 I'd like to start by thanking our hosts for creating this wonderful opportunity to come together and learn. And I'd especially like to thank all of the volunteers. I've been told several times how important volunteers who care about this work as much as all the speakers do, I'm sure, to make this afternoon happen. So I'm going to go very quickly through the first part of this presentation and slow down in the second half a bit. So the investigators have nothing to disclose in terms of conflicts of interest regarding this presentation. My event organizers posed a question to prompt exploration on this theme. How can psychedelics be employed for therapeutic purposes? And today I'm going to offer you one of infinitely many responses to that prompt. We're going to explore the use of MDMA-assisted therapy to support autistic adults who have social anxiety. So what's important to know about this population in this study, we are not treating autism. We are treating social anxiety. This is a population that is exceptionally vulnerable to developing social anxiety. But conventional treatments have not been shown to be particularly effective, including pharmacotherapy and psychodynamic talk therapy. Other speakers today have addressed potential mechanisms of action. So I won't belabor this point, but we do have reason to question why might this be a good intervention for individuals on the autism spectrum. This talk represents, finally, a move away from the emphasis on the qualitative research regarding this population when I got to play around with analogies from the Wizard of Oz quite a bit. If you've seen any of my prior talks, we've had a lot of Wizard of Oz imagery, but today I'm just going to leave that there. We've published a paper on the rationale and method, and the full protocol is also online so you can get information about all of the particular details about this study that's available to you. What's important to know today, this is a randomized double-blinded placebo-controlled pilot study. We're emphasizing safety and feasibility. I won't be able to make any bold claims today about efficacy. We have a very small N of 12, but this is also a dose-finding study asking the question if doses that are appropriate for typically developing individuals, if they're also effective or optimal for adults on the spectrum. Because autistic individuals frequently present with sensory hypersensitivities, we didn't know if MDMA might be overstimulating, and more on what we found so far later. MDMA is provided twice in day-long sessions, about a month apart. I'll go into more detail about the method later. Our primary outcome measure is the Lebowitt social anxiety scale. The investigators are still blinded. It's a clinician-administered assessment of social anxiety, and we have a blinded independent radar. We don't discuss the sessions with him, and he doesn't share the scores on the LSAS with us. So I will not be able to share data today about the LSAS. However, we will have some tables and graphs that show some of the preliminary findings from some of the secondary measures. There's also a biomarker component to the study. We take plasma samples from all of our participants, and they will be analyzed at Stanford, looking at oxytocin, vasopressin, and cortisol. So I questioned my rationale for including this slide. I think I've included it just to make the point that science is hard, and there's a lot that goes into it. But specifically, paying attention to this top line that shows the schedule of events. We have a screening period, three preparatory sessions that include psychotherapy, a weekend session where we have a full day on a Saturday, and then the participants come back the next morning for their first integrative visit. Another session about a month later, again, we repeat the integration. There's a six-month follow-up period where we collect instruments monthly, online, and then participants come back in for a six-month visit. For this study, we unblinded six months. Individuals who received placebo are invited back for two open-label MDMA sessions where we know the dose, they know the dose, so no one goes away with just placebo. And it's just shorter. So a note about autism. This is important to understand. One we're accustomed to thinking of autism as a spectrum where maybe over here you're not autistic at all, and over here you're very autistic, and I think the popular conception has been somewhere in between here there's something that exists called just a little bit autistic. I'd encourage you to move away from that thinking and think of autism more as a spectrum like this where the different bands represent different aspects of mind and cognition, and the T stands for traits. Every individual on the spectrum presents with his or her own unique expression of autism, a combination of genetics and environmental factors. So for our study, we may have someone in role who excels at language. All of our participants are speaking, but they may be very challenged with social inference or sensory integration, and their autism may not be readily apparent to others, which can increase social anxiety because they're expected to know and adhere to the social norms. So just a word about our population. One we work with is age 21 or over, and no prior experience with MDMA. Little bit more on the additional inclusion and exclusion criteria, I'll point out that all of our participants agree not to use MDMA or ecstasy during the study. So we've heard a lot today about studying. I'm not going to go into a lot of detail, but I do want to point out one point here that we have made an extra effort to make this space supportive of autistic adults, and that includes creating a space that doesn't look like it was decorated for children. Frequently adults on the spectrum go for treatment, and it looks like they've walked into a pediatrician's office, so we've avoided that, give you some of the other elements that we've taken into account to help autistic adults feel comfortable. So regarding the preparatory psychotherapy, how is it different for autistic adults? I could speak on this topic for an hour, but a couple key points I want to point out. We go the extra mile to provide visual supports for visual thinkers. We work from a near diversity perspective that advocates