Chapters Transcript Effects of Psilocybin in the Treatment of Addiction Course: 2025 NYU Langone Psychedelic Medicine Review OK, so I'm gonna try to. Zip through this and um. Let me skip through some of the things that are. I'm guessing will be Familiar or Less compelling OK, great. Yeah, OK, these are my disclosures, um, so I have some. Commercial relationships. So, um, Just uh This one is focused on um psychedelics and and really mostly um psilocybin for substance use disorder treatment, and I'm going to Discuss, um, some of the methodological challenges that came up in John's talk this morning, um, that, that are maybe not unique, but particularly acute in the study of psychedelic drugs, and, um, then I'll also talk some about challenges in um implementation, um. And um Well, you know, moving forward into a real world, um. Applications, but, um, John also um touched on some of that this morning, so, um. The methodological issues I will discuss primarily in the context of two new trials that we're About to begin, uh, which provided some examples of possible solutions or maybe not solutions, but approaches to managing some of these challenges. Um, So background, this is uh quite redundant at this point. Uh, I thought I would just say, um. The, uh, the term psychedelic, we, we seem to like that better now it it then better than the, the alternatives, um, but, um. Does anybody know, um, the little rhyme that, um, Aldous Huxley, uh, well, first of all, uh, Huxley proposed the term fennerothyme, which just doesn't roll off the tongue particularly well, and his little rhyme, this was in a like a Letter exchange between Osmond and Huxley, so it was uh to make this mundane world sublime. Take 1.25 g of phennerothyme. Not so great, right? Huxley was a great writer, but not a great poet apparently, at least this, um, so Osmond shot back to fathom hell or soar angelic, take a pinch of psychedelic. And then Timothy Leary couldn't have said it better, right? Oh, very snappy. So that's the one that stuck, for better or for worse. Uh, but we're focusing on those classic psychedelics that have already been described, and I think we've talked about this, um. The first wave of research, the, uh, psychedelic versus psycholytic models, um, uh, John also, uh, spoke to this, um, the, the, uh, meta-analysis of the Alcohol use disorder trials from the 1960s, um, which demonstrated a nice, uh, consistent effect, uh, with the number needed to treat at 6 at the first follow-up, uh, and, um. Still in the remaining three studies was, was, uh, I, I think still be a 0.05 at six months just in those three studies, but, um, the, these studies really did have a lot of methodological problems, um, which I won't get into, uh, at this point, but, um, it's nice to see how consistent the effect was, but they might have been consistently biased even though they were kind of all over the place in terms of their methodology and very weak in terms of their follow up. Um, and this is the other one which was, uh, the opioid use disorder, uh, trial with LSD. This was a pretty, uh, for the day, uh, this had some really good methodological features and one, sort of unavoidable weakness. It was a randomized trial. Uh, it was open label. The patients were Uh, coming out of prison. And they had all been previously addicted to heroin, and prior to release, I mean, who knows what the informed consent was like on this one, but uh they, they were randomized to either go ahead and be released or have an inpatient stay in which they'd received quite a bit of preparatory therapy, and then a single high dose LSD session with a dose in the range of 304 to 450. Micrograms, and you know, they never say how they decide the dose either. It, it's like there's this this range and you just like, I, I don't know how they did it, but um it's a range, and um and then, then they were referred to the same follow up, and the follow up was at a parole parolee clinic where they had to report daily and give a urine drug screen. So, um, very clear, you know, good collection of, of outcomes. And um so what you see, these effects are, you know, the, the total end here was 74. It wasn't a very large study, but um out at um. Uh, 6 months and a year, there is a nominally uh significant effect, uh, between the groups, and you can see it's roughly 30% to, you know, 5% or less, um, out at at 12 months, which, and this was pre-methadone, there was no other, uh, pharmacotherapy or really therapy of any kind other than the monitoring and the continuency of going back to prison. Uh, so, you know, for no, no medication for a year, that's 30%, you know, it's pretty, is pretty impressive for what it's worth. The real problem with the study was that, um, you know, the amount of therapy and preparation and, um. And and and all the expectancy biases that go along with it, um, between the groups, so you can't, uh, it's hard to attribute all of that, we can't attribute all that necessarily to the, to