 Good evening, I'm Peter Szaroszy and you are watching Drug Reporter Cafe. Today we are speaking about a trendy subject that is much hyped by the media, LSD microdosing. We could read countless reports about its alleged effectiveness in boosting our mental skills, but there has not been much scientifically sound research findings, at least up to now, because today I have the pleasure to interview a researcher who conducted the first largest self-blinded placebo-controlled trial on LSD microdosing, Balas Sigati from the Imperial College London. Balas, thank you for accepting our invitation and welcome to Drug Reporter Cafe. My pleasure, thank you for the invitation. So let's start with explaining what is LSD microdosing and why is it perceived as good for our mental health. Okay, so psychedelics are always enjoying a moment in popular culture and what has started that trend are the research results from psychedelic therapy. And I think it is very important first to make sure that everybody understands there is a big difference between psychedelic therapy that has generated a lot of promising scientific results and microdosing, which is a completely different use case of psychedelics. So specifically when it comes to psychedelic therapy, typically it is psychedelic use embedded within a larger folk therapy. So most often the therapy lasts two to three months, something like that, and there are one or two drug sessions within that therapy. And typically the drug session is on a high dose. So with LSD we are talking about somewhere between two to 400 microdems, which I would like to say is much higher than typically recreational users would use. Also in terms of like mushroom, like in the most state what is the equivalent of a therapeutic dose is about five grams of fried mushroom, which is again higher than what the average recreational user would use. So there's a therapeutic application, you are undergoing a talk therapy, a classic therapy, and within that therapy you have a few large doses of psychedelic experiences. Now in contrast with that, microdosing is the practice where you are using psychedelics in very small quantities, but very frequently. So typically about three times a week, two to three times a week, something like that. And as I said, the doses are much smaller as well. In the case of LSD it is typically somewhere around 10 to 20 micrograms, and in the case of psilocybin containing mushrooms, it is about 0.1 to 0.2 grams, somewhere in that range. What needs to be said is that microdosing is another phenomenon, so it's not that there is like a very valid definition of the different people microdosing differently, and because of that there is a significant amount of variability in what people mean by microdosing exactly. Why is microdosing so popular among the managers of Silicon Valley? You would have to ask the managers of Silicon Valley about that. At this point I would like to add that this is a very popular notion that microdosing is very popular in the Silicon Valley in the tech industry. I am not a vet of any hard data staff that would prove that. I think this is something that everybody mentions about microdosing, but as far as I know nobody has real actual data on it. It might be just something that is too cool not to be said about microdosing, and it's a bit of a legend that I think your life of its own. I think what the appeal of microdosing is, is that you can get the benefits of psychedelics without the psychedelic experience. Obviously this is well established that why psychedelic therapy can be beneficial, but very often within that psychedelic experience there can be difficult moments, and not many people like those difficult moments. The promise of microdosing is that here is a way of using microdosing where you can get the same or very similar benefits without having to underquote the difficult experience which can be a psychedelic ritual. What evidence did we have on the effectiveness of microdosing before your study was published? Let's distinguish between two categories of studies about microdosing. In the first category we have the so-called observational studies, and the most critical feature here is that they do not have placebo control. These are typically online survey studies where a researcher puts a question in online and recruits microdoses online. Again we have to complete that questionnaire either before or after during the microdosing regime. The other big category of studies are the clinical studies, and very crucially these clinical or lab-based studies have placebo control in them. So the difficulty with the observational studies is because of the lack of placebo control, there is no way that they can provide evidence for beyond placebo efficacy. So clinical studies are the way to go, but the issue with the clinical studies is that they are very expensive to run. Clinical studies are expensive in general, but clinical studies on psychedelics are particularly expensive because of the schedule of one nature of the drug. So what we had previously is a relatively large number of observational studies, all showing positive results, and a very small number, specifically three lab-based studies about microdosing that had the placebo control. However, all of these had the fairly small sample size, and I would also like to say is that these studies are also by and large negative. I don't want to get lost here in the statistical details, but I think it is fair to say that by and large, if you look at those three previous clinical studies, they are negative, they were not really supporting the analytical evidence behind microdosing. Did all these studies research LSD or do we have any other studies on other drugs? No, all of the studies that have been lab-based studies on microdosing use LSD so far. So why and how is your