A (3:37)

Brilliant, brilliant. And can you speak Spanish?

B (3:39)

Yes, I can, yeah. I became fluent while I, while I lived in Spain. So that was also something I felt very blessed to be able to experience.

A (3:46)

Absolutely. That's awesome. So, okay, so you called it C. Ocd, Am I saying that right?

B (3:52)

Exactly, yeah.

A (3:53)

Okay, cool. Okay. So, yeah, I guess initially, what is psilocybin? Maybe that's probably the best place to start.

B (4:01)

Yeah, that's a good place to start. So psilocybin is a naturally occurring hallucinogenic substance that is found in many, many species of mushroom in the wild. And, you know, it has recreational associations. People will use phrases like, you know, magic mushrooms to describe these, to describe this compound. But psilocybin is the active compound and it's metabolized into something called psilocin. And it has very wide spanning effects on the brain. At high doses, it induces all the stereotypical psychedelic effects, which include marked changes in perception, emotional shifts and trips, as people would call them. But at much lower doses, you can have microdoses that are very, very subtle. People don't have any of these outward effects. You can also have doses that aren't micro but that are still perceptual doses where you just get a gentle emotional change and an increased openness to processing things. And that was the type of dose that we used in the study.

A (4:58)

Okay, okay, excellent. So what, yeah, well, what brought about the study? Who kind of drove it initially or got the ball rolling on it?

B (5:08)

Professor David Nutt heads our research group at Imperial. If anyone's familiar with the psychedelic landscape in the uk, who's amazing, very prominent figure and Our groups always had an interest in different psychiatric conditions. There's now more of a shift towards addiction. But the OCD side of things was inspired by a study conducted by Moreno and colleagues at the University of Arizona in 2006. And interestingly, they used different doses for OCD. It was a very early stage pilot study. All of this research is early stage, but this was particularly small study. Um, but they used three doses. One was very low, one was more moderate and one was higher, you know, roughly in line with the highest doses used today for depression. But they found that all three doses elicited significant improvements in symptoms 24 hours after the dose. So that's obviously, you know, really short follow up period, but that is noticeable, you know, for the OCD community to think that something could possibly move the needle in that short space of time and that could potentially, you know, support therapy and things. Um, so our study was inspired by that pilot study and we opted for a 10 milligram dose that sits in between their lowest and their medium dose because we wanted, you know, something. Yeah, you know, something just more accessible for people who don't necessarily want that element of loss of control, which I think rings true for a lot of people with ocd.

A (6:29)

Yeah, absolutely, yeah. I personally would struggle to do psilocybin purely for that fear of loss of control. So, yeah, it was probably smart positioning it at that level.

B (6:41)

So, yeah, I definitely think so.

A (6:43)

Yeah, yeah, okay. Yeah, I remember that study. Yeah. So it's what, 20 years ago now, right?

B (6:50)

Exactly, yeah, 20 years ago. And things have definitely been slow moving. And I think in some ways OCD can be slightly underserved as a condition. But I think there's loads of potential now going forwards for like, precision psychiatry to kick in and for compounds like psilocybin to support existing therapy. And hopefully we'll see, we'll see more shifts.

A (7:12)

Yeah, so precision psychiatry is that where someone would go see the psychiatrist and it would be. They would go through this whole process of getting the. What do we call it? Not trip, surely, what's the order?

B (7:26)

So, yeah, so, so precision. Precision psychiatry as a movement just describes, you know, the shift towards looking at people on a personal level and better deciding what, yeah. What treatments would be suitable for them. And I think psilocybin could sit well in that kind of frame. But yeah, I mean, if, you know, if psilocybin becomes incorporated into the nhs, for example, into the available treatments in the uk, I personally see it as something that's most likely to support existing therapy. I think therapy is so important for ocd, you know, exposure response, prevention, erp, as you'll know much more about than me being the gold standard and then, you know, others being helpful for people like ACT and ICBT as well. But I personally don't know if any pharmacological tool like psilocybin could fully supplant therapy and replace it. But yeah, I definitely think that, you know, in years to come, hopefully, as we have larger randomised control trials and things, we could see psilocybin being accessible and people would be guided with therapists in a calm context, ideally.

A (8:28)

Yeah, yeah, really, really good point. And I guess for Those people that SSRIs, for example, have not worked for, it might be another good option for them.

B (8:39)

Exactly, yeah.

A (8:41)

Yeah. Okay, cool. So what, what's the, so you mentioned the dosage. What, what did the actual trial look like? So for those listening, if they were taking part, for example, what would have happened? What would they have gone through?

