own shame and guilt in a pretty profound way. In this way, I see psychedelics as a potential accelerant to the therapeutic process, whereas psychedelics themselves just kind of intensify the process. And here you see a graph of the different kind of general states. There's this peak experience, which we talked about earlier, measuring this via the alternative consciousness scale, the hallucinogenic rating scale, or the mystical experience questionnaire. And that's relatively short acting, but then there is this kind of afterglow and residual effects, which may represent some neuroplasticity and some eventual behavior change. And that may have some strong application in our substance using patients. Conceptually, I think that Bogen Schultz put together this nice flow chart that really highlights a lot of what I'm saying. He essentially says that the substance use reduction is the final outcome of a series of events involving the drug, the participant, and the setting, resulting in both acute brain changes and acute psychological effects, which sum to persisting effects resulting in reduced cravings, improved efficacy, and increased motivation, all eventually resulting in reduced use. And this is really how I see psychedelics as potentially having some therapeutic value. So from a safety perspective, patients will often ask, are these compounds safe? I generally try to explain pharmacologically, a lot of these compounds are quite safe. LSD, psilocybin, and ketamine are quite safe. There is some exclusionary criteria that needs to be reviewed. MDMA has some concern because it can look more like an amphetamine, and so it can increase sympathetic tone. And then ibogaine, as mentioned earlier, has some cardiac concerns. But the way that I frame it is that there's kind of pharmacologic safety, there's psychological safety, and there's situational safety. So pharmacologically, we've discussed that. Psychologically, there's this kind of general cultural myth about frying your brain and never coming back from psychedelic use. This really isn't the case. There's not really strong data to suggest this. It's probably more possible or probable that people who are experimenting with psychedelics are also in a similar age range where they may present with a psychotic disorder or they may have an underlying psychotic disorder, and this is kind of like a stress test and kind of pushes them into an acute episode. The thing that concerns me and that I bring up with patients is situational safety. Given that a lot of these treatments, people are going overseas to get or they're getting them illegally without any oversight, we're starting to hear stories of abuse from therapists and people putting themselves in sketchy situations with some sketchy characters. And so I always really warn people about that probability that you're taking compounds that can profoundly impair you and that intrinsically carries with it some risk. And then the next thing I'll say quickly is that the reality is that the cultural shift is happening in the same way that cannabis kind of state-by-state, there was legislation passed to increase use, the same thing we're seeing with psychedelics. In 2023, psychedelics, psilocybin will be medically used in the state of Oregon, and we're gonna get a huge slew of data, hopefully from that experience. And there's a number of other states that have other similar legislation on their books. And so I suspect in the state of Washington, there was recently a measure that was proposed and there's a number of other states that recently enacted similar legislation. So we're gonna see more and more of this. And so what I also, the last thing I'll say here is that I always warn patients that to me, so this graph is from this latest phase three trial of MDMA for PTSD that was recently published. It got a lot of news. And essentially what this shows is that the blue line is the therapy alone and the red line is MDMA with therapy. And they had amazing results. Essentially there was close to 30% loss of diagnosis for the PTSD group who had therapy alone versus a little over 60% with therapy plus MDMA. And I will bring this up with patients and say, this to me highlights the fact that still 30% got better with therapy alone, which is pretty amazing. And that psychedelics really are a way of amplifying the benefit, but they're not necessarily a required element at this stage. And I try to use that to kind of temporize some of the excitement that people often have about psychedelics. So quickly, some resources. So I get referrals all the time about people interested in psychedelics because they've read some news report about how is this gonna fix their alcohol use disorder or whatever. I often will go to clinicaltrials.gov with my patients and try to look for trials. The reality is it's very hard to get anyone in a trial because the exclusionary criteria are quite high. MAPS, the Multidisciplinary Association for Psychedelic Studies has a lot of good information for patients as well that I often refer to. Similarly, the Center for Psychedelic and