the LSD per se. So, uh, flashing forward, um, about 30 years, actually, I guess it's, um, 40 years. This was published, uh, uh, almost 40 years after the previous study. So this was our pilot study from the University of New Mexico. Um, this is all old news, so we'll go relatively quickly here too, but, um, uh, single group study, um. And I'll show you a slide with a little bit of detail, but not too much on the, the, the model, but this was 2 psilocybin sessions, high dose, um, a month apart, 12 weeks of um. Psychotherapy, outpatient psychotherapy sessions, which were, you know, roughly 1 hour long, and the psilocybin sessions happened at 4 weeks and 8 weeks. So it's sort of a psilocybin club sandwich with 3 buns of therapy. Uh, balanced meal Um, and, um, so the patients improved, uh, significantly here from baseline pre-treatment where they had, um, approximately 35% heavy drinking days. Heavy drinking days means on a given, you know, how many, how many of the days out of, you know, 100 did they drink heavily, which is 5 standard drinks for a man or more, 4 or more for a woman. Um, so there was some effect just in the, the preparatory therapy phase, a big drop after they received the first psilocybin session, and then those, uh, gains were basically maintained for the duration of the follow-up out to, to week 36, which was, uh, 7 months after that second psilocybin session. So these are large effect size within group pre-post effect sizes, even if you measure from here after accounting for this sort of run in. Uh, psychotherapy response, so that looks good, but, um, you know, we, we know we should not get too excited about, uh, open label single group studies. Um, unless you're treating, you know, ALS or something, and everybody gets better. Um, so this is the, the randomized control trial that was, uh, published in 2022, and, uh, the treatment model is, is pretty similar. So again, here's our, our, um, Uh, psilocybin sandwich, um, with the preparatory sessions, uh, psilocybin versus diphenhydramine at week 44 more sessions in between, the dose of psilocybin was increased, uh, based on the intensity of the experience reported in the first session, and the diphenhydramine likewise. And then we followed them again out to week 36 as in the pilot. There was an open label extension phase, and as John alluded to this morning, one reason to do this is to collect more safety data. Another is our strong hunch that we would have a lot of demoralization in the patients who got placebo, which could affect outcomes and also dropout rates and confound the study. So we wanted to keep people in the study until that point and it seemed to be pretty effective for that, um, if nothing else. The, um, and the results, this is published, uh, so this was in the the JAMA psychiatry paper 2022. Uh, the percent heavy drinking days were the primary outcome, and, um, the other continuous drinking outcomes were percent drinking days, just how many days were they abstinent versus drinking, and drinks per day, which is total number of standard drinks divided by the number of days. And um, so you see the same pattern in in each case, again, the psilocybin is the red, and again we have this. Substantial drop during the the therapy run-in phase and then a clear separation that begins in that first month after the first session is more or less maintained. It doesn't increase more after the second session, and I don't know, you know, how we can interpret that various ways and um. You know, you looking at this, you would think it looks like the effect is, is diminishing, and it may be it wasn't a statistically significant time by treatment interaction, meaning there's no, we don't have statistic statistical evidence that the effect was less at the end point than it was at. In the earlier months, but it numerically it was somewhat less. And so these were, uh, you know, solid for the primary outcome, solid, uh, medium sized effect, um, hedges give 0.52 and a, and a significant p value, so that was our primary outcome, so we win on that, but, um, it was a pretty consistent pattern of, uh, results, um, if you looked at. The, um, these dichotomous outcomes as well, various measures of response, uh, the pattern is all, you know, pretty consistently favors the, the psilocybin treated participants and just for a couple of sort of easy to interpret examples, I mean clinically meaningful examples, uh, abstinence during the, the final month. Of the follow up period. So this has not been continuous abstinence is here, and you see that's a big difference too, but it's um it's much lower, it's like 23% for the psilocybin group. In the final month, though, it's 48%. Uh, versus 24% in the placebo group, so twice as much and almost, uh, you know, close to 50% totally abstinent at least during that month. So that looks pretty good. And, um, in terms of heavy drinking days, no heavy drinking days in the final month. Uh, 62.5% versus 40% were not doing any