Psychedelic drug therapies

[00:00:29]

RICK WEISS: Hello everyone. Welcome to SciLine’s media briefing on psychedelic drug therapies. I’m SciLine’s director, Rick Weiss, and for those of you not familiar with us, SciLine is a philanthropically funded, editorially independent, free service for journalists and scientists. We’re based at the Nonprofit American Association for the Advancement of Science, and our mission is pretty straightforward. It’s to make it as easy as possible for you, as reporters, to include scientist sources and scientifically validated information in your stories, whether those stories are about science, as today’s topic is, or just about things that are going on in your local communities or region where some scientific evidence could help strengthen that story and add credibility to it. And of course, in our view, there’s almost no story you could imagine doing in journalism that wouldn’t be strengthened with a little bit of scientific research, and I can assure you that someone, somewhere studies what you’re writing about. So, we can help you do that. Among other things I want to mention, our Experts on Camera service, which lines up scientists to be available for one-on-on broadcast quality, interviews with you on topics in the news, go to SciLine.org and put in the search box Experts on Camera, and check out that and the other services that we have to offer, all of which, again, are philanthropically funded and so entirely free for you.

A couple of quick logistical details before we get started. We’re going to have three panelists today discussing different aspects of the topic of psychedelic drug therapies. To enter a question either during their presentations or afterwards, please just hover over the Q and A icon at the bottom of your screen and insert your name and your outlet and your question. And if you want to direct that question to a certain speaker, let us know about that as well. A full video of this briefing should be up on the SciLine.org website by the end of the day. Transcript to go with that will be up over the next day or two. If you need a rough draft, raw copy of that film immediately after the briefing today, let us know, and we can get that to you as well. Just put a note in the Q and A box. And of course, if you have any technical problems, the Q and A box is a good box is a good way to reach us as well.

I’m not going to take the time to give full introductions for our three speakers today. Their full bios are on the website, on the media briefing page, but I will tell you that we will hear first from Dr. Jennifer Mitchell. She is a professor of neurology at UCSF Weill Center for Neuroscience—I’m sorry, Institute for the Neurosciences, who will get us started with an overview of psychedelic drugs and a focus on their potential therapeutic value for mental health issues with a special focus, in particular, on post-traumatic stress disorder or PTSD. Second, we’re going to hear from Dr. Albert Garcia-Romeu, an assistant professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine, and he’s going to focus on psychedelic therapy for addiction-related health issues. And then third, we’ll hear from Dr. Alan Davis, who is an associate professor and director of the Center for Psychedelic Drug Research and Education at the Ohio State University, who will get into the potential value of these drugs for clinical depression. And so, why don’t we just get started and over to you Dr. Mitchell.

[00:04:00]

JENNIFER MITCHELL: Thank you very much and it’s a delight to be here today and to have the opportunity to share with you. I will start by sharing my screen, and then hopefully—all right, hopefully you can see that. So, I will start with a couple of definitions, because what our group primarily studies are psychedelics, and psychedelics are slightly different than hallucinogenics. And I think some people use these two terms interchangeably. But psychedelic means mind manifesting, and so the idea here is that we are interested in the potential therapeutic efficacy of these compounds for a number of mental health conditions that these compounds might help garner insight into the psyche. And that’s a little bit different than the term hallucinogenic, which means seeing something that isn’t there, hearing something that isn’t there. So, you could imagine that there’s a lot of overlap between these two groups of compounds, but for the sake of this discussion, we’re really focused on psychedelics. And some examples of psychedelics include LSD,  which I think people typically think of when they think of the term psychedelic; and then psilocybin, which is the active ingredient in what you usually hear as magic mushrooms; DMT, which is the active ingredient in ayahuasca; mescaline, which is found in a number of different cacti including peyote; and then MDMA. And I should mention also that psilocybin and MDMA are farther along in clinical development than some of these other compounds. They are in what the FDA refers to as phase 3 testing. So, this is the last step in the drug development pipeline before you create something called a new drug application and then submit that to the FDA for assessment and for potential approval for a clinical indication. And since our group has been primarily focused on MDMA for PTSD, I’ll probably tell you most about that today, but we have done a few other studies as well with psychedelics including looking at psilocybin as a treatment for demoralization, and that was in long-term HIV/AIDS survivors, MDMA for PTSD, as I already mentioned.

We have a grant from the FDA to look at psychedelic safety in community settings where they’ve been used, obviously successfully for millennia. We are also looking at psilocybin for end-of-life distress. That is a common indication first pioneered by Hopkins. And then lastly, we are interested in looking at set and setting, and I’ll get back to that in a couple of slides, but the idea here is that the environment in which psychedelics are administered could be particularly important for determining their therapeutic efficacy. So, with respect to MDMA for PTSD, I was going to walk you through a few stages in the development pipeline and the research that we’ve actually done to date, because it’s been seven years. We didn’t think it would take this long, but, you know, it did. And so, it started in 2017 with what we call a special protocol assessment with the FDA. And this is a mechanism by which a sponsor can sit down with the FDA, and they can sort of flesh out a scientific protocol so that when they go back and submit this new drug application to the FDA years later, the FDA doesn’t say, ooh, shoot, no, we don’t want you to do it that way. So, this sort of greases the wheels in the drug development pipeline. Then not long after, MDMA was awarded breakthrough therapy status. This again further facilitates communication with the FDA when you’re ready for that new drug application.

