#16 Series A talk with Samuel Thomas, Venture Scout at Rebel One - RBL1 based in NY

At its very core, drug science must remain independent. This means we don't accept sponsorships. It's with the support of the drug science community we're able to do this and make the podcast in the first place. If you're able to become a drug science community member and support the show, you too will be supporting the dissemination of evidence-based drug policies. Without you, none of this will be possible. For anybody interested, there's a link in the show notes. Thank you. Hello and welcome to the drug science podcast with me, David Nut. Here, we're bringing together experts and activists for a rational, honest and informed conversation about drugs. Hello and welcome to another drug science podcast with me, David Nut. Today, I'm delighted to have with me Robert Schuvers, who is professor of psychiatry in Greeningham University in the Netherlands. He's also one of the pioneers of psychedelic therapy, both in the Netherlands and in Europe. So welcome, Robert. Thank you very much, David, for the invitation. Well, I've been wanting to talk to you in depth for some time. It's particularly since you did this amazing thing and raised, I think, five million euros to study psychedelic therapy from the European funding councils. But we'll come into that in a minute. Firstly, I like to do what I do with all my guests, which is awesome to tell me a little about yourselves, themselves. You'll tell us about why you got into psychiatry and why you eventually came through and decided to work, I believe, with ketamine in the first instance. So just tell us a bit about your path to this, please. Okay. Thank you. I did my medical studies in Amsterdam and I worked for some time at the psychiatry emergency service, which I really thought was a wonderful and also sometimes difficult job, but which taught me about you could say the multi-layered aspects of psychopathology, they're within a person, they're in the interaction of a person with the social environment. And also, of course, the biological and neurobiological aspects are always at play and you could say in every individual the puzzle is different, although some of the pieces are equal. And I thought, yeah, that's the kind of puzzle I'm interested in, so that's sort of my determined my fate. Oh, well, that's really interesting because that's exactly exactly why I went to psychiatry. Because as you say, every, every person you taught with is different. The rest of medicine, it's an organ, but in psychiatry, it's the person, isn't it? And you never, ever get tired of bored with talking to people because they've all got such complex and interesting components, it build up their psychological profiles. So we share something in that. And that's how, by the way, that's how I try to communicate the excitement of psychiatry to junior doctors and presumably you do the same. You've got plenty there as well, I think it's, Holland is actually quite well endowed in terms of junior trainees, I believe. Yeah, I think we are. And somehow, I mean, things can always be better, but I think if you look at mental healthcare in the Netherlands, compared to many other countries, we are relatively privileged in the sense that services are well organized, that we have, I think, quite trained staff, psychiatrists, psychologists, nurses. We are relatively okay, organized in terms of ICT, data collection, and that sort of thing. Even though there is always a lot of criticism, there's waiting lists and everything, but I think relatively we should be mindful of the fact that unfortunately in other parts of the world it's quite a lot more difficult. So you're in Amsterdam, you're dealing with people, they're very extreme edge of presuming a lot of psychosis there and drug abuse on the streets, and then how do you can end up going into the borders of Denmark? Well, I did my psychiatry training also in Amsterdam, and basically I wanted to become a good clinician. That was my goal. I thought research was not very interesting, actually to be honest. I thought it would be quite boring because it took so long. And then only when I was near my graduation as the license of psychiatrists that I realized that I had to do something with my curiosity also in terms of research. So I embarked on a PhD, which in my own time, which was on psychiatric epidemiology because I thought epidemiology is a good basis for research. You learn a lot of skills and I also thought that I could still back out if I didn't like it because I wouldn't harm anybody because I was doing it in my own time anyway. And then one thing led to another and I got sort of the flavor of it. I got more enthusiastic. I got my PhD after 10 years, but by that time I had already become director of residency training in a very large Amsterdam mental health provider with university affiliation and I was doing research mostly on depression. My epidemiology research had been on incidents and determinants of depression and then I worked in a group that had a lot of clinical studies, treatment studies, psychotherapy versus pharmacotherapy, all kinds of combinations. And then Denmark came along to ask me if I would be interested to move to the north of the Netherlands to the beautiful university town of Groningen, which happens to have a large academic hospital and also a very large psychiatry department in that hospital. Yeah, I jumped into the deep and became head of the department and I have been in that position for the last 15 years and as an academic mental health provider we of course see many patients for whom our regular treatments are not sufficient. They don't respond and their suffering is always impressive. So it's the chronic treatment resistant patients that I think have the largest unmet need even though there's a lot of need also at other severity levels and that's more or less by accident. There was a colleague of mine who had who followed the literature and he said it was like 2013, 2014 he said, wouldn't you be interested in working with ketamine? So that was long before I even knew the J&J or whoever was interested, there was the studies from Carlos Arata and his group, some smaller open label studies with ketamine. And then we developed with my group, we developed, I learned that from a German colleague, we developed oral esketamine because we thought that would be patient friendly. We put the generic esketamine in a glucose drink, the pharmacy did that and we started in an off-label, compassionate use treatment program for individual cases. For patients who had really had all the steps that we have to offer in terms of depression treatment, so different psychotherapies, a whole range of pharmacotherapies and also ECT. And that's where we started with esketamine and we saw quite positively surprising results in some of those patients and that led us to with public funding embark on larger randomized clinical trials. Most of the audience, if