binge drinking during that month. So, you know, the, the higher you raise the bar, the lower the numbers go, and you can get numbers, you know, ranging from Idaho, but the pattern is pretty consistent. These, I won't talk about the WOHO risk levels, although I'm, I'm rather fond of them, but um. Uh, it's sort of stratified like, uh, how much are you, you know, how, how, how. How hazardous is your drinking mildly, moderately, severely, very severely, um, and you know, and we saw similar patterns there. OK, so these, uh, this is some things that, um, some it's been, this part has just recently we published a paper on the personality changes. And we did see between the groups and the people who made it to 36 weeks, um, uh, Brock Pagney, postdoc in, in our, um, center, um, was the first author on this paper, and we saw substantial decreases in neuroticism, which is associated with depression and anxiety disorders, uh, increases in extroversion and increases in openness. Uh, there was also an increase in conscientiousness, but that was not different from the increase seen in the control group, and that all of these effects are conceivably consequences of reduced drinking. They're not necessarily that this is a chicken and egg problem because we, we didn't measure the personality changes early on. We tend to think of them as traits, so you can't really do, you know, see what, how was your personality last week. But you might be able to say the past 3 months, maybe we should have done that, but um we waited till till 6 months and um and this is what we saw. These um these other measures here just really quickly. This is craving, pen alcohol craving scale. And uh this is, um, yeah, these are all uh mixed models for repeated measure, uh, and I, I don't have the, you know, the statistics in here, but uh these are all uh less than 0005, I guess. I mean, they were, they were highly significant, uh, when you look over the time points, and, uh, so you see here the psilocybin craving, psilocybins lower. And it begins after the arrows here are again the drug administration, so it seems to perhaps the separation maybe increases over time. I Can't remember for sure if there were, um, if there was a significant interaction here for the AASE there definitely was it, it continued to get broader. This is confident, uh sorry, this is temptation, which is related to craving, but it's not quite the same. It's like it's, it's condition specific. It says if you were were walking uh past the bar and your buddy said, hey, come on in and have a beer, um, how tempted would you be to go in and and join him. Um, And then, uh, confidence is the same question, how, how confident are you that you could walk on by? Um, so you see less sensation and a lot more confidence, and these effects do seem to get larger over time, which you'd expect if they had been successful and not drinking for a while. The last one here is this, uh, self-compassion scale. Which is a pretty well validated scale um of uh self compassion, you can think of it as self compassion is, you know, being forgiving and sort of uh sort of nurturing of oneself, and if if that makes any sense, and it also includes the opposite of, you know, not being harshly judgmental, um, self disparaging or or uh self loathing, um, so it's Being nice to yourself. And uh this was of all these self report measures, this was the largest effect, this was really kind of a whopping effect, um, not that, not clear how strongly these are related to the the drinking outcomes. I mean it's not, we're sorting it out, but it's, it's not like a none of these stands out as being the, the magic key, um, at this point. Just on the personality, um, within neuroticism, the. Um, particular domains that were, um, affected by psilocybin were, uh, depression, not, not surprisingly, but good to see impulsiveness decrease, decreased depression and decreased impulsiveness. Uh, again, that some of that could be have to do with drinking behavior, and, uh, we didn't have a way of teasing that out with this particular measure. Um, and decreased uh vulnerability that would be emotional vulnerability, which was consistent with, um. Of what we saw in one of the other studies, the extraversion was, which was a little puzzling when we first saw extraversion, but it didn't mean they wanted to go out and party. Uh, it meant, um, increased positive emotions was the only sub only facet of that dimension that was significantly increased in the psilocybin. Group and um which again is very consistent with the uh you know, especially the citalopram versus psilocybin study where um that was really the the area where the the the psilocybin group seemed to really do better than the escitalopram group. And the openness, um. This, um, again, you know, I, I, I hesitate to call this, you know, cognitive flexibility, which is sort of a, a vague term, and it, it, this is, this is not very closely related to. Um, cognition necessarily, but