Consciousness Research at Johns Hopkins is a great resource that I often refer patients to. If you wanna learn more about psychedelic and their application clinically, you know, there are a number of training sites that are popping up. Psychedelic support is a good one. They have a lot of good educational models. If you want a good review of the literature or the handbook on medical hallucinogens, I think is probably one of the better books that has essentially a collated list of really good articles that are quite high quality that I would suggest looking into. And then there's a number of organizations. There's a ketamine organization that has a lot of good trainings on it for people who are interested in learning more about ketamine. Specifically for psychedelics in substance use disorder, there is this group, Psychedelics in Recovery, which essentially follows an AA model for people who have used psychedelics. And that's a good resource that I refer patients to who are interested in this. And then finally, you know, harm reduction is a really important thing here. And the Zendo Project, I would highly recommend exploring their resources because they can provide a lot of good resources for patients who perhaps will pursue this in an underground setting and you wanna make sure they do it safely. This is a potential way to kind of use harm reduction to help that move along. So these are all my resources that are listed here for you, which you can take a look at. And I think that is the end. Thank you. All right, Dr. Saga, thank you so much for an amazing presentation and for bringing this topic to our audience. We really do appreciate it. My pleasure. Before we move into the Q&A section, I do just wanna remind everyone that if you do have a question, feel free to put it into that Q&A section down below in the attendee control panel. Okay, so to kick off the Q&A section, we had one comment come through the chat saying that LSD also requires two shifts of researchers to cover for the entirety of the experience, which is a financial disincentive to further research. Do you have any comments on kind of how to structure your study to possibly avoid that conundrum? Yeah, so the issue of using long-acting compounds, I think is a real challenge that we're gonna face when we move from the research realm to scaling this into real clinical application. So, I think there's a lot of interest in compounds that are shorter acting to see if perhaps, does a two-hour psychedelic experience lead to the same outcome as a 12-hour one? There's just not data to really know. And I think these are the sorts of questions that are gonna be increasingly asked in the near future so we can better address this. Because yeah, it's just not sustainable to have two providers for 12 or 14 hours. I think that provides a big logistical challenge. All right, one more question also just came in. What are your thoughts on non-physicians, administrators, and physicians or your thoughts on non-physicians administering psilocybin, kind of like that's proposed in Oregon? Yeah, it's interesting. I know that's a big controversial topic among a lot of... So then, this is just my personal opinion, but I generally tend to think that as it relates to the psychedelic experience, specifically, I don't think you need a physician to be in the room. Like again, thinking about scalability here, it's not cost-effective to have a doc sitting at someone's bedside for six or eight hours or even a therapist. And the reality is for those six to eight hours, you're not really doing therapy. So I'm on a clinical trial right now using psilocybin. You're just really making sure they're safe. You're sitting at their bedside, you're making sure they're safe and comfortable. The real work is in the integration therapy afterwards. So as it pertains to Oregon, I think it's fine to have non-licensed folk be kind of a sitter. As long as there's some understanding or utilization of therapy afterwards. I'm a big believer that for these compounds to have clinical utility, they're not a cure-all by themselves. They need to be paired with behavioral interventions. So that's what I always emphasize people. Does that answer the question? Yeah, I definitely think so. And then let me just tap into your thoughts again on scalability too. So what about taking this from say a clinical trial to perhaps a county or state level? Any thoughts there? Yeah, I mean, scalability is a huge, huge issue. And my thought with that is I'm personally very interested in the idea of how do we use a different model like group interventions to potentially increase our ability to tap into different populations and to basically reduce the cost, right? I mean, it's so cost prohibitive per patient at this stage in the game. So I think moving forward, there's gonna probably be a big push to do group integration or group psychedelic work as well as even like group integration work. I know there's some groups looking at that as well. Yeah, so that's what I suspect could emerge. Yeah, moving forward. Got it, thank you for that. And