they've even if they've heard of esketamine, they won't realize what you were using was not the same as bravato, so I'll tell you what I think you would be doing and you can correct me if I'm wrong. So my understanding is at that time esketamine was licensed as an anesthetic alongside ketamine in your country and some other countries. So you were using esketamine, the anesthetic escape and you're putting it into a drink which has actually, that I did not know and that is rather interesting and it presumably has a similar effect to whether you're drinking it as injecting it then. Yeah, there haven't been any direct comparisons and the patient category that we are treating is overall probably much more treatment resistant than in other studies in the literature. So if you take that into account, I think our efficacy and effectiveness are well within the range of other variants of ketamine or esketamine and indeed in the Netherlands and also in other European countries, esketamine is what most of the anesthesiologists would use. So we used the injection fluid that had been around for many years which was cheap and off patent and we put that into a glucose drink and then we did individual titration because well you know everything about that but like the biological availability, if you consume it orally is relatively low. So in intranasal, it's like 50 percent, actually is of course 100 percent but through the gut it's 10 to 15, sometimes 20 percent, so what we do is we do individual, we dose higher and higher until we get sufficient immediate response and subjective experience of a patient that that's more or less where we stay at. So just explain to most of the listeners won't understand, are you talking about titrating up in a single session or each session you give a large dose? Yeah, we do, in our first randomized controlled trial, we do it fixed dose and we used three times per day, 30 milligram orally, seven days per week. So that was totally different scheme than what we do today and I think we learned by doing that you need higher doses and that you can do it less frequently to have better outcome. The one good thing about our clinical trial is that it was fully blind because patients and the treatment team couldn't guess at all in what condition the patient was. So these were impatience presumably, viewing it three times a day, seven days a week. No, no, because we made capsules and we started, I think we started the first days or the first week maybe we started impatient but then we, people could take it from home and it was, it didn't affect a lot of, of course I couldn't drive, we were safe with those kind of things but it was hardly, so it was with hindsight, I think you could say, it was sort of subliminal catamene treatment. Interesting. Any outcomes results? Well, no effect, nothing better than placebo. However we, for ethical reasons we wanted patients who had been allotted to placebo to also be able to try whether catamene or escatamine would work for them. So we had an open label phase two where all the patients got escatamine open label, weren't deep blinding at that phase and then we thought, well why not try a different regimen? So then we tried two times per week, a significant, the higher dose. And that's because we thought we didn't see a lot of effects of course but when you are still blind it's very hard to tell but we also weren't sure and of course we followed on literature, we weren't sure whether our application scheme was optimal. And then we saw in the patients who had been through the clinical trial whether they had catamene or placebo that we saw quite substantial reaction in part of these patients. So we learned a lot from that project. And you moved then from, I suppose you started off thinking it was a bit like a, like an SSRI or conventional medicine, you give it every day and you sort of saturate the receptor and you get an effect over time and then you began to get moved more into the direction of the sort of perturbing the brain and more overtly and then looking at outcomes there. So what's your preferred catamene approach now then? Yeah, it was really a learning journey for us. So we started with this like 2014-2015 and we did a clinical trial and of course it takes ages and one of my PhD students, Joost Brexmer, who's also the founder of Open, he's a philosopher and he was very interested in qualitative research. And we had the idea that it would be worthwhile in the patients who had the higher dose so two times per week high dose to ask about their experiences and Joost who had not been involved in the clinical part just curiously asked them about their experiences. And then even though we had been, hopefully I think, well we had been treating the patients in a nice gentle way and putting them in a quiet room, taking their blood pressure and all of those things that you would usually do. But we hadn't realized at all that or not sufficiently that people were struggling to maintain control at the moment we were giving them something that is strongly dissociative. And of course we knew and we told them and I think that's how the intranasal spray is applied all over the world in the here and now. So people are told you may have some funny feelings, you may feel bit nauseous, you can close your eyes, you can stay relaxed and then after 2014 minutes you will come out of it and then the treatment is doing its job. And what we found was that it's sort of a slow realization. So patients told us they were trying to stay in control which is of what you, the opposite of what you should be doing. But we hadn't prepared them to let go and we hadn't given them enough confidence that this experience in itself may be helpful that you make across thoughts, feelings that are relevant to you that may even play or have played a role in your depression and that you might learn something from that. So moving backwards we developed something that looked like psychedelic assisted therapy because what we now do is we have what we call support module where our therapist prepares the sessions, the ketamine treatment sessions with the patients, they stay with them in the first sessions and depending on what they prefer they can do that also in the next sessions. And then I have the talk about what came up and how that relates to the themes they are struggling with in their lives and what we see now is that the outcome we haven't had done a comparative study one on one but it is very much our own impression that we have much better results now and that we have hardly any patients who do not support as ketamine treatment anymore. Gradually doing I guess what doctors always do which is try something and then refine it and refine it so you've got to a point where you've optimized it. Is that standard practice now in your clinic and has it been taken up elsewhere in the Netherlands? Yeah, that is an interesting story so it is standard practice in our clinic in research. So we, the one trial that