it, it, it has to do with, uh, being accepting of, you know, what one is observing within oneself, so maybe it's related to mindfulness and self compassion in some loose way, um, and, you know, we, we could look at the correlations and see if that's You know, how that holds together, but that's kind of how just that that's the the story that comes to mind when I see this. And uh and then and within conscientiousness, it was increases in deliberation, which again speaks to the possibility of improved executive control or um ability to, um, you know, stop, look, listen and and make a decision without just responding in a conditioned way. We were able to do, this is one of those studies that before the um. NIH was really open to. Um, funding Work on psychedelics. I was not able to get funding for a pilot study which we submitted and um it got a good score on but it was not funded. We um got some small amount of private money and we're able to do the scan, a total of 11 patients ultimately with pre and post scans, and it's, you know, it's kind of a pathetically small sample size, but we did find some patterns of uh changes that are kind of consistent with what we would hope to see. So we had a task which was uh a cue, um, just visual cues of uh alcohol related stimuli and positive emotional and negative emotional stimuli. Um, and what we saw across, uh, especially the alcohol and the negative emotional stimuli, um, was increase, um, in some of these, uh, lateral, uh, and some other medial prefrontal cortical areas, um, and this left caudate, um. Piece here, um, and decreases in a number of other areas and, um, this is not exactly what we expected to see. We, we thought we'd see, you know, decreases in nucleus accumbens perhaps or decreases in, in certain, uh, medial, uh, emotion related, um, medial, uh, prefrontal cortical regions, but it does, it is consistent with, um, sort of enhanced activity within, uh, executive control. Circuits in the context of, uh, you know, negative emotional or um. Highly salient, um, craving inducing stimuli, so that's consistent with, you know, that part of the model at least, and, you know, we may just not have picked up the deeper activity and deeper structures like the nucleus accumbens, but we'll see. Um, So The big, uh, hand waving conclusion here is, um, it's, it's all of this is, you know, speculative but maps nicely onto this three part model of addiction that's been promoted by George Kubin Nora Volkov, which accounts for the. Um, that in sali incentive salient processes that have to do with, um, uh, overvaluing the drug and seeking it and craving it, um, the, uh, negative affect, um, aspect which is related to withdrawal, but also just, uh, just a, an altered hedonic set point where you just, your, your new baseline feels lousy, and you just, you know. Normal is bad because you've been pushing your brain in the other direction with these euphogenic drugs, and so your, your, your body has dampened all of that hedonic response and you're just feel kind of dead and nothing feels good. Uh, so the depression, emotional vulnerability, and, and, um, self compassion all fit into that domain, more or less, and then, um, uh, executive function again, that covers. You know, half the brain, but, um, these, uh, you know, they enhanced self-efficacy, decreased impulsivity, and enhanced deliberation are all in that ballpark. So I think. We don't have to just say, you know, does this work by decreasing craving, or is it by improving depression, or, you know, it could be all of the above or or not, but we, we should keep looking at all three domains at this point, I think. OK, other, um, other, other, uh, substance use disorders rather. So, um, Smoking cessation, there's really, there is still just this one published, uh, trial that uh Matt Johnson published uh back in 2014. With um 15 participants, and the results of this really were quite um remarkable with um Uh, this is cigarettes per day before, and it's 6 months, and so this is overall, um, you know, went from about 17 to about 4, and if you just use the, the criterion of are they abstinent, uh, at 6 months, uh, 80%, 12 out of 15 were abstinent, um. Uh, that, that's point abstinence at that, at that time, they, you know, were negative for nicotine and codeine and, and carbon monoxide, and they reported no smoking, so that, that's the criterion, and, uh, 10 out of 15 still at 12 months, 9 out of 15 at a long term follow up they did, which was anywhere from 16 to 57 months, uh, cigarette craving was immediately went way down. And uh withdrawal symptoms, um. Well, that's actually not in this study, that's another study. Not time to talk about that. So this is not published, but I, I, this actually is available, uh, the data are available. I made the little chart, but this was the interim, uh. The result that was published was reported and is, you know, in print in a supplement, reported at ACMP a couple of years ago. So this was at the