The Tim Ferriss Show - #619: Dr. Suresh Muthukumaraswamy — LSD Microdosing, Classical Psychedelics vs. Ketamine, Science and Speed in New Zealand, Placebo Options, and The Infinite Possibilities of Studying Mind-Altering Compounds

Starting point is 00:00:00 At this altitude, I can run flat out for a half mile before my hands start shaking. Can I ask you a personal question? Now would have seemed the perfect time. What if I did the opposite? I'm a cybernetic organism living tissue over a metal endoskeleton. The Tim Ferriss Show. Hello boys and girls, ladies and germs. This is Tim Ferriss. Welcome to another episode of The Tim Ferriss Show. This episode is a special episode. It is a live recording from an event

Starting point is 00:00:33 hosted by the Edmund Hillary Fellowship. The Edmund Hillary Fellowship, otherwise known as EHF, began in 2016 as a pilot immigration program and has matured into a fellowship of more than 500 technologists, creatives, investors, entrepreneurs, educators, and systems designers, among many other things, committed to New Zealand as a base camp for global impact. From more than 50 different nationalities, including New Zealand, fellows span a range of high-value sectors such as media, education, cleantech, venture capital, and mental health initiatives and research, as we will hear in just a few moments. And that's just to name a few. EHF and its fellows aim to make a meaningful

Starting point is 00:01:09 impact in New Zealand, Aotearoa, with projects that often have global applications. We talk a bit about that and certainly explore a lot more with today's guest. You can learn more about EHF at ehf.org. Greetings to you all and welcome to today's EHF live session. The Edmund Hillary Fellowship is a collective of entrepreneurs, scientists, storytellers, creatives, and investor changemakers who want to make an impact globally from Aotearoa, New Zealand. In this session today, you're going to hear from Tim Ferris. He's an EHU fellow who's an early stage technology investor and advisor. And Tim will be interviewing Dr. Suresh, an associate professor at Auckland University. And the topic today is on mental health and breakthrough therapeutics. There'll

Starting point is 00:01:55 be plenty of time for Q&A with Tim and Suresh during the 90-minute session, but nearer the end. Over to you, Tim. Thank you very much, Michelle. It's a pleasure to be here and it's a pleasure to be doing a live session. I have been looking forward to this for some time. And without further ado, let me introduce the main attraction and the guest of the hour, and that is Dr. Suresh Mutukumaraswamy. I will here forward refer to him as Suresh. Suresh is an associate professor of psychopharmacology at the University

Starting point is 00:02:25 of Auckland, and he completed his PhD in psychology at the University of Auckland in 2005, after which he joined the newly established Cardiff University Brain Research Imaging Center as a postdoctoral fellow. While at Cardiff, he started research work with the psychedelics and psychedelic compounds in 2011 in collaboration with two very well-known names, Professor David Nutt and Dr. Robin Carhart-Harris, investigating the neuroimaging correlates of the psychedelic drugs psilocybin and LSD. In 2014, Suresh received a prestigious Rutherford Discovery Fellowship and returned to the University of Auckland, where he works in the School of Pharmacy at the Faculty of Medical and Health Sciences and leads the Auckland Neuropsychopharmacology Research Group. Suresh's main research interests

Starting point is 00:03:06 are in understanding how therapies alter brain function and behavior and in testing methodologies to measure these changes in both healthy individuals and patient groups, particularly in depressed patients. And of course, this session will have a focus on mental health, so we will delve into that. At the University of Auckland, he has conducted clinical trials in depressed patients involving ketamine, scopolamine, and transcranial magnetic stimulation, TMS. He has received several Health Research Council of New Zealand research grants to support this work, including a grant to investigate the effects of microdoses of LSD on brain and cognitive function. Suresh has published 117 papers, and his work has received more than 8,000 citations. Suresh, welcome to the session.

Starting point is 00:03:47 Thanks for being here and taking the time. My pleasure, Tim. Nice to see you. Hopefully I didn't butcher the name too badly. And I will start with trend lines and perhaps just an overview of where we sit currently. And perhaps you could just take some time to describe mental health and or addiction statistics trend lines in New Zealand. That may be a meaningful place to start and serve as a canvas upon which we can discuss other things. So New Zealand has pretty good data on this because every year the Ministry of Health runs a survey called the New Zealand Health Survey. And they've asked for a long time about psychological distress and the amount of psychological distress that the adult population is experiencing.