for the view that human minds are different, and we don't assume that what works for us is typically developing individuals as best for our study participants. We also use a balance of indirect and directive approaches if we ask the sorts of open-ended questions that are very common in conventional psychodynamic psychotherapy that may go nowhere with someone on the spectrum, sometimes being much more direct is helpful, and if you watch some of the videos of the therapist's presence in the room, especially in the earlier office visits, we might look like a video of how to do therapy completely wrong. For example, I may start by making no contact, eye contact whatsoever, and have kind of a quiet, closed body posture. All in the interest of helping develop that rapport by understanding what will help autistic research participants feel comfortable. The intervention we provide is dialectical behavioral therapy, DBT, Marcia Linhand developed it, and apparently some people like it so much they'll wear a T-shirt with her face on it, we're fond of it. It was developed for other populations, not specific to autism, but it's intended to support individuals who are challenged with interpersonal relationships, emotional regulation, and distress tolerance, three areas that are often challenging for individuals on the spectrum. So I think most people here today are familiar with the classic kind of Grafian model, the model that's been used quite a bit with using eye shades and music to go within, but this is a social anxiety study, so to have someone have that kind of experience and at the end say, so how was that for you? It doesn't quite seem sufficient. So we also include interaction with the investigators, and I'm going to show you a bit about what that looks like. So this is a tool I don't have stake in this company, but I think this is the greatest product. It's a deck of cards, like regular playing cards called mixed emotions, and each one has a really lovely illustration and a feeling word and some synonyms down here. And for individuals who might not excel at verbal communication, sometimes providing something much more visual is helpful. We may say, we're checking in now, pull a few cards that give us an idea of what your experience is like right now. And these are three cards that were actually drawn during a session. I don't want to give the impression that they're always this cheerful and comforting. Sometimes the cards are also used to describe challenging emotions. Another technique that we use, I call them a visual diary. Near the end of the session, we make art supplies available and provide a big piece of paper folded in thirds each way. So it's kind of like a comic strip. And participants are invited to document through collage or even journaling or drawing what they want to retain from their experience, what stands out in their memory. And this later is helpful for state dependent memory. This is an actual image from a session. It was a rainy day and I just feel kind of happy every time I see this image of the smiling clouds, raining rainbows. This individual has been unblinded and I can confirm now this was an MDMA session. And this is what the larger visual diary looks like. There was that initial image and it started out kind of concrete. And then this participant switched to watercolors and drew this kind of crouched bird. And this is how he described it to us. Crouched bird that then started to take flight. And went through some kind of transformation. It went within and then emerged as this Phoenix figure. So the integrative psychotherapy, we have seven days of daily phone calls. There's three of them. And we provide a lot of multi-sensory memory aids to help people revisit the MDMA experience. We provide a CD of the playlist for audio memory. We have the artwork they can take with their visual diary home with them at the end of the study for individuals who have difficulty with proprioception or who stim a lot. Doing those stereotypical self-stimming behaviors. We offer a marble that's used as part of a ritual at the opening and at the closing. We imagine it as a placeholder for the intention set for the study. The support team imagines charging it up like a battery with all our well wishes. And this object kind of takes on a symbolic meaning at the end of the study. And it's a good transitional object because it's very difficult for some of the individuals who've connected for the first time to detach and move away from that. So this is something they can take with them and remember that they have a supportive team behind them. Also art is used, other modalities for expression. Based on Marsha Linehan's model of the reasonable mind and the emotional mind that overlap in that Venn diagram with wise mind in the middle is sort of the ideal we all strive for. I invite our participants to draw their mind map. And this study participant drew this, whoops. To this figure where you can see reasonable mind is very large. Emotional mind is much smaller and wise mind is kind of stuck as a cog in the middle of gears that don't fit together. It's somewhat mechanical and this was a depiction of how this individual depicted their inner mental experiences. But post treatment, clicker's not working. Post treatment what we have is a diagram that's much more organic looking. Rational or reasonable mind is much smaller now in relation to the larger emotional mind and wise mind is much bigger. And it looks like it's connected here by pathways or arteries, a much more integrated depiction of mind. So a brief update, 11 participants have been enrolled, 10 have been treated. We're seeking more females to get a good ratio there, but they're hard to find. One participant was dropped for a non-safety reason after the first treatment session. We've had 288 screening inquiries, not only from across the United States, but also internationally, thanks to maps and their global reach. But participants need to be in the LA study to enroll. We're currently screening the last two participants. We received a generous gift in April that will allow us to treat two more subjects. So the rest of this talk is primarily about preliminary data, our safety data. I can say at this point so far the study drug has been tolerated very well. No serious adverse events. Everyone has