And then, all of the 15 study sites that participated in the phase 3 data collection had to practice so that we could show the FDA and the sponsor that we were all doing everything identically, that there were no differences, and that the data we were collecting was homogeneous between these different sites. In Israel, in Canada, and the United States. And then once we were able to demonstrate that, we started what is called an RCT, or randomized control trial. And you have two types of randomized control trials in phase 3. So, typically, the first one is called pivotal, and then there’s replication. So, for the pivotal phase 3 trial, we were focused on efficacy and safety of MDMA-assisted psychotherapy for the treatment of severe PTSD. So, you had to have severe PTSD to qualify for that study. And then, because the FDA believes that maybe lightening can strike once but not twice, you start all over again, and you do replication. And the good part about replication is that you can typically relax your inclusion and exclusion criteria a little bit. So, groups that perhaps couldn’t have been involved in a pivotal phase, because they have say another major illness like cancer or diabetes or HIV, can often be included in replication, and then you can also sort of increase your pool of participants. So, for PTSD, before we were looking at severe, but in replication we could look at either moderate or severe. So, it was casting a slightly broader net for participants. And then lastly, we’re also looking at long-term followup data from everyone that participated in phase 3, because one of the big questions is how durable are psychedelics as compounds? Do they last, as some people would suggest, for several years? This is an important question when we talk about decriminalizing and when we talk about what insurance companies might be willing to pay for in western medicine.

So, now I was just going to show you this tiny little snippet of data. This is a little picture on the right, and I’ll explain what this means. But I should start by saying that even though we all sort of know what PTSD is, and I think we all use that term rather frequently, we have to adhere to the strict diagnostic definition of PTSD for clinical trials. And so, the diagnostic definition says that PTSD is what occurs in response to witnessing or experiencing a traumatic event. And most importantly, that traumatic event must follow exposure to actual or threatened death, serious injury, or sexual violence. You could imagine, there are a lot of traumas that we all face that wouldn’t meet this criteria for PTSD. But with these criteria in mind, it’s actually still quite a common diagnosis. So, between 7 and 8% of the U.S. population will have PTSD at some point in their lives. And so over here on the right you have a picture with two lines, one in blue, and one in red. And this is an assessment of every participant’s PTSD symptomology, how much PTSD symptom they had. And what you can see here is that there is a blue line that indicates participants that received psychotherapy with placebo and a red line that indicates participants that received psychotherapy with MDMA. And you can see that both groups improve over time. So, down on the x axis you see that after three different long experimental sessions, these are therapeutic sessions, both groups do better, but if you compare the red line to the blue, you can see that the group that receives MDMA plus psychotherapy is significantly improved by the end of the study, compared to the group that received psychotherapy with placebo.

So, then just shifting gears a little bit, I also wanted to mention set and setting, because we know that the therapeutic efficacy of these drugs seems to be somewhat determined by the environment in which they’re administered. And so, the typical example that I like to give is that of Advil, because Advil is great for headaches, and for me, Advil works equally well if I take it when I’m sitting with my mother versus if I’m at work versus if I’m at home with my kids. But psychedelics are different. They are actually very much dependent on the set and setting in which they’re administered. So, we have to pay particular attention to all of these different environmental cues and be very considerate when we sort of formulate an environment for administering these drugs. So, here we have two photos. The photo on the right is taken from our psychedelic treatment room at UCSF, and you can see its sort of shaped like a comfortable living room, low light. It has nice music, lots of blankets, comfortable pillows, and there’s a very well-trained group of facilitators that sits with a subject while they are in one of these psychedelic treatment sessions. The picture on the right, excuse me, on the left is from our room at UC Berkeley, which is not a psychedelic treatment room, and you can see it looks more like a standard exam room. And you can just imagine that taking a psychedelic in the environment on the right is going to result in a different set of effects than taking a psychedelic in the room on the left. And so that’s something that we’re currently studying as well so that we can really potentiate the effects of these drugs and make sure that they do as much therapeutic benefit as possible. And so, with that, I think I’ll stop sharing my screen, and I will turn the presentation over to our next presenter.

[00:12:59]

RICK WEISS: Fantastic introduction and overview of that work. Thank you, Dr. Mitchell, and over to you Dr. Garcia-Romeu.

[00:13:12]

ALBERT GARCIA-ROMEU: Great. Thanks very much and are you able to see that okay? All righty. Yeah, so my name is Albert Garcia-Romeu, and I’m going to be talking about emergency research on psychedelic-assisted treatments for substance use disorders. And I just want to point out, you know, from a pharmacological standpoint, there’s different types of psychedelics, and Dr. Mitchell mentioned this a little bit, but we have drugs like psilocybin and LSD. They’re often referred to as classic psychedelics. They’ve shown good data for treating depression, existential distress in patients with serious illness, and also in treating addictions or substance use disorders. As we just heard from Dr. Mitchell, we also have MDMA, which is often talked about as an entactogen or an empathogen. This has shown really good data in the treatment of post-traumatic stress disorder. It’s really important to note that both the classic psychedelics and MDMA are still in what we call schedule 1, meaning that they’re the most restricted class of drugs, and they’re basically considered illegal throughout the U.S. even in places with decriminalization and therapeutic mandates at the local level. And this is due to the United States Controlled Substances Act, which supersedes some of the smaller jurisdictions. Now there’s also often talk about ketamine-assisted therapy as a psychedelic therapy, and I will talk a little bit about that as well. It’s a slightly different type of drug. We call them dissociatives, but it’s shown very good data for treating depression and also for treating addictions. And it’s something that’s legally available, though it’s not an insurance covered, and so it’s only available to people who can pay out of pocket. And, you know, we talk about these as psychedelic-assisted treatments or psychedelic therapies because this is often not just a drug that’s being administered, but the drug that’s being administered in concert with some level of psychological support, often some sort of talk therapy or counseling. And something that’s important to note is that we think that the mind-altering effects of these drugs, of all of these different types of psychedelics may actually facilitate the therapeutic process. And so that’s something that’s still being investigated, but it’s worth noting.