Starting point is 00:04:30 So in terms of trend lines, so this is conducted every year. So in 2000, I think 11-12 when the survey was conducted, 4.6% of adults experienced psychological distress in the last month and we've seen that slowly creeping up to the last data point from 2021 2020 where it was now at 9.6 so we've seen a doubling over the last 10 years in the amount of adults experiencing psychological distress which is anxiety depression or sort of psychological fatigue so it's more than doubled. And actually the last, and COVID is definitely going to impact on that. We see a little bump on the last one

Starting point is 00:05:09 from the first sort of impact to the first wave of COVID and those lockdowns. And I expect that that's going to only get worse when the next year's data point comes out because in New Zealand, you might not be aware, but in New Zealand, the second lockdown was quite hard

Starting point is 00:05:22 that just finished at the end of 2021. So that will definitely have impacted on people's mental well-being. So we'll expect that to go up. So it's not a good place to run. So it's not just COVID. It's been trending up for a long time, and it's not getting any better. And I would imagine, although I don't want to assume that the costs, and there are many different types of costs,

Starting point is 00:05:44 but the healthcare costs of these upward trend lines with mental health issues, let's just call them depression, chronic anxiety, treatment-resistant depression, are, if anything like the United States, quite high in New Zealand as well, not to mention the personal costs. Let's talk about just a few compounds first. And actually, as way of background, could you mention just a few other classes of compounds that you've also done research with? Because I think it's important to note that you have done more than study what we would consider to be psychedelics. So perhaps you could just give a bit of context there. Yeah, so my background is in general psychopharmacology. So before studying psychedelics and concurrently to studying psychedelics, I've spent a lot of time studying anesthetics and GABAergic drugs. So GABAergic drugs tend to be kind of sedatives, so alcohol is a GABAergic drug, benzodiazepines,

Starting point is 00:06:41 a lot of the anesthetics like propofol. So I've studied all those drugs at various times various anti-epileptic drugs so that kind of class of drugs and then also we recently did a study of scopolamine which is a muscarinic drug and remifentanil we've looked at in the past i've done a lot of psychopharmacology studies that have nothing to do with psychedelics, although the psychedelic studies are the ones that probably I'm most well known for in the public discourse because they attract some interest, I suppose. They catch the attention. So we're going to talk about the contrast between, say, ketamine

Starting point is 00:07:18 and traditional or classical psychedelics. But before we get there, because I am personally very curious, why did you decide to study scopolamine and what did you find in terms of its effects on conditions, whether depression or otherwise? Because scopolamine, for those who don't know, is also naturally occurring in many plants that are considered psychoactive or hallucinogenic, some of which are considered quite risky. But how did you determine this as a subject of interest for research? We had been doing studies on the antidepressant effects of ketamine, and we'll talk about this later, but you see this rapid antidepressant effect. And so what we were interested in was, are there other compounds out there that might show similar rapid antidepressant effect. And so what we were interested in was, are there other compounds out there that might show a similar rapid antidepressant effects?

Starting point is 00:08:08 And there was a series of studies that came out of the NIH intramural program. There was two or three intravenous scopolamine studies that appeared to show a similar sort of pattern of antidepressant effects. So, and scopolamine works very differently to ketamine or other antidepressants being a muscarinic antagonist. So, I thought, well, that's really interesting. If that works, then we can study that. And even though it's got a completely different kind of receptor binding mechanism that we

Starting point is 00:08:37 could investigate that and then potentially look at, in our study, we looked at antidepressant and then if we could then identify neurobiological markers that would go along with that, then we would sort of have a converging theory of maybe what causes rapid antidepressant responses. The downside, of course, is that we found no antidepressant response in that study. But, you know, that's the data, right? We did a really carefully controlled study. We, unlike the previous research that used an inactive placebo, and we'll get back into this, we used an active placebo, a compound called glycopyrronium that's used a lot in surgery that doesn't cross the blood-brain barrier but still is anti-muscarinic