point of, um, having treated 61 participants of this 80 person trial. This is an open label study with a psilocybin or nicotine patch, uh, plus cognitive behavioral therapy for both groups, and it's a single psilocybin session. Uh, it's open label. Um, but it's a credible control condition, so it's, I think this kind of study, you know, comparative efficacy, we usually do it after you, we do the, the, uh, a comparative effectiveness, I mean, sorry, we usually do the effectiveness studies. After we do the, you know, established efficacy, but it's a nice compliment since, you know, we can't really do double blind studies that have blinding integrity anyway. This at least you have a credible control condition, and you see with the patch, again, this is interim, so don't, don't, uh, quote anybody on this, but, um, it's uh 27%, which is quite good for nicotine replacement, so they're, you know, they're, they're getting real treatment. Uh, versus 52%, uh, and this is out at, um, Um, 12 months, all the way out to 12 months. So, uh, so looking good at that point, and unless things really fell apart in the last bit of the study, it looks like this, this may, may provide some meaningful information. Uh, I mean, somewhat, uh, compelling data, at least. Uh, this is another study that's underway. This one also has been finished, but has not been published. Uh, and this is a 40 person study that Peter Hendricks conducted at the University of Alabama Birmingham with, uh, cocaine dependent, uh, men and women, mostly men, mostly African American impoverished, uh, many homeless people living in, um, in Birmingham, and, um. It took them a long time to recruit, but, um, you know, they were able to do it, and I think the retention overall is going to be pretty good. This is the interim results for just the very 1st 10 patients, so I, I don't want to say too much about this, but they, uh, in the Uh, 5 or so patients who received psilocybin, you can see the uh. Yeah, that this was before, again, people, the attention always in, in addiction treatment, you just have to contend with this. It's not a placebo effect, it's an attention and being in a trial and wanting to stop effect. Uh, so their, their, um, percent abstinent days go up quite a bit, then they receive the psilocybin, and then, um, the placebo group continues, stays about where they were, and the uh. The psilocybin participants were almost entirely abstinent, so this is not likely to be to hold up at that level, but um it was, was headed in the right, the first step went in the right direction. That's about all we can say about this. So that, um, hopefully we'll, we'll see this publication, you know, this year. So, yeah, so that's about it for published studies. Um, I'm not going to talk about the other disorders because we've And I've done that. Um, I don't think I need to talk much about the adverse effects cause we've, let me just see what is here that we might not have covered, um. Uh, yeah, the acute psychoactive, you know, the acute, um, subjective effects really are the single most. Biggest thing to contend with. There is a possibility, there's some evidence that there's a slight prolongation of, of QTC, uh, which is probably not clinically significant at the, at the doses that anybody's going to be using clinically. Um, it's maybe a more concern if you're dealing with patients on methadone, for example, which is another QTC, which is a QTC prolonging drug. So something to know about and will probably require some more, uh, data to, to be sure about that. Uh, this serotonergic toxicity in combination with other drugs, it hasn't happened very often. It's usually, uh, I mean, if somebody today starts Prozac 80 mg and takes a big dose of psilocybin, that might be a problem, or if they're on, um, MAOIs, then I think all bets are off. But, uh, with uh people on Stable doses of sero serotonergic antidepressants, actually there's evidence now that that's a safe combination and, and may or may not, it doesn't completely abolish the subjective effects and, and, and may or may not affect the, the efficacy. Um, we talked about the suicidal ideation, um, which we don't really know if it increases, but it certainly can happen acutely after dosing. And a hallucinogen persisting perceptual disorder, which is a terrible disorder, uh, which can be, you know, chronic and disabling, uh, it has not been observed in controlled trials, but in people who've used, you know, particularly combinations of drugs and, and, um, may or may not be dose related, but occasionally people will get, you know, have these re-experiencing, uh, experiences of the Similar to the intoxication effects which are, um, you know, very disturbing and, and can, you know, lead to suicidality and, and real impairment. Um, We always worry about precipitating a psychotic episode in somebody who may be predisposed or, you know, have an underlying diathesis. Um, again, that hasn't really been observed in the clinical