So, psilocybin has been studied primarily at the lab where I’m working here at Hopkins, and psilocybin is one of the classic psychedelics. It’s been around for a long time, longer than people have been around, and it’s the psychoactive agent found in over 200 different species of mushrooms, often called magic mushrooms. And we know that there’s a long history of indigenous use of these mushrooms dating back thousands of years, and we have that in written record such as the Florentine Codex from the 1500s. There is—the first introduction to psilocybin mushrooms in terms of western science happened in 1955. So, this is relatively novel phenomenon for western scientists to be studying, and there’s an indigenous healer in Northern Mexico name Maria Sabina, who first introduced westerners to the psilocybin mushroom. And on that note, I think it’s important to really think about how we use psychedelics and how we’re talking about their use, because a lot of what we’re going to be presenting today is based on this sort of top circle here in this therapeutic medical model. And as I have mentioned, is something that’s a relatively novel development. Psychedelics really didn’t come into the focus of western science and medicine until the 20th century. However, there are a long history of spiritual and traditional use coming from indigenous cultures that predate western medicine. And we also have, obviously, a very long history of recreational use and sometimes called psychonautic use for people who are exploring their psyches. And so, it’s very important to note at that time when people are using these substances, how they’re using them, and what angle or approach that they’re coming from. I think that all of these approaches have valid and valuable knowledge and traditions, and so when we’re dealing with people, they need to know and we need to know we’re working with these substances, and for the most part, today, I’ll be talking about this therapeutic medical model.

So, there was a lot of early research looking at these classic psychedelics—primarily LSD—during the 1950s and ’70s, and one of the main areas of interest at that time was looking at potential benefits in treating substance disorders. Data from randomized control trials that were conducted back in those days found that individuals with alcohol dependence who received a single high-dose LSD treatment were about twice as likely to improve in terms of the alcohol misuse as people who receive some sort of nonpsychedelic control treatment. We have also seen preliminary data from a study that was published in 1973 showing that among individuals with a history of opioid dependence that there was four times greater opioid abstinence up to a year after a single high-dose LSD treatment as compared to a treatment as usual control group. So, dating back to this early era of research, we have some initial indicators that these classic psychedelics could be useful for treating substance use disorders. Since 2000, we’ve seen a major uptick in research with psilocybin, and the data are very consistent in showing antidepressant effects, and Dr. Davis will talk more about that in a moment. But we also have growing evidence looking at psilocybin for treating addictions, including alcohol and tobacco, as well as work looking at the use psychedelics and psilocybin in existential distress. So, the drug sessions themselves typically take place in a living-room-like environment. They usually last about eight hours, and depending on the scope of the treatment, we may use anywhere from 1-3 high-doses sessions interspersed over the course of a few months. We are typically doing this work with a couple of facilitators who are present throughout the dosing sessions and the preparation. And we have a very nondirective approach, for the most part, when we’re working with psilocybin, meaning that we ask participants to lie down on a couch, listen to a program of music, and to focus their attention inward, but we’re not providing any real-time talk therapy during the dosing session except for in unusual cases where people might be particularly anxious or dysphoric. And so, you can see here, one of the session rooms here at Johns Hopkins.

And so, what do the data say so far on psilocybin? In a study that was done here and published in 2016, we found that about 80% of patients with cancer and clinically significant depression and anxiety showed improvements up to six months after a high dose of psilocybin, and that data has been now replicated in three other studies to date, including studies at UCLA, NYU, and here at an oncology center in Maryland. There’s also been small pilot studies that showed improvements in people with alcohol dependence and treatment-seeking cigarette smokers after receiving high-dose psilocybin treatment. These are small studies with just 10 or 15 participants so it’s considered preliminary data but that data has been very important for us to then go on and conduct these larger randomized trials. And so, now you see that there’s been a 95-person randomized control trial of psilocybin for alcohol use disorder where individuals who receive two high doses of psilocybin with talk therapy did significantly better than people who received a placebo with the same talk therapy. So, very similar to what we heard with MDMA and PTSD. Similarly, I recently completed with Dr. Matt Johnson here a randomized control trial in 82 cigarette smokers, and we have not yet published these results, but I can tell you now that the participant who received one high-dose of psilocybin with cognitive behavioral therapy were doing better in terms of quitting cigarette smoking than people which received the same talk therapy with nicotine patches, which was a control condition in that study. We also are anticipating a colleague, Dr. Peter Hendrix, publishing his data from a study of psilocybin for cocaine dependence, which the results so far—looking very promising. So that’s, you know, really the state of the data, and I think there’s going to be a lot more to be heard about in this realm in the next few years. Other psychedelics including MDMA have shown some preliminary data suggesting efficacy for alcohol use disorder, for instance, in a small study of 14 individuals, and there’s been also a lot of other work done using ketamine-assisted therapy for treating a number of different substance use disorders including opioid dependence, alcohol dependence, and cocaine dependence. So, I think that that’s another promising area to keep and eye on.

You know, I mentioned the mind-altering effects of these drugs. I think so this is really interesting to let the participants speak in their own words, and specifically what you have here is data from one of our smoking cessation studies, where we found that 80% of the cigarette smokers in the study quit after three high-dose sessions of psilocybin and talk therapy. When we asked them afterwards what was most memorable about their experience, you can see that all of these people had some really interesting insights to share, many of which seemed to be very much in alignment about what was notable to them. So, you can see this person said this idea that we are all one, the awareness that all is one, oneness with the universe, a feeling of becoming one with the universe. So, I just want to mention, these are all people that came here to quit smoking cigarettes, and these people never met each other, never spoke to each other at all, and yet there’s a lot of consistency in terms of their recollections of their experiences.