study innovative compared to the previous studies? Can you talk about the methodology used in this study? So we call this methodology self-blinding methodology, and as far as I know, this is something which is completely new, not just in the research literature of psychedelics, but in the medical literature in general. And what we did is basically find a compromise between the previous dimension observational studies and clinical studies. So basically the way our study was run is that everything was run through the internet, and that was very helpful to get participants global. But very different, very different from your typical observational studies is that participants who did our study, when they signed up, we send them what we call the study manual, and this manual was basically a set of step-by-step instructions, how you can implement placebo control at home without clinical supervision. I'm not going to get, I'm not going to explain all of the details, how that works, but basically the way it worked is that you first had to hide your microdose within non-transparent gel capsules. So the microdose is just a small piece of flutter paper, you put inside a capsule, snapped it, and then you were also preparing empty capsules, and those are going to function as per seables throughout the study. And then you were putting these capsules into zip bags, and there was also some QR codes involved, you put them into an envelope, you shuffle them, there was some random number generation, and so on and so on and so on. But the natural result of the process is that people have ended up with capsules enough for four weeks of microdosing, but they did not know which of those capsules were microdoses and which of those capsules were microdoses. The other big part of the system is that when the QR codes were scanned from the envelopes, they're linked with the IT infrastructure of our study, and that gave us a way of knowing who was doing microdose or placebo at what time. So this is the process that we call self-blinding, where blinding has a very specific meaning in science, blinding means it is that participants are unaware of whether they're taking a placebo or an active component. So we call this study design self-blinding because you are the blinding to yourself, which is, as far as we know, have not been done before. You are setting up your own placebo control, and that's the innovative part of it. That's the twist of the whole story. Others have used internet-based services before, but nobody put a placebo control on top of that. And this is very important in the context of microdosing, because as I said, typically the observational, sorry, the clinical study is a very small sample size because of course considerations. But here we managed to find a way of doing a microdose study that potentially could have a large number of participants and have the placebo control and crucially at a very, very cheap price. This study costed us about $10,000, which in terms of research money is absolutely zero. If we would have done this as a clinical study, then it would have been easily in the million dollar range. So roughly our costs are about 1% of the clinical study. So to sum it up, that's the exciting thing about the methodology is this combination of having placebo control, having a large sample size at a very, very cheap cost. So in your research, the participants were required to buy their own LSD in the black market. So how could you make sure that what they purchased was really LSD or did you have any way how you could ensure? The short answer is no. This is not a chemical study. This is a citizen science project. Our results are not representative of any clinical microdosing regime where you would know the micrograms, where you would know the doses with micrograms precision. This is a citizen science project that is the mind how microdosing affects real people in real life going about their everyday life. And I may add that actually in the context of microdosing, I think this is much more interesting than a clinical study would be. And the reason for that is because microdosing is something that has emerged from the underground from people who are microdosing with the exact same variability that our study also represents. It's not like that the microdousers who are reporting over these fantastic benefits that they are doing clinical microdosing, that they are getting their LSD from a legal source. No, they're also getting it from the black market that comes with the same very affinity as is represented in our study. So I think this is a crucial element of the study is that we don't want to grasp it up as like the clinical study. I don't want to advertise it as such. And yes, there's a side effect of that we are going to lose some control. But however, the lack of control from another perspective is actually a positive because it brings us closer to the real life use case. How microdosing is affecting people in their real life going about their everyday life. The video you are watching now is produced by the Rights Reporter Foundation, a nonprofit organization which is not supported by any governments or political parties. If you like this show, please support our work on our website to drugreporter.net. Make a donation today and become our supporting member. It makes a difference. Thank you. Can you talk about the results and findings of your study? So first, let's just focus on the microdose group in the study. So people who have microdose in throughout this entire four weeks long duration. And that we can see with the red here. So first, you have the pre-regime that's your baseline measure, and then you move along the x-axis, and then you see post-regime that's after the four weeks. And then there was also long-term follow-up, but I'm not going to talk about that