trials, but Um, it remains a possible concern. Uh, misuse of psilocybin certainly occurs, um, it, you know, we really, it, it is not the kind of drug that is, uh, used in a compulsive daily pattern ever. It doesn't even work if you, if someone tries to do that, and it's self-limiting because of, not only because the effects diminished, but because it's just people eventually start, will, will probably have some bad experiences and no, it's not a reliable way of feeling good. I guess is the bottom line, and that's, that's what drugs of abuse basically have in common. Um, undesired changes in personality or behavior, um, undesired by whom, maybe undesired by, you know, somebody's spouse or family, that may or may not be a bad thing, but, uh, this is something that, you know, we really do need to talk about in, in an informed consent process that, you know, change these drugs, if these drugs enhance the capacity for change, uh, you know, we have to admit that change is not always a good thing. And um if if you're trying to change in a certain way and you're already in a bad place, it's probably much more likely to be a good thing, but Uh, you never know. OK, and then vulnerability of participants, I think we talked about that already. Um, so this, um, just talk about this a little bit. Um, John talked quite a bit this morning, I mentioned a couple of times that the issue of, uh, allegiance and, you know, uh, investigator, uh, bias, which, um, you know, is not necessarily, you know, a devious, uh, lack of, uh, integrity, but it's the natural things that happen when we're enthusiastic about things that we, uh, hope will be. Useful, right, but it can still really bias our interpretation and um uh of results. So, um, we talked about unbinding and expectancy bias, so, and, um, this, you know, very complicated net of possible interactions between. The pharmacologic and non-pharmacologic aspects of the treatment model, which I think for many of us is, is one of the things that's most interesting about this field, but it really, it, it's not something the FDA wants to deal with, and it, it, it really is, um. It, it is quite complicated. Um, So, um, and, um, yeah, I think I'll not talk about this so much because we've, um, I think it's really pretty much been covered the, the, the milieu in which all of this is happening. So let me tell you just a little bit about these two new studies and some of the methodological decisions we made in designing the studies and, and why, and you can tell me why it was a bad idea or or not, but, um, at least it provides some um. You know, an example of, of, of how, uh, we thought through some of these issues. So this first one is an alcohol use disorder study. Um, and this is, uh, fundamentally a mechanistic study, OK, so the primary outcomes are neuroimaging, uh, it, it, it's the brain, uh, response to, uh, the alcohol and negative emotional cues that we're using a task similar to what we used in that pilot study. Uh, but we are, you know, it is also an efficacy trial and we'll be collecting outcomes out to 6 months, and we also are getting objective measures of executive function now as, as well as, um, objective measures of uh drinking with the uh blood biomarkers, which we did not have in a consistent way in the previous study, and then some of the same self-report measures that we had before. So those are the sort of all the main effects of the drug. What does the drug do versus placebo. The, the second aim is, uh, has to do with the relationship between these, uh, brain effects and, uh, and drinking outcomes, as, as well as other self-reported changes. And the third aim is, um. Looking for uh predictors, baseline predictors of response. So this is the, you know, personalized medicine or precision medicine or whatever, um, which, you know, we all agree is a great idea, and it's been remarkably difficult to find consistent biomarkers for, for a lot of things. Uh, this study, you know, the, the sample size here is 120, we're a little small to do this kind of thing. But, uh, but we're gonna see what we can, what we can come up with. Um, so. So I mentioned that the end of 120 is because that's as many as we could afford, more more is, is clearly better always, um, double bond randomized control trial is basically, you know, the for, for causal inference, that's, that's pretty much the best, that is the best way to go. The single session has to do with, um, for the, for the neuroimaging. Uh, measures, it just simplifies a lot of things and it's also because we're, these are patients who are in a residential treatment program. So this is good for, for scientific purposes. This is good because they're, they're not going to be drinking and we're expecting to be able to get almost 100% of the data, you know, immediately pre and post. So so that the fMRI data will be very clean. Uh, and you're dealing with a sample there cause they're inpatient, they're residential patients, they have