So, shifting gears before I wrap up, I just wanted to mention specifically to the classic psychedelics, the risks seem quite low because these drugs are physiologically nontoxic, meaning that it’s very difficult if not impossible to have a fatal overdose from a drug like LSD or psilocybin. However, they can cause increased blood pressure and heart rate. So, people with heart conditions are typically not thought of as good candidates to receive these types of treatments. These drugs, these classic psychedelics in particular can also interact with serotonergic medicines like SSRIs and MAOIs. So, we’re still learning more about that, but it’s something we’re keeping an eye on. But, you know, pertinent for treating substance use disorders, these drugs are not typically thought of as addictive. The classic psychedelics do not create a withdrawal syndrome. There’s a very low prevalence of past-year hallucinogen use disorder, most of which is related to PCP or phencyclidine, with is a completely different kind of hallucinogen that’s not a psychedelic. But these drugs can produce psychological dependence, and people can and do abuse them. In terms of use of psychedelics, they sometimes come along with something called hallucinogen persisting perception disorder where people have ongoing visual or perceptual problems and distress that lasts months or years after using a psychedelic. This is not something we typically see in our controlled lab studies but more so seen in recreational users, and this is also often thought of as related to flashbacks as they’re called colloquially. We do do a very intensive screening process with people before they receive these types of interventions, and that mainly consists of mental health history where we make sure people with personal or family history of psychotic illness or bipolar mood are not participating because we’re concerned it could cause adverse responses in those individuals. Now, when people do use these substances outside of lab settings, they report very challenging experiences, and we see that sometimes too in the lab setting. However, in the lab setting, we’re able to control the environment and make sure that people remain safe. When people are doing this outside, they can sometimes put themselves or others at risk of physical harm, behave in physically aggressive or violent ways, or need to go seek out medical or psychological treatment. So, it’s something worth keeping in mind that these are not completely innocuous.

And I think most importantly, as media members, you know, there’s been a lot of sensationalism around these substances over the last couple of decades, but it’s important that people know these are not a magic bullet. They’re not going to fix everyone’s problems. They’re not going to work for everyone. And though there’s been changes in laws in certain areas like Oregon or Colorado, for instance, there still can be criminal penalties for use and for possession including loss of licenses, professional licensure, loss of employment, and of course, incarceration. When people are buying these substances on the black market, it can be very difficult to verify the dose or the substance that you’re getting, and people who are doing underground therapy at this time are untrained often and certainly unregulated, meaning that it’s a little bit of a buyer beware situation. Again, there’s also other types of toxic hallucinogens that are out there including these N-bomb drugs, and if you’re buying so on the black market, you may be getting something like that. It’s hard to say.

So, where we’re at is, you know, phase 2 and phase 3 studies are now underway with MDMA and psilocybin. So, there’s a potential FDA approval coming in the next years, but this wont be a take two and call me in the morning situation, and this will not be like Canada’s dispensaries where you pick up the substance and take it home to use it at your own facility. This will be much more like a surgery and general anesthesia-type model, where it will be administered in controlled settings only by especially trained professionals with substantial preparation and followup.

One last note that I want to leave before I wrap up here is, you know, the diversity in the current clinical trial samples have been very low, and so we’ve seen over 80% Caucasian/non-Hispanic participants. So, we really want to try to widen the net in terms of our recruitment so that we can also make sure that these drugs are safe and generalizable to other populations. And ultimately, we want to make sure there’s treatment access so that people who need these treatments, if they’re effective, are able to access them and not just people who are well off being able to access them. So, that’s something that we’ll have to think about more as we move closer to implementation. So, just want to thank everyone for your attention. I’m going to leave my e-mail up there momentarily, and I’m going to go ahead and hand it off to my colleague, Dr. Davis. Thank you.

[00:28:24]

RICK WEISS: And Dr. Garcia-Romeu, thank you for that. A lot of great data there. A lot of important context. I want to remind reporters that these slides will all be up on our website after the briefing today, so you’ll be able to look at those more closely and pull those data. Also, to remind you that you can be putting questions in the Q and A icon below, and over to you, Dr. Davis.

[00:28:46]

ALAN DAVIS: Thank you so much. Lots of great information in these presentations so far. I just wanted to highlight a little bit of the work that we’re doing at Ohio State at our center here. We’re involved in leading trails on psilocybin for veterans with PTSD. We’re also going to conduct the first comparison of psilocybin and another classic psychedelic 5-MeO-DMT in lung cancer patients, and we’re working on trial in a variety of marginalized communities as well as hoping to lead one of the first trials in MDMA therapy among adolescents with PTSD. But the work that I wanted to really highlight today was something that was done while I was at Johns Hopkins from 2017 to 2019, where I was part of a team that led the first randomized clinical trial of depression treatment using psilocybin therapy. This was a waitlist controlled trial, which means that there was a group that was randomized to receive treatment right away, and there was another group that was randomized to have to wait eight weeks before they received treatment. And we used that as a controlled or comparison condition. We also measured their depression at 3, 6, and 12 months long-term followup appointments as well. This was published a few years ago in JAMA Psychiatry, so you can find this online. And this is all open access and usable for the public.

What you see here is a trial schematic of that waitlist condition. So, up on the top line here where it says immediate treatment, what you’ll see here is a depiction of what Al just talked about a little bit in terms of how this usually works for trial participants. In this study, they received two preparation meetings totaling eight hours of therapy prior to receiving two doses of psilocybin. In the first psilocybin session, they received 20 milligrams dosed by body weight, and in the second session, they received 30 milligrams dosed by body weight. And then we conducted depression assessments and what we call integration therapy after that at one week, one month, and then all the way through the 12-month followup. Everything was exactly the same in the delayed treatment condition. The only thing that was different was that they had to wait eight weeks, and then they started the same exact intervention. And the reason why we had them wait that eight weeks was to see whether or not their depression changed on its own, and if it did or didn’t how that compared to the changes that might be experienced in those without received the treatment.