we hope to finish in the next year is a comparative study where we, it's a non-afferiority trial where we compare oral as ketamine in the context as I just described, versus ECT, Electrical Fels of Treatment. So that's patients in the end of the regular treatment protocol and if we can show that it's non-afferior then the Netherlands Care Institute will provide, will work on a registration file and that hopefully may lead to oral as ketamine being in the insured category of treatment. So currently it is off label and before before's profata was on the market the insurers would pay for that and now only if the profata is an exclusion so it's a patient, if a patient doesn't match the criteria for profata because that is now the regularly registered medication. I understand that now so tell me a little bit about the, what's the therapist you use in this because obviously it's Nevada doesn't use therapists but you do so I'd like to learn a little bit about how you developed the therapists skills because I presume they're going to feed into what we're going to talk about in a minute about your psychedelic treatment. Yeah, we thought about that a lot so it depends a bit on the patients because not all patients have a deep need for dog therapy so there's people that are only briefly and others are already in treatment with another therapist elsewhere and we treat the depression including the psychological support and then their regular treatment is followed up by their own treating psychiatrist or psychologist but our modules is mainly based on ACT acceptance and commitment therapy which is relatively eclectic approach to the themes that come up and we try to prepare the treatment also and which is of course also what you do in psychedelic is the therapy that with the guides or the therapist or whatever names they have in the different regimes you build up a relationship and also it's important that the therapist knows about important topics in your life or important things that you struggle with in your depression for example or in trauma so as you're saying we we developed it this approach and we're still developing it and that's also how I became interested in classic. But tell us about that then. Yeah it was through the we got invited to participate in the I think compass at that point was preparing the phase 2b? I audience is largely non psychiatrists they may not be fully understanding of what the compass 2b is so could you explain that please. Yeah so we got into contact with at that time a small startup company who were producing silocybin as a medical drug and they were involved in smaller studies and now they wanted to do a larger dose finding studies so it is a double blind study the patient and the treatment team and also the researchers don't know what form what whether it's low dose intermediate dose or high dose and the idea of what this is called the phase 2b study the idea is to find the optimal dose effect side effect ratio. So that was our first entry into psychedelic classic psychedelic treatments our therapists were trained and we included like 20 something patients in that trial and we saw a range of different results so of course we the main outcomes have been published in the new England Journal of Medicine I think it was in in 22 and that I think for the field was a very was a landmark I think you could say. Oh absolutely remarkable remarkable can I just ask you about so were you the therapy was being done in Dutch yes definitely yeah so everything had to be translated into the scales and that had to be adapted so which is and the fact that the findings were so clear given that multiple countries it was actually very quite remarkable wasn't it very very convincing yes definitely definitely yeah and it was also I think a lot of effort was put into training the therapists and maintaining what we would call fidelity so that everybody more or less use uses the same therapeutic techniques the same approach the same breathing exercise so that you standardize as much as possible not only the pharmacological procedures but also the psychological procedures around that and that of course in the field is quite a challenge and also a discussion so you're part of the compass are you part of the follow up trial as well yes but only very briefly yeah so the phase three has now been finished and we're all looking forward to hearing the results date we've got our fingers in legs crossed but you've gone on you've gone on beyond that to to set up this thing to the cypher which is truly remarkable so yeah we had gotten interest and and we'd like to do a bit of pioneering work and together with a group of colleagues from different European countries we tell one step back I think one of the most promising indications for psychedelics apart from the treatment resistant severe mental disorders is psychological distress in patients near the end of life and palliative care so where people have all kinds of existential questions that they may struggle with and that's normal if you are severely ill and if maybe you see that you're you're no longer getting better etc but for some people this burden becomes very heavy and they start to become clinically depressed then they're emotional processing of what's happening to them and sharing feelings with the people around them and being able to to direct the months that they still have in life all of that is sort of frozen in depression the current treatments for that indication are not very effective and they take they usually take relatively long and so there's really a need and also a very worthwhile moment in somebody's life to see whether a short intensive psychedelic treatment may help people to get out of I think you they're stuck in a rut psychologically so to help them open up to the feelings and all the difficulties of their situation and process the emotions share whatever they want to interact with the people close to them so that's quite a promising indication but there have been at the point we were writing the grounds there had been virtually no or hardly any double blind control trials and most of the trials in that field had been had also been quite small and if you're thinking of broader application which of course of course we are all very interested to see whether that could fulfill the promise that you can see in it then you need to do larger studies and we applied in the EU horizon program which is a large research program from the European Union which was focused on I think it was innovative interventions in Ballet with care it was something like that well all I can say is Robert you I agree we don't know it's fantastic that you and your group are going to be providing us with so much more interesting and important guidance in that direction so thank you very much for being on the program thank you for your success in raising funding to do the research and I really look forward to the results in a year or two's time so again thank you very much