B (8:54)

Yeah, it's definitely nice to touch on the trial design. It's easy to skip this step. So the studies spanned roughly two months, just over two months. So an individual would, you know, be rec or the screening tests and we check for things like, you know, no first degree relative having had any psychotic episode or manic episode. Because whilst, you know, we're not even sure that a low dose would be risky in that context, we want to be incredibly risk averse and careful with it. You know, in general, in clinical research, I think that's definitely the right approach that people were checked for all those kinds of comorbidities and things like that and then they were, you know, deemed suitable. They would start and then have four weeks of supportive therapy, but nothing specific to ocd. And this was led by an amazing therapist called Sarah Reed and she, she and other volunteer therapists. So she'd pair up with another volunteer therapist and the two therapists would then guide the participant through the study. The participant would be given. Yeah, so four weeks of these preparations. Sorry, not four weeks initially. One week of preparation sessions, you know, just preparing them for the dose. They'd then have a placebo dose and this was 1 milligram, which is an active placebo, but it's effectively a microdose and shouldn't elicit any noticeable effects. And then after that was when they had the four weeks of follow up therapy. And we also measured a lot of mechanistic outcomes and I can touch on some of those findings as well. Measured things like neuroplasticity through EEG, cognitive tests. This was all four weeks. And then they'd be given the experimental 10 milligram dose, which was the dose of interest, of course, which is considered low to moderate, sat in between those first two doses that Moreno and colleagues looked at, as I mentioned, and then they would have another four weeks follow up. So the idea is you kind of have two parts of the study, it's fixed order, you have the placebo, then the follow up for that, and then the real dose. And the idea is the participant is treated the same after the placebo as after the experimental dose.

A (10:57)

Okay, wow. And how many people went through it?

B (11:01)

19 participants were recruited for the study, but one individual had to drop out before they received the active dose, you know, due to, due to reasons completely unrelated to the drug in the study. So we had 18 completers.

A (11:14)

Okay, wow. Wow. And what were the sort of demographics of these people? Is it a broad range of ages, genders?

B (11:26)

Yeah, it was very mixed. We really tried to keep it as diverse as possible. We had people age 20 to 60 and we had, I think there was slightly more men than women, but just marginally. And people had very varied, heterogeneous, you know, presentations of ocd, you know, all sorts of different themes, which is, you know, of course, very common because, you know, I guess OCD can latch onto virtually anything under the sun. So some people had, you know, responsibilities, concerns, harm, OCD contamination, OCD taboo, identity related themes or just a real combination. But people didn't have that many comorbidities because a couple of people had some ADHD symptoms. But, you know, we didn't, we didn't recruit two complex cases just to, you know, try and create as good evidence as possible at this stage.

A (12:16)

Yeah, yeah. Correct. Yeah, yeah. Okay. Yeah. So the study, I believe, correct me if I've read this wrong, but showed that the effect was strongest after a week of taking it and then diminished.

B (12:33)

Yeah. So if we look at the 19 participants that were recruited, which is what the clinical paper looks at, we see the signal drops after one week. So, you know, symptoms were significantly improved at the one week point. And then this drops below significance at two and four weeks. But if we look at the Completers, so if we remove that participant from the analysis, which is probably more objective, because that individual didn't drop out due to OCD or drug related side effects or anything. They just had family circumstances occurring. So if we look at the Completers, we see a slightly stronger signal and we see that this effect is maintained at the two week mark as well. So the Y box White box scores, you know, obsessions and compulsions collectively are significantly decreased one week and two weeks after 10 milligrams of psilocybin.

A (13:24)

Okay, okay. Was there. Yeah. Would, you know, like an average of what that decrease was on the Y box?

B (13:32)

Yeah. So I know that in ocd, a strong response or just, you know, significant response is considered an improvement greater than 35% in Ybox scores. And we saw that 39%, or about 40% of the group achieved a strong response at the one week mark. And 10 of the individuals dipped below the moderate to severe groups that they were initially in. So all individuals that were recruited had OCD that was deemed moderate to severe. So a Y box of over 16 and 10 of these dipped into the mild band at the one week mark. So that's just after, you know, one dose without any OCD specific therapy.

A (14:15)

Yeah.

B (14:15)

Then of course, there is that uptick again of symptoms. And I think this really stems from the fact that, you know, psilocybin induces, you know, a period of openness, which we can look at the molecular level, we can see. Well, people believe that there's increased neuroplasticity. My study actually didn't really find that through the assay that I use, and I can speak about that if it's not too complex and irrelevant. But there's probably that molecular mechanism going on where it's easier for neurons to make connections. You can look at that more psychologically and just say the person's more open to treatment. And of course, without something like ERP a couple of days after the treatment or any other form of therapy that targets ocd, we didn't really capitalize on that. So I think we need future studies that incorporate an ocd, you know, specific therapy regimen.

A (15:07)

Yeah, yeah, I agree. I think that would be really interesting to see. Yeah. When the brain's in that period of malleability, how. Or flexibility, how they people would take to erp, and then whether those gains from ERP stick, you know, once.