then another substance that perhaps wasn't mentioned in the talk, but do you have any experience with DMT or ayahuasca in the psychiatric field? Yeah, yeah. So DMT is really interesting. So, and ayahuasca is really, really interesting. And actually there's some interesting observational studies to suggest that ayahuasca may have some benefit. It's a serotonergic psychedelic. Ayahuasca is a combination of DMT and an oral form can mix with a vine that has a MAOI in it that essentially allows for absorption in the GI tract. So it's long acting. I certainly think there's some utility there. I know a number of people who are using it in the underground community for alcohol use disorder and they're seeming to have some good results. And there's, I think a big interest in its potential use. You know, the short acting DMT, again, this goes back to that question of duration. Like I wonder about, you know, DMT is very short acting. And so would a 10 minute DMT experience lead to the same outcome as an eight hour ayahuasca experience? Again, we don't know yet, but these are the sorts of questions I hope that we can be answering more quickly. Gotcha, thank you for that answer. And then one also just came in. Is it safe to use psychedelics to treat patients with previous disassociative episodes? That's an interesting question. And so in the MDM, if you talk to MDMA folks and in the PTSD literature, one of the benefits they say of having a therapist at the bedside is that, you know, most of the time when we have 50 minutes in therapy and someone starts to approach a disassociative episode, you're trying to like quickly wrap it up because you don't wanna destabilize them and you wanna make sure that things are relatively contained. But when you're sitting with someone on MDMA for six or eight hours, you can actually kind of lean into it. And so if you talk to MDMA therapists on a lot of these MAPS trials, they'll actually say that absolutely, people with disassociative states, you certainly can treat them. You know, I think it makes people nervous. It would make me nervous. I would be very hesitant because I don't feel necessarily skilled enough and that's not my area of expertise to work with that. But in a controlled setting, in a research setting where there was a lot of kind of trauma-informed therapy, I think that it would be very, very reasonable to explore that. Got it. And I have two questions on dosing specifically. So the first one is, are there any data on the effects of single dosing sessions as part of a psychosocial treatment versus multiple dosing sessions? It depends on the outcome of measure. There are different protocols. There are some studies that they do a single, I'm involved in a trial right now, we're doing single dose. And so that's obviously yet to be determined. Most clinical trials do multiple dosing. They do two to three dosing sessions. And so I think I'd have to look back and see more clearly, but if you're looking at an outcome of like depression, I think you see more robust results with multiple dosing. Whereas I think end-of-life distress and psilocybin single dosing has been the predominant thing. So it varies by indication. It will be the short answer. Got it. How about any therapeutic benefit for psilocybin microdosing? Yeah, microdosing is an interesting question. There's a lot of kind of cultural interest in microdosing. I personally feel that the benefit therapeutically really comes from the subjective experience. And so I worry a little bit about microdosing as a way of kind of sidestepping that subjective experience. Now, an area of interest that I have is, is there a way that we can use macrodosing with microdosing to kind of reinforce it, say for like relapse prevention? So I'm very interested in exploring whether or not we can use microdosing to help with relapse prevention when it's paired with a macrodose. But I think, you know, the way that I think about it pharmacologically is if you're using low-dose psilocybin in a microdose form, you're probably giving like a low-dose SSRI, right? I mean, it's probably behaving in a similar way, though there's very little data. I mean, the studies that I look at microdosing right now, there's a few more coming out recently, but the last I looked about a month or so ago, you know, they're all observational studies with very little clear outcome. So it's really, really hard to know, but as it pertains to substance use disorders, there are zero microdosing studies as it applies to addiction right now, which is interesting. Gotcha, and in your answer there, you mentioned an SSRI. We just got two questions on that. So let me jump over to that topic. So the question is, what is the latest data or clinical experience treating patients who are on an SSRI, specifically with psilocybin? So the standard kind of practice right now in all the clinical trials is to get people off SSRIs because the kind of narrative is that it reduces the subjective experience. And so people are generally tapered off for a couple of weeks prior, and that's often part of the inclusion