almost by definition severe alcohol use disorder, uh, and they're not, and they're sober for a little while, so it, it really is a good window of opportunity to look at the short term effects of psilocybin. Um, we're doing a 2 to 1 randomization really primarily because of that, uh, that third aim, uh, that gives us 80 participants treated with the active drug, and we have a better, better chance of trying to find some, some, uh, moderators. And um that's um we decided um after much debate to allow SSRI's in the study. Um, because, you know, we, we. Could justify that on safety grounds, uh, pragmatically, it helps with recruitment and, uh, although it could diminish our, our efficacy signal or our FMRI signal, it's a very important population to start to get some information on and um. In a double blind trial, so, um, we decided that overall we that it was worth that the extra information was worth the possible, um, hit that we take in terms of power because of the, the variability. Um, otherwise, um, yeah, OK, this is the other main thing I want to mention, and this is true for both of these studies, um, you'll see in a moment, um. Where this with an eye towards eventual, um, you know, dissemination and implementation, um. One of the issues, you know, we have. Uh, there's a lot of training that's required and set up, and, um, it's, it's not, you can't just start doing, giving people psilocybin you, I mean you need a facility and you need some training, and it, it's not something that I would imagine that it's going to be available, you know, in every doctor's office or every primary care clinic or every addiction treatment program. Uh, and we're seeing this, you know, as we're moving along, it's looking. Like, uh, it's probably psilocybin in most cases is not going to be a first line medicine in most cases, um, so what really is practical is that if the patient is in. First line, uh, regular treatment for whatever disorder, and they're not doing as well as their provider would like them to be, if you can add on an episode of psychedelic treatment, um. Uh, while maintaining that other treatment. Uh, you don't have to create the, the, the primary treatment doesn't have to create a new psychedelic treatment program, and the psychedelic provider doesn't have to pre-create a mood disorder program, an alcohol use disorder program, an opioid use disorder program, so you're, you know, it's, it's an add-on that could plug into various, um, various, uh, forms of, um, sort of not primary, but the secondary care for the psychiatric disorders, um, and the other advantage. At least in theory, we'll see about in practice, but uh the person already, uh, if they're in treatment for depression or they're in treatment for substance use disorder, they have a a counselor or, you know, maybe they have a well. In England, they'll for depression, they'll they'll get therapy. In the United States, they usually just get to see their PCP. So that's maybe a little more complicated in that case. But in addiction still here, almost everybody gets some form of counseling. So they have an established therapeutic relationship with someone who will continue to see them for the foreseeable future. You don't need to start from scratch and, and, um. Make sure that, um, you know, you've established a really strong alliance with the with the patient de novo with the psychedelic provider. So we're having the, the therapist from the Um, who's working with the patient in the program, the, in the residential program, uh, accompany them to the preparation session and the, uh, uh, drug administration session. We, we're having just a single preparation session, 2 hours, and it's mostly the, the, the physician then is, uh, you know, definitely getting to know and establishing rapport with the patient. But is also the one who's responsible for providing all the information about the, about the session and being the expert in in psychedelic treatment and um then and and also for, for monitoring safety and is, you know, is on the hook for following up on any psychedelic related adverse events and problems that that arise there longer term, but they will be, in this case, they'll actually be in a controlled environment the day, you know, the night after the session, so they're They're, they're safe, safely ensconced in their, um, residential program for at least a couple of weeks after the, the session, so that, you know, also provides a measure of, of safety. Um, OK, so that was an important one. we have, um, we, we are going to do our very best to evaluate expectancies and unblinding systematically, and we have some, uh, you know, statistical models for accounting for that. Uh, we talked about the Yale adherence and confidence scales, uh, which really Kathy Carroll, who died in an untimely way a few years ago, uh, terrible, but she was really, um, uh. Did some seminal work in terms in in making psychotherapy into a You know, something that that you could