B (15:22)

Exactly.

A (15:23)

Yeah.

B (15:24)

Yeah. And I really hope future studies can focus on that. Although there is also a case for really looking at the pharmacological signal. That's often what regulatory bodies want to see. You know, they want to see a larger randomized control study looking at how psilocybin alone can, you know, can. Can improve symptoms. But, yeah, I mean, we do have two big studies going on in the US Looking at psilocybin alone, so hopefully that will open up pathways for more specific studies.

A (15:53)

Yeah. And are those psilocybin for OCD in

B (15:56)

the U.S. yeah, I mean, there is, but it's not so, I mean, there are states where psilocybin is decriminalized, where people can go and be treated for, you know, a wide range of conditions. Also just, you know, emotional healing, those kinds of things. I believe in California, I know in Colorado and I think a few other states, but it's not available as a treatment for ocd, you know, medical treatment in the US or in the uk. Yeah, we, I mean, we do think that, that psilocybin will be FDA approved at some point soon in the US for treatment resistant depression. You know, there are some major companies working on that, especially compass pathways. They actually supplied the psilocybin for our study and they've had some positive phase three result results for treatment resistant depression over in the us so it may be that it's, you know, medicalized over there and then the UK lags a bit. And then of course that, you know, that's speaking about depression, not ocd, but I think it being approved for anything will be a move in the right direction.

A (16:53)

Yeah, 100%. Yeah, that's it. Okay. And those two studies you mentioned in the states, are they viewing sort of higher dose psilocybin or similar dose to what you guys did?

B (17:06)

Both are looking at higher dose. Yeah. So ours was 10 milligrams and theirs look at 25 to 30 milligrams. And just for reference, 25 is, you know, the typical high dose that's given in most psychedelic studies. So typically when, you know, when we talk about psilocybin, we give for depression, it's typically 25. So that just really emphasizes how low our dose was in comparison. And I think, again, I think it's really beneficial that we've looked at this lower dose approach and that, you know, that we saw some significance.

A (17:36)

Yeah, of course, of course it is. Yeah, absolutely. I want to make a joke here about Americans always having to go bigger.

B (17:45)

No, it's very true.

A (17:48)

Most of my audience is American, so if they take that joke.

B (17:51)

Well, yeah, the cars, the washing machines and things. It's amazing going over there and seeing it. Huge.

A (17:57)

Yeah, the washing machines. Okay, so I was gonna say there. Yeah. And I guess just for anyone listening, that at least in how I understand it, it's never that psilocybin would be like an antidepressant where you take it obviously daily, but it's not. It would be. Maybe if you had to do multiple doses, it would be massively spaced out. It would not be A like I have to go every week to do.

B (18:27)

Exactly, yeah, exactly. I mean, even if we did adopt a more psycholytic model, you know, if it ended up, we ended up gaining more evidence for maybe like three doses of 10 milligrams, it would definitely be spaced apart by several weeks. If not, if not a couple of months.

A (18:40)

Okay.

B (18:41)

Yeah. It'd be way too overwhelming for individuals to have close together dose dosing days, I think.

A (18:47)

Yeah, true. And on that, is there anything you, else you want to say about what, what's happening in the brain? Because from what I've understood more from psychedelics more generally outside of the, the psychiatry field or field of psychiatry, is that yes, it's opening up the brain, but sometimes, especially in things like ayahuasca, they will talk about being shown things or learning a super quick rate and seeing. I don't know, you know, I mean. Yeah, you see where I'm getting at? Is that.

B (19:22)

Yeah, definitely.

A (19:23)

Any evidence to that or is it kind of.

B (19:26)