In terms of safety, which was one of our primary things that we were assessing in this study, there were no serious adverse events reported during this trial. However, nonserious adverse events often included headache, which typically showed up for people in the afternoon or evening of their psilocybin session. All of those were typically considered no more than mild or moderate headaches and easily treated with over-the-counter analgesics. However, there was also a variety of challenging emotional experiences that were typically mild or moderate and typically transient—anxiety, fear, or sadness—that might come up during the psilocybin session or in the period of time after the session. There was also transient increases in blood pressure, but for the challenging emotional or physiological experiences, there was no medical treatment required or obtained or sought during this study.

What you see here is our primary finding, which is that depression scores, they decrease after psilocybin treatment, but they do not change in the participants in the comparison group while they were waiting for treatment. In the figure, the orange squares is the group that received treatment right away, and the gray circles are the folks that were waiting eight weeks for treatment. So, their depression, if anything, slightly increased during that wait period, which as you can imagine, you know, having to wait eight weeks for treatment, sometimes things get a little worse during that time. But when we looked at everyone together after everyone got the treatment, what we see is that after everyone has psilocybin therapy, depression scores decreased substantially at one week and also four weeks after the treatment is over. And these effect sizes of this treatment are considered very large. In terms of response and remission, which are two terms that we use to understand how meaningful were these decreases in depression, we looked at how many people could be considered as having a clinically significant response—which is at least a 50% decrease in their depression scores. And what we find here is that almost three-quarters had a clinical response to this treatment. Remission, we also measured, and that’s folks who basically at the end of the treatment were no longer above a threshold to be considered as having clinically meaningful or clinically significant depression symptoms—basically undiagnosable. And we found that approximately one-half of the participants were in complete remission from depression at one week and four weeks after the treatment was completed.

We’ve also since then published our long-term findings. This was published recently and is also available open access, and what we found was that up to one year after the treatment was completed, 75% of the people in the study were still considered as having a clinical response. So, at least a 50% drop in their symptoms, and still, approximately one-half were in complete remission from their depression up to a year later. There were also no serious adverse events reported during that long-term followup and no psilocybin use outside of the trial. I also particularly like this figure, which shows all of the individual trajectories. So, each line represents a different participant in the study, and I like to highlight this figure because as you can see, it’s not a uniform trajectory for people. Some people, their depression got better initially, but then got worse after long-term followup timeframe, and for some people, it went down and stayed down. But you can see all the different varieties of trajectories that people have had after this treatment was completed.

So, in terms of some conclusions with future directions, they’ve already mentioned from the other presenters about the current status of phase 3, especially for psilocybin for depression. But what we do know from this trial, as well as several other trials that have since been published from other teams at Imperial College in London and some other companies that are pursuing indications in this space, is that psilocybin therapies appears safe and efficacious for people with depression. Of course, we still need to wait for those phase 3 studies to be completely completed and then see what the FDA decides in the coming years. However, as Al mentioned, there’s been a lack of inclusion for diverse study participants, not only based on race and ethnicity but also sexual orientation and other marginalized identities, and so a lot needs to be done to address those barriers. If approved by the FDA, it’s also going to take a lot of time and effort to make this treatment available to the public. So, because of all of the particular infrastructure needs that will have to take place for the study, including things like training the workforce of potential providers and making sure that sites are able to provide this type of treatment, it’s going to take some time to get that done, and a lot of work that’ll need to happen in these spaces. And that’s all I have. Thank you.

[00:36:11]

RICK WEISS: Fantastic. Thank you, Dr. Davis. Thank you, all three, for a really strong set of data and information to get us started here. I often start these briefings with a first question from me, which asks you all to talk about things that you’ve seen in news stories on this topic that you thought were good or weaknesses in how reporting is going in this beat. But, you know, we’ve gone a little long on presentations, and I want to leave enough time for questions from reporters, so I’m going to skip that for now. Although if along the way you have thoughts about ways that reporters might improve or keep doing well in various ways, feel free to work that into your answers. Why don’t I just jump into a question here from Katrina Scales, who is a producer with Graham Media Group. Can a panelist explain how psychedelics, psilocybin, LSD, were administered to their trial participants. There’s a few different ways of ingesting these things. One of you want to pick that up?

[00:37:09]

JENNIFER MITCHELL: I can speak only to MDMA and psilocybin, and then I’m sure others will join in. But both were administered orally on site for us, and MDMA in particular because it’s already being commercialized, comes in a cute little blister pack that looks a lot like an allergy medication. You push it out the back, and then you take it with a glass of water.

[00:37:29]

ALAN DAVIS: Yeah. There are other administration methods as well. We’re actually pursuing an intramuscular injection for some of the psychedelic administration that we do here at Ohio State, and of course some psychedelics can also be inhaled, but largely they’re primarily orally ingested.

[00:37:43]

RICK WEISS: So, that means just eating mushrooms raw.

[00:37:47]

ALAN DAVIS: Yeah. Although I should highlight: we’re using all synthetic substances. So, we don’t use any plant matter for the trials. They’re all done using pharmacy controlled and, yeah, synthetic drugs.

[00:38:01]

RICK WEISS: Okay. That’s a great clarification. Thank you. Here’s a question from Tiney Ricciardi from the Denver Post. Many of these studies include a pretty small sample size. Why is that? And are larger-scale studies upcoming in the future? As journalists, further, how should how should we consider the size of these studies when weighing the potential benefits of psychedelics? Are small studies as promising as we’re meant to believe?