been able to escalate from the lower dose to the higher dose in each of the groups, and I'll say a little bit more about suicidal ideation later. Not everyone in this study, only about a little less than half of the participants presented with clinically significant depression. So I don't have very interesting data to share because not everyone is depressed, but of the participants who were at borderline to severe clinical depression at enrollment, we've seen some acute and lasting, very notable anti-depressant effects that may be an area of future inquiry, but not all of our, not even half, presented with clinically significant depression. But we're not seeing depression get worse. That's a safety point there. Brief word about systolic blood pressure, if you notice, oh, keep doing that. In this FAR column here, one individual, one subject for one observation, had systolic blood pressure above the cutoff, but diastolic pressure was well within the normal range, so that wasn't a big safety concern. And no subjects have had, that's supposed to be DVP there in the FAR column. None has had diastolic blood pressure above the cutoff. So I'll say again, no serious adverse events. Serious adverse events being something that may be life-threatening or require an emergency medical intervention. But we have had events reported in the mild intensity range. These are things that don't interrupt daily activity. You can more or less go about your day. In the moderate range, there may be some disruption of your day. And severe, it prevents you from going about your day normally. But these adverse events have all resolved, and none of them were considered serious. Regarding spontaneously reported reactions for the first treatment session, you can see these are, these are through day zero is the treatment session day. And then we have seven days of daily phone calls where we just take note of somebody reports, spontaneously reports a reaction. So you can see people, individuals who were reporting in the moderate intensity range, there were only a few. Never more than two subjects in any one of the categories. All expected reactions that we may anticipate seeing with MDMA. And for day two, we had one subject reporting reaction with severe intensity. That was a headache that kept him in bed most of the day, the day after treatment that resolved. And he hasn't had a problem with headaches going forward. And there's a list of the very few subjects who reported moderate intensity. We also track mild. The largest category is definitely the mild reactions. But for time, I'm not reporting them here today. So the first graph I've been able to show, I'm going to just give you a snapshot of some of the very early findings as long as we have an agreement that what you're seeing is not statistically significant. It's not making any claims about effectiveness. It's a progress snapshot showing us where the trends are headed. And I'll give you a little interpretation here. I'd like to get this. Let me see if I can try this one more time. No. So with state anxiety, this is anxiety. How are you feeling right now in this moment? And the green line, the state is usually used for research. It's not widely used as a clinical instrument. But if you consistently see state anxiety over 39 or 40, that probably indicates that this is clinically significant anxiety and somebody maybe should be recommended for treatment. Our MDMA group, they both group started at about the same level of state anxiety. And let's see. Oh, it's tiny. There we go. And the MDMA group at the end of treatment during follow-up when they weren't coming in for regular office visits had a drop in state anxiety. And it remains to be seen what this drop in the placebo groups about. We'll see when I have all of the data if that changes or if that trend continues. But the MDMA groups stayed most of the time well below the level considered clinically significant. The trade anxiety tells us something a little bit different. For the MDMA group, we saw a drop after the first treatment session and a plateau, another larger drop after the second treatment session, and trade anxiety or how you generally feel, are you kind of an anxious person in general, it stayed much lower. During follow-up, there was a spike in the placebo group and again, I'm not sure what's going on here. So we'll see if we have more interesting data there. So this is the perceived stress scale. How often have you felt a certain way in the prior month? This blue band here is the mean from the norm table for the PSS, generally where most typically individual typically developing individuals regarding stress. And our MDMA group presented, there we go, as much more stress than our placebo group. Don't know why. However, they enjoyed a notable sustained drop that persisted. And after they weren't seeing us for treatment and offices regularly during follow-up, it went down even more and came back up, whereas the placebo group appeared to be more susceptible to stress in the follow-up period. I have two more slides. That's it. OK, the Rosenberg self-esteem scores. This is the kind of stuff I get excited about. You see the ranges here on the left, we have the range from 15 to 25, being what's generally considered the range for normal self-esteem. 15 and lower is low self-esteem. Our MDMA group was lower, below the threshold in the low self-esteem category. The placebo group was doing a little bit better, but not much. And both groups ended up about here at the end of treatment, kind of at the upper ceiling or near the upper ceiling of healthy self-esteem. We really don't want people popping up in here. We don't want to be creating a bunch of egomaniacs. So more evidence that we're not doing any harm. That's one of the reasons we monitor these secondary outcome measures for safety, to look for any hydrogenic effects. Are we providing something that's actually doing the reverse of what we hope it will do? And finally, I'll end on maybe the most interesting slide. The emotion regulation questionnaire looks at two domains about how we control our emotions. So cognitive reappraisal is, when you sound like this, I changed the way I'm thinking to change the way I feel about the situation I'm in. So the story that this is telling is both groups, even over the follow-up