Yeah, I mean, this is, it's interesting, this topic, because there are so many hierarchical levels of the brain and you know, of, you know, if we talk about like the effects of any drug on the brain, we can talk about, you know, the molecular level, the, you know, emotional effects. But in terms of psilocybin, I guess just to answer your question about those more phenomenological emotional experiences, meaningful symbolic experiences that people have, people definitely do have them. That's just, that's mainly mediated by the effects of psilocybin on, on, on a specific receptor called the 5ht2a receptor, which is a serotonin receptor. So serotonin, you know, will soak the whole brain and act on different receptors, same with other neurotransmitters. And this specific receptor is very richly expressed in the cortex in areas like the occipital cortex, which is the visual. So that will generate, you know, it binding there will generate the visual effects that people will see at very high doses when they take hallucinogens. And also it binds to receptors in all sorts of areas that mediate emotion and things like symbolic feelings and feelings of awe, that kind of thing. Feelings that people might experience in nature. People can induce, I guess artificially in a psychedelic experience. So people do have very intense experiences that can be sublime, they can be challenging. When we're talking about the lower dose that we used, no one's having what people would consider an ego death or a strong trip or anything like that. People wouldn't have strong visuals. Although people are typically encouraged to wear eye masks and just recline and listen to music. When they take psychedelics therapeutically so that they can work through things internally rather than focusing on their environment or exploring in that way. But yeah, so people definitely had symbolic experiences even at the low dose that we gave, but nothing was particularly psychedelic or particularly strong, relatively speaking. But to speak more about the brain mechanisms, there are many different ways we can frame it. We can talk about the tiny molecular level. On that level, psychedelics are believed to induce or increase levels of something called brain derived neurotrophic factor, or bdnf, which things like intense exercise or any exercise actually. You know, certain antioxidant rich foods like blueberries, you know, coffee, tea. So many different things increase BDNF levels. And BDNF is key to neuroplasticity. So it's one of the mediators that's involved in, you know, neurons, as I mentioned, you know, branching out and creating new connections. And neuroplasticity is pretty much at the crux of anything of learning, of memory, even of forgetting. You know, helpful forgetting occurs when we sleep. You know, we become slightly less sure of tiny, trivial details. The brain's always molding itself to the environment and updating. And in a condition like ocd, this is really relevant because I definitely see it as a condition of learning, which sounds very overarching. But you do come to these more overarching theories the more you study it. And whether we look at the effects of SSRIs on the key OCD circuitry, or we look at something like erp, you know, people learning from exposures, I think healing from OCD or, you know, people's symptoms, you know, dramatically improving can be seen as the brain updating and learning that those specific hypotheses that it once adhered to about fearful things or about triggers, you know, are actually not worth holding onto. So it's definitely a learning process, you know, recovering from a condition like OCD or significantly improving. Same for something like, you know, panic disorder. So, yeah, I see psilocybin as a real potential facilitator of this process. I think it could streamline it, improve it. And that's why I see it as really synergistic with therapy. But, yeah, we can also talk on a more conceptual level. There's something called the rebus model that Robin Carhartt Harris came up with, and he used to be at the Imperial Group that I did my PhD at, and he's now moved to San Francisco. But it's really interesting and it stands for relaxed beliefs under psychedelics. And it's a strange acronym. It's like sum, capital sum, lowercase. But there's a really interesting paper on it, if anyone's interested. And it just describes the brain through a slightly different lens. Not really molecular, not really specific areas. But it's just talking about how under the influence of psychedelics, people's predictive priors. So what the cortex is generating, what it believes to be true about the world, is slightly altered temporarily. And that individual is able to actually get more input from the environment and from experiences, whereas typically their predictions would rule because that's how the brain works. It's very predictive. So that model will focus on how psychedelics afford someone a window in which their brain is slightly destabilized in a positive way and the dynamic landscape is flattened a bit and they can learn new input. Yeah, I don't. I don't know if this is helpful. It's definitely interesting. Just lots of different ways of looking at how psychedelics improve learning and make room for. For someone's beliefs and entrenched fears and things to be updated.

A (24:37)

Yeah, that's really interesting. And. Yeah, yeah. Neuroplasticity in AKA in my very basic way, I explain neuroplasticity to my clients, in my base, my own basic understanding of it, because I think it's a very hopeful message of learning, that the brain wants to learn, adjust and. Yeah, grow. And so just going back to you said about blueberries, coffee, those sort of things increase neuroplasticity. So the ability to learn.

B (25:08)

Yeah, I mean, science says so. You know, there's quite a lot of research on this type of thing, but we don't know how well this, how precisely this map to behavioral change. I think there's, there's often that explanatory gap. The things, you know, models and things aren't perfectly scalable to real world learning and things like that. And I also wouldn't want someone to, you know, to focus too much on those details and to think that it's kind of a silver bullet for ocd. I think that's something I feel responsible for kind of avoiding because I know that sometimes when you communicate the science, it can come across like that, but it's more that, yeah, you know, certain elements of a healthy diet, definitely exercise, you know, all these things improve neuroplasticity and people have it all throughout their lives. It's not just that you can learn things. As a child. We know that the brain changes and updates and I think it's definitely a very hopeful message for a condition like ocd, because another way I look at it is it feels like a really vicious cycle for people. But there are lots of ways to intercept the vicious cycle. And the brain does want to learn. It doesn't want to expend energy on fears and avoidance and things like that. If it's, you know, if it's showing that actually the triggers, whether they be emotional, like very meta triggers in ocd, it can be like thinking about thinking.

A (26:21)

Yeah.

B (26:22)

Once it learns that those triggers can actually be tolerated in the uncertainty around them, it is happy to start to let go of things. And it can be very stubborn. And, you know, some, for some people it's harder than for others, but there's always the capacity to improve.

A (26:36)

Yeah, yeah. Excellent. Yeah. So that the brain wants to be as efficient as possible.