[00:38:28]

ALAN DAVIS: Well, I’ll just say one thing really quickly, but I’m sure everyone has lots to say about this topic, but from my perspective, the reason the studies have been so small is because there has been absolutely, you know, almost no governmental support for the science for the better part of the last three decades. And so because of that, we have had to do these studies on a razor-thin budget, often pulling together volunteer hours from investigators and really trying to pull in private donors and the public to help fund some of this work. Our depression trial at Hopkins was completely funded by a crowd-sourced funding campaign from people out there in the real world. So, now that’s changing somewhat. More recently there’s been some buy-in from the government to start funding some of this at scale, but those studies haven’t yet been published. So, we’ll see the larger samples as soon as we see the dollars come in to actually support this work.

[00:39:18]

RICK WEISS: Al, do you want to add anything to that, or Jenny?

[00:39:22]

JENNIFER MITCHELL: Go ahead, Al.

[00:39:23]

ALBERT GARCIA-ROMEU: I was just going say, you know, to echo what Dr. Davis said, it’s hard to do these studies because of the regulatory burdens. So, that takes a long time to get all the approvals in place. It’s very expensive, and so that’s why you’ve seen such little work up until recently because we are having a hard time coming up with the funding to do the studies at scale. Finally, once we’ve done—we’ve seen a few of these studies that are starting to get up into the hundreds, you know, including the largest study of psilocybin with 233 people recently published.

[00:39:58]

ALBERT GARCIA-ROMEU: And so, what’s nice is that many of these studies have been consistent from the smaller studies to the larger studies, meaning when we start with smaller depression studies and they’re good, we’ve seen followup studies with depression that have been also good. And same with the substance use disorders. But yeah, we don’t want to look at, you know, a study of 10 or 15 or 20 people and say, oh, yeah, this is approvable treatment, and this definitely works, because there’s so many moving parts and so those often need to be replicated in larger samples, which is what we’re working on there.

[00:40:30]

RICK WEISS: Hmm. Jen?

[00:40:30]

JENNIFER MITCHELL: I’ll add that there are a couple hundred people that have participated in the phase 3 trial for MDMA for PTSD. So, you can look to see larger trials in phase 3 and also that it’s, again, those are FDA-guided trials, so the FDA decides what the N should be, and that gives you some, you know, hope that perhaps the trial is well powered to make the claims that it’s making.

[00:40:54]

RICK WEISS: Mm-hmm. Yeah. For reporters not used to reporting on medical issues, the N that Jenny refers to is the number of participants in that trial. So, interesting that the FDA is weighing in on what those numbers should be in those trials, so hopefully when the results come in, they will say that was a big enough trial, and you don’t need to do another one. Okay. Here’s a question from Thomas Lyden, who is an investigative reporter at KMSP Fox 9 in Minneapolis. This is interesting. The Minneapolis mayor recently passed an executive order attempting to decriminalize psychedelics in an effort to advance therapy, and yet, there is no infrastructure or licensing system in Minnesota currently set up for psychedelic therapy. My question, are efforts like this sending a false message at the availability and promise of psychedelic therapy or doing more harm by potentially confusing the notion of simply tripping for fun with an actual therapeutic approach? Are public officials posturing the psychedelic therapy because they believe it’s a good demographic issue. So there’s a question that’s everything from medicine to politics, and I can ask each of you to step into it, if you like.

[00:42:09]

ALAN DAVIS: Just yes. That’s my answer, yes. It’s all of us.

[00:42:13]

RICK WEISS: Yeah.

[00:42:13]

ALAN DAVIS: I mean it’s tricky, because you—on the one hand these substances, I believe there’s enough scientific evidence to suggest that they do not need to be criminalized, that they should not be considered schedule 1 drugs, and so decriminalization is important because they shouldn’t be considered problematic in the way that we’ve been told that they should, and that’s what the science tells us. And at the same time, if we don’t have the infrastructure and the support ready yet to support people’s access then that’s also problematic. So, I do think that people are pandering to constituents in some ways, but also, you know even if we try to take it with, you know, the best intentions, it’s likely that they are also trying to rectify in their local municipalities this issue of like, yeah, it doesn’t make sense that we’re criminalizing and spending taxpayer dollars to prosecute these types of offenses either. So, I feel like it’s both of those.

[00:43:03]

RICK WEISS: Hmm. Anyone else want to weigh in on that?

[00:43:07]

JENNIFER MITCHELL: Sure. This is a hot topic. I’m personally a firm believer in regulated access, so I do think that there should be access to those that are in need, but I do also believe that this decriminalization that’s sort of, you know, spreading like wildfire across the country is putting the cart before the horse, and I’m concerned that it could derail facilitated access because there will be adverse events. There will be significant adverse events. We’re seeing some already in California where you can get adorable looking psilocybin laced chocolate bars that, you know, look like candy. So, I am concerned about the sort of the safety aspects of decriminalizing without that infrastructure.

[00:43:43]

ALAN DAVIS: And if I could add something really quickly that I think addresses your earlier question, Rick, that we didn’t have time for, which is that one thing I think the media could do better with reporting on this topic is understanding that the headline needs to always say the drug-assisted psychotherapy, especially if you’re talking about the clinical trials that have been done, and it’s not the drug in and of itself. Because part of what I think that politicians miss when they do these recriminalization efforts is they assume, oh, well, psilocybin or MDMA has been found to be safe, but no, psilocybin and MDMA assisted psychotherapy with two highly trained doctoral level often professionals who know what they’re doing in a very safe setting, that has been found to be safe, not giving someone a chocolate bar and sending them on their way and hoping for the best.