criteria in most of these studies. But I do think it'll be interesting moving forward, especially as state medicalization occurs with psilocybin. I think that doing drug-drug interaction studies is gonna be increasingly important, because as we know, like if you're treating treatment-resistant depression, it's gonna be hard to find people, to take people off their meds and then try the experimental conditions. So I think this sort of model of a DDI study is gonna be incredibly important in the next couple of years. Awesome, well, you're reading the audience's mind here because there was another question on treatment-resistant cases. Do you see psychedelic approaches being used for treatment-resistant cases or as an initial modality in the near term? You know, it's interesting. Since I have been doing, I've been like lecturing and trying to start some research in this area. And so I've received a lot of referrals from folks interested in psychedelics. And the thing that's most interesting is that I get, I'm now starting to see a subset of patients who are sort of psychiatrically naive, I would say, or they just have very strong opinions about meds and they don't wanna try any meds. And so I have been surprised at how many people have approached me for a consult because they're interested in psychedelics but have never tried anything else. So to answer that question around, you know, kind of using it as a first line, again, I think given the unique way in which this data is moving forward, which is it's actually driven much more by kind of public interest and research, I suspect that we are gonna see more and more cases of people treating themselves, either going abroad or illegally or using ketamine because they don't wanna go down the route of multiple SSRI trials, antipsychotic augmentation or whatever. So I suspect that'll be the norm. Do I see it? I mean, I discourage it just because it's not, I mean, I feel like it's my duty to try to go through the paths that we have the data on. And right now, you know, I have to work with what I got. So if someone really has, you can also make the argument, I mean, if they're treatment resistant, they've already failed two prior SSRIs. So those people, there are treatment resistant trials. Johns Hopkins have done a few. And so those seem to be a, there is some data on that sub-population. But you know, that's a hard group to study. They're high risk, there's a lot of concern. And again, that's not my area. I focus more on addictions. All right, why don't we take one last question before we wrap up and go into the CME credit and housekeeping items. Is there a time projection to publish a clinical practice? Guideline? Yeah, guideline. Yeah, yeah. It's funny that that question comes up. So this is something that we're working on right now is to try to develop some like best practice guidelines for people because, you know, as I said earlier, we are at a phase now where these compounds are gonna be used, whether we're supporting it or not. And we should be in a place where we can at least give people best practices. And so we're trying to figure out ways right now to develop some sort of clinical guidelines and just kind of standardize, you know, safe practices, if you will. And so my hope would be that there'll probably be some published guidelines, hopefully in the next year, I would expect. Let me sneak one last question in because it just came in. Are psychedelics absolutely contraindicated for patients with psychotic disorders? And is there any potential for their use in patients with bipolar or schizophrenia? It's interesting. That's an interesting question. So the data, yeah. So right now it is a pretty hard line for psychotic disorders that psychedelics will generally not be utilized in a research setting. Now we know in the underground, people are doing all kinds of stuff. So who knows there. With the bipolar question, there's actually been a lot of interesting question about the utility of excluding people with bipolar disorder. And in fact, I've heard a number of cases of people with bipolar depression who have used psychedelics successfully. You know, there is this like theoretical worry that you're gonna flip someone into mania, but I think that concern is probably overblown. You know, that being said, like I would never encourage a bipolar patient of mine to go out and try psychedelics. Like, you know, that would make you very, very nervous. But I do think, I know for ketamine, there's been some trials of bipolar depression. And I suspect that in the very near future, we're gonna see a little bit of expansion to bipolar depression. I think with the thought disorder group, it's gonna be much harder to go there. And I think that's more of a historical remnant. I just think it's gonna be really hard to get an IRB to approve schizophrenics getting psychedelics. That's, we're a little ways out from that. I suspect, I could be wrong. I hope, you know, I hope we can explore it, but I don't know at this point how long that'll be.

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