because it's less interesting. So if you focus on the red line, you can see that it increases sharply. And indeed, if you check the top bars, you can see that it actually increased in a statistically significant manner from baseline to after the four weeks long microdose. So in a way that completely validates all of the positive anecdotes about microdosing because people have been microdosing for four weeks, their psychological outcomes have improved. On this figure, you see the outcomes specific to the mindfulness skills that we used in the study. But the basic story is true for all of the psychological outcomes that we have measured. It's true for well-being, life-satisfactions, and all of the other variables. So mindfulness and everything else increases from baseline to after four weeks of microdosing, for the microdose group. But what happens with the placebo group? That's what you can see in group here. And as you can see that the placebo groups improved somewhat less, but it is still statistically significant compared to their baseline levels. So yes, microdoses have improved throughout these four weeks of microdose energy, but so did the placebo control group. And as you can just see by eye from the overlap of the error bars, the difference between the microdose and the placebo groups are not statistically significant, you know. So just thing is that there is no statistically significant difference between the microdose and the placebo groups in terms of input time. And again, this was true for all of the psychological outcomes that we have measured in this study. So in terms of interpretation, what does that mean? I think what it means is that the anecdotal reports about the benefits of microdosing are true. That's clear from our data. Microdoseers have improved, you know, by the way of psychological outcomes. But the mechanism behind those improvements, it's not a pharmacological one. It's explained by placebo-like expectation events. Did you observe any adverse reactions to microdosing among the participants? Very short, no. There was one single person who emailed us that he's feeling unvaluant. He's going to drop out of the study, but none of the other participants. So a short answer, no. So can you say that microdosing is safe then? I wouldn't say that. And the reason for that is because there is some concern by the research community that psychedelics have activity at the cytokine 2b receptor and activation of that is linked to heart problems. I wouldn't say I'm overly concerned about that, but I also don't want to publicly say that microdosing is safe because of that issue, which is still under investigation by the research community. Are there any other interesting effects or results which you would like to report? Yes, I think we do. And those results are about the acute outcomes. So acute outcomes means that these effects were observed a few hours after the participant had adjusted the capsule, either a placebo or microdose. So I'm going to show you here on this figure one particular example, which is about activity motions and use panacea, which is a valestation of psychological questionnaire to measure these. I'm going to focus on this one specific example, but generally all of the other outcomes follow the same factor. So what do we see on this figure? So if you go to the bottom of the figure, you can see that there are two roles. One of them is condition and the other one is gas. And the condition is what participants have actually taken. If there's two values, P L stands for placebo, the M D stands for microdose. Now the role below is the gas. After they have completed all of these questionnaires, the very last question at every time point was that you ask participants, hey, if you have to take the gas, what do you think? What did you do earlier that day? Was it the microdoser or placebo? In the gas role, you can also see that there are two values. It's either a placebo or microdose. And this way, the data is divided into two times two equals four categories. So let's walk through these four categories and let's start with the leftmost one, where it's placebo, placebo. So in this case, participants have taken a placebo and they thought it was a placebo. And on this particular scale, you can see that the effect, sorry, the score is about 30. Now you can think about it that that's the based on value. If you go to the next column, the second column left, that's when participants have taken a microdose, but they thought it was a placebo. So the difference between these two categories is the true drug effect because they think it's a placebo. In both cases, the only difference is that the first time they have taken a placebo, in the second case, it was a microdose. So you can see that the second column, the score is a little bit higher, but not by much. And if you just look at the error bars, you can just visually see that the difference is not going to be statistically significant. Now the really interesting part is when you look at the third column. In this case, participants have taken a placebo, but thought it was a microdose. And now you can see that the score really goes up all the way to 18. And you can just again see from the error bars that this is going to be a statistically significant difference compared to the first case. And in the last category, when you have taken a microdose and you thought it was a microdose, you can see that it roughly stays about the same. Now to be statistically precise, you can see some bars with p-values at the top. I think that's important because that's basically the quantitative version of what I just said. But if you look at the top bar, which is comparing the first and the second categories that shows it has a p-value of 426, as I'm sure many of the listeners know, finding a significant percentage