[00:44:26]

RICK WEISS: That’s a super great point. Thanks for making that. I think all of your emphases on set and setting is actually really interesting and a really interesting angle to explore journalistically and scientifically. It’s hard to think that any other component of the modern medical armamentarium where it matters so much how you take it, when you take it, with whom you take it. So, it is a really new and difficult model, it seems to me. Here’s a question from Paul Vogelzang, a podcast producer based in Virginia. Is there any research or indications of use from older-age adults?

[00:45:06]

ALBERT GARCIA-ROMEU: I’ll just—oh, go ahead, Dr. Mitchell.

[00:45:09]

JENNIFER MITCHELL: I’ll just say really quickly the phase 3 trial didn’t have an upper age limit or cutoff, and so, we actually used—it had a really large age span in that study, and we didn’t see any detrimental effects as people got older.

[00:45:20]

RICK WEISS: Hmm.

[00:45:22]

ALBERT GARCIA-ROMEU: Yeah. And we’re starting to look at psilocybin in a number of different neurodegenerative conditions—one of them being early stage Alzheimer’s disease—and mild cognitive impairment, but this is, you know, it’s still very early stage work. You know, I know that folks at UCSF are working also in Parkinsonism and, you know, so there is a growing interest in using this in older adults, but it’s not something that’s been well established yet, so.

[00:45:51]

RICK WEISS: And there was mention earlier of end-of-life anxiety, I think. Can one of you say a little bit more about that?

[00:46:01]

ALBERT GARCIA-ROMEU: There’s been a number of studies, and this actually goes back to the 1960s using psychedelics in palliative care settings, basically. So situations where people are struggling with a very serious illness, such as cancer, and you know, those data are pretty consistent as well across a number of different studies showing significant quality of life improvements, reductions in depression and anxiety after one or a few high doses of psilocybin, LSD, and DPT—dipropyltryptamine—which are all similar classic psychedelics. And MDMA, as a matter of fact. And so, you know, that’s something that could happen when you’re younger or older, you know, certainly it has skewed some of those a little bit older, but it’s a very promising and important area for the research.

[00:46:52]

RICK WEISS: Hmm. Question from Rossana Longo-Better from KGNU Radio in Boulder, Colorado. Indigenous communities have been expressing concerns about getting their ancient medicines taken away due to penalization or commercialization. What are your thoughts on this conflict?

[00:47:15]

JENNIFER MITCHELL: I think that within—I’m sorry, Dr. Davis, did you—?

[00:47:18]

ALAN DAVIS: No, go ahead, go ahead.

[00:47:20]

JENNIFER MITCHELL: That’s something that we’ve discussed locally and on a state level an awful lot over the past 12 to 18 months, and certainly it is a great concern for drugs like peyote that are already quite difficult to come by and have perhaps been overharvested in recent years by psychedelic enthusiasts. But at least at a state level, we’re not talking about decriminalizing to include the use of any sacred medicine at present. And the drugs that we’re using for clinical studies are typically, as Dr. Davis already said, made in a laboratory, so it’s not like we are overharvesting a natural plant medicine that would then take it out of the hands of indigenous groups.

[00:48:00]

RICK WEISS: Mm-hmm.

[00:48:01]

ALAN DAVIS: Yeah, I was going to say the same thing and just maybe add that one of the challenges though is that as people through media reports hear about the beneficial effects of psychedelics, often they’re reading about stories that are related to synthetic substances. But what they have access to out in the real world are often the natural products. And so they will do and try to seek and obtain, you know, peyote or 5-MeO-DMT, or psilocybin, that are plant based or from animals in the case of some substances, and so because of that, I think there is, one thing that would be helpful to do I think better in the reporting is to highlight, you know, this issue of the challenging ecological impact that this might have in addition to the challenging impact it might have for communities that do use these as sacred medicines in different parts of the world.

[00:48:52]

RICK WEISS: Yeah, I think that’s an important reporting tip that I, at least, was unaware of that a lot of these experiments are not involving the natural products that people are imagining. In fact, why don’t we just take a minute on that topic as long as we’re talking about reporting skills, and I wonder if Dr. Mitchell or Dr. Garcia-Romeu want to weigh in at all on things that you see in the reporting on these topics generally that are either a thumbs up or maybe thumbs across and need more attention.

[00:49:23]

ALBERT GARCIA-ROMEU: Well, I’ll just say, just briefly too, there’s no shortage of psilocybin mushrooms. They’re very easy to grow, and they grow all over the world. MDMA is not a nationally occurring substance, and LSD neither. DMT is found in ayahuasca. That’s something that, you know—from banisteriopsis caapi—something that can be overharvested. Peyote, you know, from the cactus, that can be overharvested. So, there’s certain psychedelics that this is a real concern for and others not as much. You know, just given the nuance there. But I think that’s leading into the question, which is there tends to be a lot of oversimplification, which I understand sometimes is necessary, you know, in a short headline or something, but I think the nuance needs to be brought into the conversation. The caveats need to be there. As Dr. Davis noted, you know, we’re always just talking about the drug themselves that are having these, you know, these impacts clinically, but it’s a drug with supportive therapy often. And, you know, when you see a—and this is something I often will show a Rolling Stone article, saying well, can psychedelics save the world? You know, when people see that, I think they’re getting the wrong message, and they are, you know, coming away with this idea that, oh, this is going to fix their problems. And it’s much more complex and involved than that. So, that’s just my main point to take away here.

[00:50:46]

RICK WEISS: Dr. Mitchell?