B (26:43)

Exactly. Yeah. We definitely have a lot of evolutionary glitches though, and we see these in mental health conditions where something like panic disorder is a great example adjacent to ocd. Common comorbidity of the brain really working as an oversensitive smoke alarm. And evolution wants the brain to trigger fear more often than potentially more often than fear is actually warranted, rather than be under. Reactive. And while some people are underreactive, it's more common for people to be overreactive in terms of anxiety because it doesn't really cost people that much to be a bit anxious. So evolution is okay with keeping that in. And then people who deal with those symptoms have to find ways to show the brain through exposure and things that those triggers aren't actually an issue. And it's probably a little bit more complex than ocd. There's definitely a bit more rigidity involved, but yeah, I definitely see it in that way.

A (27:40)

Yeah. Yeah, that's really interesting. Okay, cool. So with the. Going back to the trial. So was it. I know there were those initial sessions, sort of counseling style sessions. Was a therapist involved during the actual administration? So, for example, a colleague of mine has been a therapist on a trial not for ocd, but for psilocybin. For. I'm not sure what it was.

B (28:09)

Oh, I wonder whether it was one. It was one conducted at Imperial. Do you know whether it was?

A (28:13)

Don't think it was Imperial. I think it was for a private clinic that obviously is supported by a university. It was all trial. It wasn't like people pay and do it. It was a. It was a trial, but it was, I think, a private institution doing it.

B (28:26)

Yeah. Probably just a site that was involved in a bigger study. Maybe.

A (28:29)

Maybe. Yeah. Yeah. And she got employed as a. I don't know if she got paid or not, but as. As a trial therapist. And she would have to sit there while they were going through the experience, which would be like three hours long, I think, while the. The patient client was laying there and she didn't have to do anything unless the client needed her. But was there anything like that or was there like. What do they call it? Is it integrating sessions after. What's the phrase?

B (28:56)

Integration sessions? Yeah. Yes, it's. So silo CD involved both of those elements. Participants had those two therapists allocated to them at the start of the study, and the same therapists gave them all the preparation sessions, all the integrations after the placebo and after the active dose. And importantly, they sat in during the placebo and the active dose sessions themselves as well. So each participant would be reclining in a very nicely lit room, quite scandi. Aesthetic, like mushroom lights and nature, scenes of nature and plants and things around. And yeah, each therapist would be on either side of their bed, just, you know, sitting there, not really interacting too much with the participant unless the participant directed it and wants to discuss something. And they're of course there for, you know, safety reasons as well. If the participant becomes anxious or anything like that, they're able to, you know, engage in breathing exercises and things, but they weren't there to deliver any kind of, you know, again, OCD specific therapy or anything during the session or outside of it.

A (29:55)

Yeah, yeah, because I, you know, I think. What. Because I. Yeah, I used to always be wary of talking about psychedelics and not because I'm against them, just because people can get the information and think, oh, I just need to take psilocybin or magic mushrooms and. And everything's going to be okay. But, you know, part of the trial is it's all this having the therapist throughout. It's the, the environment in which it's done, it's the, the dosage, it's the. Right.

B (30:23)

Exactly.

A (30:24)

It's come from a clean source. It's, you know, it's the sessions beforehand, the sessions after and without that can be quite. I don't say traumatizing, but probably for some people.

B (30:36)

Yeah.

A (30:37)

I know someone in my own life, I asked them a long time ago, I won't say any more than that, but I asked them, have you ever done. I would have called it magic mushrooms at the time. And what did you think? And their response was just, yes and never again. Because obviously they didn't have all these other factors. They didn't have OCD or mental health. They were just doing it for silly reasons. But the point is it just shows you that actually can be scary if it's not done in the right set and setting.

B (31:07)

Yeah, exactly. It's definitely really important to highlight that people can have very challenging experiences, even traumatic experiences if the setting isn't right. It's definitely these compounds. Everything's a double edged sword, especially when it comes to, you know, psychology and how people feel. And you know, these, these compounds do, you know, increase learning temporarily and all the, you know, through the mechanisms that I touched on. And you know, if someone has, you know, takes maybe a high dose of psychedelics and is out somewhere and you know, in the city and it's a very unpredictable environment, they could have a really unpleasant experience that could equate to PTSD and they could need therapy for that. So there's, there's always that risk. And I wouldn't, you know, wouldn't want to scare people by saying that. No, but it's why it's, it' so important that it's done ethically and you know, in a, in a highly regulated way. And our, our study, you know, safety was of the utmost concern. And speaking of safety, we didn't have any serious adverse events. So in terms of side effects, people typically had very minor ones. And you know, obviously everything gets reported to the pharma company. You have to detail absolutely everything. But most minor ones are probably unrelated because, you know, if someone has a sore throat and is sneezing on the day with a very mild cold and they decide to go ahead, that's still recorded and logged. So there were some instances of things like, you know, minor headaches, some, you know, minor, some dizziness that passed and things like that. And I think a lot of that could be attributed to the fact that some participants skipped breakfast on the day or had a very, very light breakfast and just, you know, didn't really want to eat before. And you know, the session lasted about five or six hours. People would have lunch afterwards, but people, some people did have an uptick. A couple of people had an uptick in symptoms. I think it's important to mention that, sorry, not specific symptoms as measured by the ybox, their symptoms improved, but some of them had an uptick of some anxiety related symptoms that were adjacent to their ocd. There were a couple of reports of people having some very vivid dreams, a couple of nightmares after the session and things like that. So overall it seems like it's very safe, especially at this dose and it's all about risk reward ratio in terms of this condition and it being really tenacious is that nothing is entirely risk free, although it's overall safe.