test rigorously in a trial, so we're going to be adapting those um scales and and using them in this study. Um, OK, here's the other one, so I think I can tell you a little bit about this, uh, in 3 minutes. Um, so this is for patients who are, um, We have opioid use disorder and are currently. Enrolled in and regularly adhering to methadone treatment. So these people on methadone will come to the clinic almost every day, especially if they're still using illicit drugs, which uh these, these people in this study will be. So they're, they're in, um, they're stably unstable in a way. So I mean they're, they're, you know, high severity, especially nowadays, um. Almost all of these patients are in the United States are using fentanyl or some other kind of high potency analog. I think there's, there's a little bit of a fentanyl shortage recently, but I, I think, you know, something will be that that stuff is here to stay because it's, it's so easy to make and so easy to smuggle, um. And um, so, um, so again, they have an ongoing long term actually therapeutic. Relationship, but they're continuing to use um illicit drugs and um they will, as in the other study, have um come with their counselor to for preparation and uh dosing and then to the um well actually the the uh. Follow-up sessions will be done remotely, so they, they'll, they can do those from the from the methadone program. Um, this is a multi-site study, so we got, uh, Nida was amazingly willing to kind of jump in and do, I mean this is a site study you really need to do to, to, to answer, to, to do a real efficacy trial, but usually we have to mess around with. Doing, you know, in a 40 and maybe 80, and then, um. So, I, I really am grateful that they're willing to take a chance on this, and, and we really have to deliver. Uh, so we'll have, um, sites in. New York and then sites in New Mexico and in both cases again this is a test of the sort of um hub and spoke model what we have on on a very small scale we have in in New York we have our center and we're working with two very large uh publicly funded methadone programs and similarly in New Mexico there's the academic center with the psychedelic expertise and two large um. Methadone programs there, um, and that's, um, you know, again, we are allowing SSRIs. These patients don't tend to be on as many psychiatric medications, although they certainly have some comorbidity, um. And um we're going to do single lead ECG monitoring during the sessions to try to address this QTC issue. So they'll be screened. They won't, we would not dose somebody with an elevated QTC. Um, but we'll, uh, just with a sample like this, the, the, the single lead EKGs are actually pretty, um, pretty decent for measuring change, you know, they, they don't give you the absolute value as well, but, uh, we, we can get a pretty good estimate of is there an effect here and hand and how big it is. Which will I think will be very useful to the field and, uh, yeah, and then we do not have this one we kept it sort of uh lean in terms of not adding all of the, the, the fancy even ques some of the questionnaires that we'd like to have and, and none of the um uh mechanistic things we, we both of these studies, uh, we want to try to get a little supplemental funding to collect uh blood uh at baseline and, and maybe at one or two follow-up points for. Uh, for genotyping and then also for, um, whatever else we can get, uh, mRNA, uh, probably being first on the list, but there's all all kinds of other. Omics we could look at, um, but I think, um, yeah, gene expression would probably be the the one that we'll we'll try to get if we can, um, and I think that's About it. Um, so, uh, yeah, I guess it should be pretty clear by now that there's a lot of questions remaining to be answered here, and, um, And I kind of tying back to um. Josh's talk with about the the levels of of analysis or scales of um measurement. Uh, this is, I think, more so than most other areas of psychiatry, we, we need to look at multiple levels of analysis in order to get a clear picture of how these drugs work. It, it, it appears, I mean, I believe that the, the, the, you know, the interactions between the Um, the basic neurotrophic kind of, uh, effects of these drugs clearly have, and the unusual experiences and the memories of those experiences, which, you know, that, that, that is something that is, you know, physically in the brain in some manner, and those the the memories, I mean that is one thing that is very striking about these experiences is how vividly, how meaningful they are held to be and how vividly they are remembered and brought. Uh, you know, called up and, um, on a daily basis by some of our patients years later, so. Um, so that's where we are, and I, um, That's all I'm gonna say, um, but, um, thanks for coming, and if we have the patience, I can take a few questions. Published January 25, 2025 Created by
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