period, continued to use cognitive reappraisal with more success over the course of the time they were participating in the study. Emotion suppression sounds like this. I suppress my emotions, or I control my emotions to avoid expressing them. That's how I control my emotions. I keep them in. So what we're seeing here is the MDMA group through the end of treatment and over the six-month follow-up continued to suppress less, to be more open with emotion expression, whereas the placebo group enjoyed a drop after treatment that began to increase after treatment. So it remains to be seen as we collect more data if that difference will become more pronounced over time. But the takeaway is there are implications for potential future research in this area. And I very much look forward to breaking the blind with our primary outcome measure and sharing with you what we've learned about social anxiety for this study. I did it again. And I was supposed to think of something funny to say about this cartoon. I really just liked it because so many people contact us for enrollment. Well, maybe not so many. But from time to time, I have to ask, but wait, are you autistic? Like, no, I'm perfectly happy. I just want MDMA. I think they want to be in the out of control group. So there's some contact information. If you know of anyone who made the study criteria in Los Angeles, we are currently screening to enroll two more participants. And I'd really like to get a couple more females in the study. So thank you very much for this opportunity to share. I have a few questions. OK. So thank you very much. I just want to mention what I forgot. I hope you forgive me for that. That is how this project was initiated. It was done mainly by the collection of preliminary data from naturalistic settings where people have been autistic and taking MDMA and showing a kind of reduction about their social anxiety feelings. And Alicia was doing her dissertation about exploring these peoples and how their experiences with MDMA were. And so it was well-based when they started the research. Just want to mention that. We are open to two questions. Please. I always recommend when starting a new inquiry in psychedelic research to make a healthy investment up front in the qualitative research. Talk to the population you want to work with. Listen very closely to them and analyze those themes. That's one of the ways we struck upon the idea that we should focus on social anxiety. I don't think that would have been as intuitive to us if we hadn't first done the qualitative inductive research. That's where the Wizard of Oz came from. Hello. Hello. Hi. Yeah, you mentioned that you were looking for female participants specifically. And it's been suggested by other people that one of the reasons why females are perhaps underrepresented or hard to find is because the criteria used doesn't really pick up the traits as they're expressed. Is there any way that you can possibly comment on that? I couldn't hear the last part. Well, basically, could you just comment on the fact that it's been suggested that the criteria used to look for autism in females is that they're not really developed or adapted for how they're expressed, you know what I mean? Yeah, it's an underdiagnosed population. And they're frequently misdiagnosed with other diagnoses such as bipolar or borderline personality disorder. But in the course of time, I've been looking at this population. There are more and more groups specifically for women on the spectrum. And the internet technology is providing a means for them to connect and get a little more political power as a group. But that is one of the reasons we're having so much difficulty finding them as they're underdiagnosed. Women or females are often better able to mimic social norms. And they fly under the radar as maybe quirky or shy. And they often, for their restricted special interest, will choose something that's socially more acceptable. So as opposed to, I'm going to draw on a stereotype, memorizing all the train schedules, they may be very into makeup. And line up, I'll then know everything about makeup or something that blends in a bit better. So they often get overlooked. That's one of the reasons I'm making an extra effort to reach out to them. Thank you. I wanted to thank you for your very interesting talk on this fascinating approach. I was wondering, you spoke before about not viewing autism as a spectrum, but more as different bands and differential profiles. I realize it's a very small sample. But are there any indications that particular profiles? Oh, I'm sorry. I realize what happened to you now, John, with the microphone. Is there any indication that particular profiles of these bands respond better to treatment? I realize it's a very small sample, but there's this differential profile within autism. Do you have any trends that you're seeing? I love that you asked that question. And my most sincere response is it's early days yet. So I try to make notes and the progress notes to start maybe developing some grounded theory based on observations. But I think we would need many, many more observations. There are some developmental indicators, one that I'll share because it may be relevant across projects here, is that an individual needs, kind of from an Ericksonian perspective, needs to reach a certain level of development to have a certain degree of individuation and really understand the sense of agency required to set an intention as opposed to passively waiting for a pill to do something. And often with the developmental delay, adolescents can be kind of prolonged with autism. So listening very carefully, although this individual is 35 chronologically, where are they developmentally? And are they matured to a point where they're on board with the idea that they need to be an active agent and to draw on the model that Michael and Annie Mithover have popularized, it predates them, but they've done a great job of raising awareness about the role of the wise inner intelligence or the wise inner healer. And I listened in dialoguing with autistic adults to see if that concept has meaning for them and if they're able to work with it. Cool, thank you. All right. Sorry, but we have to stop right now with questioning. Thank you. Thanks again. I appreciate it. Thank you. Thank you.