A (33:25)

Yeah, yeah. Everything has a side effect if we did give it to enough people, Right?

B (33:31)

Yeah, exactly.

A (33:33)

Okay. And did you measure like, because we talked before about like, like I say, one of the reasons I would always be hesitant to take it is just purely this fear of loss of control. Same reason I don't like flying. I'm not flying the plane. If I did, I would love it and be the craziest pilot ever and I wouldn't be afraid of that. But being a passenger is terrifying because I'm not on the controls.

B (33:56)

But.

A (33:56)

So, yeah, did you, on that kind of line, did you measure like how anxious are you about doing this? And then at the end how was it and how anxious do you feel about having done it? Sort of almost like managing monitoring expectations.

B (34:11)

Yeah, we did measure expectations, or expectancy, as people call it, as a factor. So that's looking, as you've mentioned, at prior attitudes towards the drug. We didn't ask people how anxious they were specifically in terms of expectancy because we thought that that could prime people slightly because people are very sensitive when it comes to these studies, especially with a condition like ocd. So they were fairly neutral questions actually, and they were more looking to kind of pass out whether people had something comparable to a placebo type effect or expectancy feeds into that type of phenomenon where someone might think something will work, think it's efficacious, think it's beneficial. So the questions that we asked them one week before the first dose centered more around whether they thought psilocybin would improve their symptoms, whether they thought that the effects would last for a while, be persevering, whether they thought it would generally improve their well being and things like that. And people would answer those questions. We looked at the analyses for them and expectancy didn't predict improvements after placebo or after the active dose. So that's quite relevant in the field that these clinical improvements that we saw weren't mediated by the placebo. Sorry, weren't mediated by expectancy.

A (35:22)

Yeah. Okay, good, good. Again just looking and revisiting my questions. Yeah, well, where do you, I mean you've addressed this a little bit, but where do you see these sort of studies heading next or where should they head next next?

B (35:41)

So I think ideally the next study in the UK would be a larger version of this study. I think it could be really beneficial to have a few different arms. I think it could be great to look at exposure response prevention alongside psilocybin, although that's quite ambitious at this early stage of research. But I also think it would be meaningful to look at maybe repeated 10 milligram doses, maybe just a second dose one month after just two doses, space developed by two months as well as the placebo. Because I think, I think it's really nice to build this, this evidence base for this lower dose. I think that's something that I'm, you know, personally resonates with me for ocd because I think, you know, having spoken to so many people, I went to the IOCDF conference in Chicago and you know, got to meet lots of people in the US as well. I think there is a big demand for a lower dose approach and you know, there are great studies going on in the US looking at higher doses. So just in terms of being efficient and generating evidence, it would be good to, to repeat this one, I think, with a bigger sample size.

A (36:45)

I agree. I think that'd be a really good idea because not everyone's going to want to take the higher dose and for those people, if they don't want to take it, it's like, well, tough luck. Whereas now you can say actually there's this lower dose and it's evidence based.

B (36:58)

Yeah, exactly. And I think some people with specifically with that fear of loss of control would opt for this approach. I think there are some people, this actually surprised me. It's interesting, I think speaking to some participants, I think some would have been fine with a higher dose, Potentially after the 10 milligram one being warmed up to it. But I think, yeah, it also really depends on the type of triggers that people's OCD centre around. I guess for some people it has nothing to do with self monitoring or loss of control of their own thoughts and it might be more something about data leaks and it might just sit there or responsibility and they might not really mind this idea of floating a bit and losing a bit of content, you know, temporary control. Whereas for many, for many people it would be highly triggering.

A (37:43)

Yeah, yeah, yeah, of course, yeah. Some people won't care about the high dose and some will be terrified of it and, and like you said, I could see that, yeah, some people would take the lower dose. They would then probably be much more open to a higher dose if they needed it because yeah, it's like erp, it's building up. Right, exactly. Building up the dose as well.

B (38:02)

Yeah, just, yeah, building up positive experiences and then that's. It Having. Having that evidence that they've gone in and been with the therapist and. And had a good experience.