on there is 0.05. You can see this is highly insignificant. When you compare the third and the fourth column, there again, the only difference is the condition that the p-value is equal to 0.45. So again, changing the condition in either case is making a statistically significant difference. But in the lines below, the p-values are very, very much below the significance level. And the difference between the third and the first column is the opposite of what was before. In that case, we are fixing the value of the condition and changing the value of the guess. So specifically about the first and the third column, in both cases, they take a placebo. The only difference is that in the first case, they have, yes, it was a placebo. And in the second case, they took it was a microdose. So to sum it up, what it actually means is that what makes a difference is not what participants have taken, but what they thought were they taking. Because microdosing is so much hyped in the media and many people try to make business out of microdosing, do you anticipate any criticism or like probably there will be many people will be disappointed? So did you experience any reactions like that? Yeah, I wasn't brave enough to check the microdosing forums when the study came out, but I did not. There was a pretty, pretty harsh internet stuff there. Let's just put it that way. Look, I mean, of course, some of members of the microdosing community are disappointed by our results. And of course, when we started the study of division voices is that let's show you that it is more than just a placebo attack. I wouldn't say that we were committed to the results in any way, but the vision was certainly to show that microdosing is more than just a placebo attack. And then, you know, we went away, we collected the data analyzed, and, you know, unfortunately, it's not the results that we expected or wanted. You know, it is what it is. We just have to swallow it, publish our results. The methodology used this is quite innovative. So and it has some promising, you know, opportunities to use it in other research. Do you have plans to use it to study the effects of other substances? Yeah, so we have plans for the future of self-blinding. And I should start with that. We are going to launch a self-blinding study 2.0. It's going to run on the Mydellica app. Mydellica is an app which is funded by Obinkara Paris, who is a very well known psychedelic researcher from Imperial College. Disclaimer currently I'm also working with him, so it's not a complete coincidence that for the second version of the study we are going to use his platform. We are launching this new study because it's going to be in a mobile platform and that's going to open up the experimental space. We are going to be able to do more compared to the first version because it's going to be running in an app. And also just like with every study, we have realized a few things that we could have done back in the first version. So we feel that there are some loose ends in the study and currently we are designing the second version of the study running on the Mydellica app that we'll be able to address that. So that's about the micro dosing future. But we have also ambitions for self-blinding beyond micro dosing. You know, the entire concept of self-blinding, there is nothing micro dosing specific and as you said you can reuse it in many other medical interventions. And the one protocol that you are actively developing at this point is for CBD oil. CBD oil, similar to micro dosing, has received a lot of very positive press, but not so many high quality research output in that area either. So there's going to be very likely a self-blinding CBD oil study. It's a little bit depends on the funding situation and how well this is going in the lab, but I think we're going to do it. That's also going to realistically come out potentially to varsity. And generally speaking, we are looking for other researchers from other domains who can bring their domain knowledge, who brings self-blinding, and we could do good science together. I was actually just contacted by a researcher from Barcelona who is studying aging and apparently there is an entire community of people who are taking various research chemicals that's supposed to slow down aging. So that's also something that we are going to explore, maybe like a self-blinding study about aging medications. The appeal of the self-blinding methodology is that again it is somewhere between that of an observational study and a clinical study in terms of the level of control that we have. But I think if you would ask scientists like what is the critical differentiating factor between the observational and clinical studies, they would say that it's the lack of control for the placebo effect. And we have shown that we can solve it. We can run citizen science studies with placebo control. We show that it works and we also show that this is a very good way to get a very large sample. Because our study, the micro-do study, is the largest placebo control study on psychedelics to date, not just among the micro-dosing studies, but about psychedelics in general. And the reason for that is simply because it was a citizen science study from the clinical study. So we see a lot of opportunities to exploit the logic of self-blinding, of weed drugs, and also with other interventions. And we are actively looking for collaborations in those areas. Barasi Gatti, thank you so much for being with us today. Thank you very much. And thank you for all those who are watching us online on Facebook. Please stay with us on Drug Reporter's Facebook page. And if you like this video, remember that Drug Reporter is operated by a non-profit organization, the Rights Reporter Foundation. So please make a donation today. Thank you and goodbye.