[00:50:47]

JENNIFER MITCHELL: Yes, thank you. I’ll add to that and echo something that Dr. Davis said earlier too, which is that obviously the set and setting are of absolutely essential importance, and if they weren’t, then everyone—as we tease—everyone would come back from Burning Man cured of all of their woes, and that’s not what happens, because we know that it has to be administered in a very particular and well-structured environment. And so, it would just be nice to make sure that everyone does get that information sort of clearly presented through media so that they don’t go off and do something that could be dangerous or difficult.

[00:51:22]

RICK WEISS: It’s as mouthful as a former print reporter to have to have a headline that says something about, you know, a therapist-assisted psychotherapy with psilocybin, but I hear the message, and I think reporters are hearing the message too that more needs to be done, if not in the headline then in the lede and make it clear what we’re really talking about here. The question here from Rachel Mipro from the Kansas Reflector. Given the uphill battle to legalize even widely accepted substances like marijuana in red states like Kansas, are researchers optimistic that psychedelics will make inroads over time as a treatment method? How are you weighing the medical progress and the political reality.

[00:52:03]

ALBERT GARCIA-ROMEU: I think the big difference is that this is actually largely been pursued actually through the regulatory pathway, meaning that cannabis was really never pursued as a botanical product through the regulatory pathway to have FDA approval for any condition. So, because of that, they had to pursue these state-level changes to legislation. With psychedelics, because they have gone through the official regulatory pathway through the FDA, or are currently hopefully getting through that pathway, that means that once it—once they do have approval from the FDA, that will essentially nationalize the potential accessibility of psychedelic therapy, just like any other medication that might be approved by the FDA. One of the nuances that’s a little bit different with this is that because it’s a schedule 1 drug, there will also have to be changes that occur with that medication in other federal governmental agencies like the DEA and also questions that will remain about insurance coverage and other things that might be a little bit different compared to other drugs that just, you know, come into the market. But this will happen at a national level, not a state by state level.

[00:53:11]

JENNIFER MITCHELL: I’ll also add, I worked for the VA, and in wearing my VA hat, veteran trauma, suicidality, and depression are huge bipartisan issues, and I think that that changes the playing field for the psychedelic drugs as well.

[00:53:25]

RICK WEISS: That’s very interesting, different pathways and implications there. I have a followup question here from Tiney Ricciardi at the Denver Post. Both Oregon and Colorado are rolling out legal psilocybin therapy, but both are using or considering using exclusively plant matter. What are the differences actually between the synthetic versus plant matter psilocybin, and is that being studied?

[00:53:54]

ALBERT GARCIA-ROMEU: It hasn’t really been systematically studied. Animal research suggests that there’s really not much important difference there between at least with psilocybin—the pure psilocybin that’s synthetically produced and the fungal material. But the first study is now underway at UCSF looking at comparing psilocybin from mushrooms with synthetic psilocybin, and we’re about to start a study here as well with the actual mushroom psilocybin, and we’ll see if that seems to work as well. But my guess would be that yes, it should work equally as well, because we’re talking about the alkaloid psilocybin that’s found in the mushrooms, and that’s what we’re using in our synthetic formulations as well. There may be other stuff in there, but it doesn’t seem to be psychoactive or particularly important from the therapeutic standpoint, at least as far as we know.

[00:54:52]

RICK WEISS: It seems like it would be harder to get a precise dosage when you’re working with natural material. Do you have—to in the case of using of using a natural mushroom—do some kind of analysis to see what the concentration is of the active ingredient?

[00:55:06]

ALBERT GARCIA-ROMEU: Yeah, there is a sort of plus/minus and x number of percent of psilocybin in those homogenized batches of the ground-up mushroom material, which has been deemed acceptable by the FDA for research purposes.

[00:55:21]

RICK WEISS: Great. This has been a fascinating session. We’re just about at the top of the hour, and I like to end these briefings with an opportunity for each of our experts here to share a take-home point, something they really want to hammer home or make sure that reporters leave with. Just before I do that, I want to remind reporters on the line that as you do log off today you will be facing a brief three question survey. None of us love taking surveys, but some of us love getting answers to those to those surveys to help us make sure that we’re doing these briefings in ways that really help you the most. So, I really appreciate it if you would take the half a minute it will take to answer those few questions before you leave us today. But let’s go around the horn one last time and ask each of our folks with expertise here to just deliver a take-home message they want reporters to walk away with, and I’ll start with you, Jenny.

[00:56:17]

JENNIFER MITCHELL: I’d say that I’m cautiously optimistic that psychedelics could function as therapeutics for a number of different mental health conditions

[00:56:27]

RICK WEISS: All right. And Al.

[00:56:30]

ALBERT GARCIA-ROMEU: Yea, I agree, I think that this is a really exciting time right now to be a scientist working this field and that we seem to be on the cusp of what could be a major sea change in the way that we see mental health treatments. And so I think that’s very—something to be enthusiastic about, but also to be aware of the caveats that we talked about as well,

[00:56:51]

RICK WEISS: Great. And Alan.

[00:56:53]

ALAN DAVIS: I actually just want to highlight something that Al had on his slides, which is this is not a magic bullet. This is not going to solve systemic issues that our country is facing with regards to why mental health problems exist to begin with. Things like oppression and other systematic injustices that are occurring based on people’s race and ethnicity and gender and sexual orientation. And so as you’re covering these topics, just remember that like this is occurring in a much broader system of challenges that we also need to be addressing.

[00:57:20]

RICK WEISS: So important. Thank you for bringing that up. Thanks to all three of you for how much you brought to this session today. I’ve learned so much. I know reporters are leaving here with a trove of information so they can do more of these stories and do them better, which is what we’re all about. For those of you who are attending, reporters, please check out SciLine.org to see what else we are offering and how we can help you in your reporting tasks. Follow us on Twitter/X— whatever you want to call it—@RealSciLine and we look forward to seeing you at our next SciLine media briefing. So long.