A (38:11)

Exactly, yeah. Yeah, spot on. So, you know, in summary, what do you think people with OCD should, should or could take from this study?

B (38:22)

So before I give a summary, should I really quickly touch on just one final thing about, about the mechanistic outcome? So this is. Yeah, one thing that I think might be interesting and then I can do a little bit of a summary. So even though symptoms improved, we also looked at lots of mechanistic measures, as I mentioned. So mechanistic just referring to the mechanisms of the disorder in terms of the neuroplasticity elements I spoke about. We measured neuroplasticity using an EEG paradigm which is just non invasive brain stimuli, not stimulation, non invasive brain imaging. And it just looks at brain activity. And surprisingly, we didn't find a drug effect for this, meaning that the 10 milligrams as compared to placebo didn't significantly increase plasticity as is measurable via this specific assay. And we also didn't find the cognitive improvements that we thought we would. Because there's a big shift in OCD research away from conceptualizing it as a simple, not simple, but as an anxiety disorder towards it now sits in the OCRD category in the DSM 5. It's considered to be driven by a lot of cognitive factors like, like cognitive inflexibility, metacognition changes where people kind of aren't as confident about making decisions and things. So there were two main tests that silo CD involved and one looked at cognitive inflexibility to see whether it improved as is measurable via a simple computerized task. And then another was a novel test that we incorporated which looked at metacognition. And when I say metacognition, I'm just referring to someone's ability to measure that, like to reflect on their own thinking. And it's something that, you know, we all do. We have this capacity allows us to gauge our confidence in things before we take an action. And this specific test looked at whether confidence correlated with performance. So whether people with OCD were underconfident, which is typically the case, they're equally good at performing in tasks, typically as people without ocd, but they often doubt themselves. And after they do the thing the task requires, whether it's a motoric task like throwing a ball or whether it's something more intellectual, they might be accurate, but then doubt their answer afterwards. So, yeah, I thought it would be really interesting to see whether Psilocybin moved these areas, but compared to the control groups that we also employed, so people that weren't given the drug, we didn't find a drug effect for these either. So this is something really fascinating about the study, which. And this made it a real challenge to write up critically for my thesis, just the fact that it improves symptoms, but not in the way that we thought mechanistically or not as far as these specific mechanistic essays could capture. So I guess for the audience, that's quite technical neuroscience. And it might. I mean, the papers will be coming out. I'm polishing them up and trying my hardest to push them out now while working in industry, but as keeping one foot in academia, which is really nice in a way, but I think that's. Yeah, it's definitely not a cause for concern. I think it speaks a lot more to the fact that these assays or tests that we use are a bit limited as well. So I'm sure, you know, psilocybin is probably doing something to neuroplasticity. It's just the test. You know, the specific test we use in EEG can only measure a proxy. But I guess like an overarching point is that. That it's still. Some of these mechanisms are still slightly mysterious. But then I guess it's almost like a philosophical question of whether we need to know exactly how it works, if it's safe and well tolerated, because we don't know exactly how SSRI. We didn't know exactly how SSRIs worked for a while, but, yeah, I just thought it might be interesting to kind of mention those mechanistic elements. I haven't actually spoken about them before yet.

A (42:18)

Yeah, no, that is. That's worth adding. And yeah, like you said, as long as we can prove it's safe and it works, is it crucial we know exactly why and how? Probably.

B (42:28)

Exactly. Yeah. I think it's good that, you know, there's a lot of scrutiny around psychedelics. I think we don't want them framed as something that should be taken without much thinking, but I think they can be held to much higher standards than other compounds because, you know, I guess we could also say we don't really know how adjunctive antipsychotics that can be given in OCD work to people that are given something like risperidone or aripiprazole on top of an ssri. We don't exactly know how the dopamine mechanism links in and how it helps them, but we'll see. Yeah, it'll be interesting to see the more mechanistic granular outcomes from the American studies as well to see if they find any kind of imaging things that our study didn't find.

A (43:12)

Yeah, yeah, no, that would be. Would be awesome. When are those complete, do you know those trials?

B (43:17)

I don't know the specific dates. I can send you the two links of the pages I found, but I believe probably in about a year or so because when I spoke to people over summer, they were just starting them, so. And yeah, I feel like that they'll probably be quite fast at getting the papers out. Like American unis are quite good at doing that quickly. But we have a little while until we can read them.

A (43:40)

Yeah, of course, of course. Yeah. I imagine they will go to the ISTF conference as well, I would assume.

B (43:45)

Yeah, that's probably true as well.

A (43:47)

Yeah.

B (43:48)

Have you been to that conference?

A (43:50)

I've been quite a few times, yeah. Yeah, I was actually going to go to the Chicago one.

B (43:54)

Okay.

A (43:55)

And then I can't remember. Something got in the way. But no, it's great, isn't it, there?

B (43:59)

Yeah, it was a great experience and it was amazing seeing Chicago in summer as well. Yeah, I've never been to that part

A (44:05)

of the U.S. no, I haven't either. Awesome. Okay, cool. So a couple random questions now for you. Nothing to do with the trial. Unless you want to make it about the trial. You can. So if you could pick up the phone and call the 18 year old you, what would you tell her?

B (44:24)

That's really interesting. I guess focus on what's interesting. I definitely would have. I wouldn't change the path that I've taken now. I would say yeah, just. Just be curious and keep moving and you know, exploring different things.

A (44:40)

Nice. I like it. And then you've got a billboard somewhere in the uk. What do you want written on that billboard?

B (44:48)

Oh, wow. Gosh. That's definitely. That's a great random question. I'm trying to think of my favorite quotes. I think I would just say maybe something like be curious rather than going for specific. A specific quote.

A (45:08)

No, I like that. I like that curiosity is important. So.

B (45:11)

Yeah, yeah.

A (45:13)

Nice.

B (45:13)

I think especially when you're an adult, I think it's important to just keep finding things outside of your work as well. Exploring different sports, books, music, etc.

A (45:23)

Yeah. Stay childlike.

B (45:24)

Exactly.

A (45:25)

Yeah, there is a really good quote on that, but I'm blanking on it anyway. Anything else you wish you could have said or shared today?

B (45:36)

That's a good question. I don't think so. I Think you've asked great questions. I think I've managed to touch on a lot of the kind of disclaimers that I think are important as well with this line of work. I don't think we've sold anything as a silver bullet solution or I think we've emphasized as well that it's still early stage research. But yeah, I think what could be helpful for people is just to realise that attention is being directed towards OCD in this specific area of research. It's quite fast growing and there's funding going into it and things. And I think hopefully over the next five years we'll see really significant shifts and then maybe people who are suited to it will be able to supplement their existing therapy program with this type of intervention.

A (46:18)

Absolutely. And that's it. I think as trials go on, we'll also get a better picture of who is this great for and who is this maybe not going to work for and who is this maybe not a good idea for and push people down those. What did you call it? Not targeted psychiatry.

B (46:37)

Precision psychiatry. Exactly. And bigger studies can better stratify people. You know, I. With. With my 19 or 18 completers. 19 participants? 18 completers. Because it didn't seem like it would have been very, you know, it could have been slightly scientifically spurious to start looking at very small groups of people with certain subtypes and considering whether they had a strong response or not. But if you have a much larger sample size, you can better stratify people. And you can also look at comorbidities in more of a nuanced way and consider, you know, what traits within OCD is psilocybin targeting. That's the kind of approach that I definitely like to see.

A (47:14)

Yeah, yeah, yeah, absolutely. And I think it's just a hopeful message for the medical side of OCD that there's this potentially this other string or arm that's going to come in that people can choose from.

B (47:27)

Yeah, exactly. And I think this will disrupt how we view mental health conditions in a really positive way. As we get more evidence for how psychedelics affect them. I think we are pivoting more towards a slightly more neuroscientifically aligned view of mental health conditions as well. Like even, you know, me being able to talk about things like learning and that being natural in this context, I think that's really beneficial because with things like SSRIs, I feel like we often don't really talk about actual brain mechanisms. And yeah, we could be moving towards a more holistic picture of how the brain actually works on different levels for all of these conditions. So that's definitely promising.

A (48:05)

Absolutely. Yeah. Excellent. Well, look, thank you so much for coming on and sharing your paper and what great PhD you did and thesis.

B (48:14)

Thanks so much for having me on. It's been lovely talking to everyone and yeah, it's great knowing that people hear about this little study that took place in England as well.

A (48:22)

Yeah, we do have a good amount of British listeners, but yeah. Yes, nice now. Yeah, it's an important study. I'm glad you did it and sounds like it was good fun, hard work, no doubt.

B (48:33)

But yeah, it was an incredible, incredible experience. Yeah, I'm really, really grateful that I got to focus on it, actually. And yeah, thanks so much for having me and for asking such great questions as well. I feel like we got to talk about it quite panoramically, which is really good.

A (48:46)

Yeah, I agree. Yeah. Thank you very much. Thank you for listening to this week's podcast and thank you to our Patreons who helped make this episode possible. And if you would like to find out more about Patreon and the rewards and benefits, then there will be a link in the episode description. If you enjoy the OCD Stories podcast and would like to support us, please subscribe and rate the show wherever you listen to the podcast. And thank you to NOCD for supporting our work. If you want to find out more about nocd, you can click the link in the episode description. And quick disclaimer. Guys, this podcast is not therapy. It is not a replacement for therapy. Please seek treatment from a trained professional and until we speak. Take care,

B (49:34)

Sam.