Starting point is 00:09:19 and it creates a slightly drowsy feeling and dry mouth and a lot of the kind of side effects that you might get. We were able to show that participants could no longer distinguish which of the drugs that they had. And actually, we are ascribing most of the antidepressant response that we see to a placebo response. So lesson learned. Yeah, that's fascinating. Escapolamine, I don't want to take us too off track, but has some very interesting effects on memory, or at least it's thought to have some very interesting effects on producing amnesia. Yes, it does. While still having agency on some level, it's a fascinating compound.

Starting point is 00:09:55 So let's jump to ketamine. Most people, or I say many people, have perhaps heard of ketamine. Very commonly used, and please correct me if I get any of the terminology incorrect, but anesthetic, dissociative anesthetic does not suppress respiration, at least at the doses that I'm familiar with. It is very widely used in medicine. I believe it's one of the World Health Organization's top 100 most essential medicines. Could you discuss ketamine and classical psychedelics and how they differ? And just from an anecdotal perspective, although there's a lot of really good research, which of course you've been a part of looking at the antidepressant effects of

Starting point is 00:10:34 ketamine, I know multiple people now who would credit their lives being saved to ketamine. And part of what makes it so fascinating to me is not that it's a silver bullet that works for all people, but it's the rapid onset of some of the effects in certain subjects compared to, say, traditional or conventional SSRIs, which in some folks, it can take six to eight weeks, say, to exert those types of effects if the people respond at all. So could you just perhaps give us a primer on ketamine and classical psychedelics and how they differ? Because both can be described as having psychedelic effects. Maybe the easiest thing to start with is with the classical psychedelics because it's relatively simple compared to

Starting point is 00:11:21 ketamine. So LSD and cytosine and DMT, they all seem to work through a common receptor called the serotonin 2A receptor. And we think that most of their effect, you know, there's probably some other receptors that are involved in parts of the response, but overwhelmingly we think that most of that sort of psychedelic experience is generated from this serotonin 2A receptor and binding there so conversely ketamine has a very different even though it has these kind of this dissociative or psychedelic effects it's receptor binding sites are many and complicated so principally binds to antagonizes a receptor called the nmda receptor and that's a glutamate receptor so glutamate is the most common

Starting point is 00:12:04 neurotransmitter in the brain, and we don't hear about it a lot. And the NMDA receptor is kind of interesting because it's actually the receptor that's really heavily involved in neuroplasticity and something called long-term potentiation. So that's essentially how brain cells, it's a receptor involved in how brain cells learn to communicate and strengthen synapses. So that receptor is really important there. But then it also has a host of other effects. So it binds to GABA receptors. Those are kind of the ones involved in inhibition and sedation.

Starting point is 00:12:34 It also binds to opiate receptors. And everyone will be familiar with opiates. And then there's other monoamine sites that it interacts with, serotonin, dopamine dopamine norepinephrine hcn channels sodium channels it just the list goes on and on as you go up through the concentration so it's an extremely complicated pharmacology and it goes even worse because actually ketamine metabolizes into norhydroxyketamine which has neuroactive sites as well. And it also, most compounds exist in the left and right state. They're called racemic. So there's a left and a right state. And so there we

Starting point is 00:13:12 have S-ketamine and R-ketamine and normal ketamine is both of those, but actually the R and S-ketamines probably have different receptor binding profiles in addition to all of that. So what we're left with is this stew. You could either call it a very rich drug or you could call it a dirty drug, depending on your perspective. It's very promiscuous in terms of its receptor affinity. Could you explain for a second two things? So the first is why scientists would wade

Starting point is 00:13:40 into this soup of variables clinically from the perspective of mental health, what makes it interesting. And then second, what an antagonist does, just for people who may not have that vocabulary. When drugs are in the brain, you know, broadly speaking, it's more complicated, but broadly speaking, an antagonist is something that blocks the activity of something that is going on. So an NMDA antagonist blocks the NMDA receptor, so it stops glutamate working there. In terms of, for ketamine, in terms of,

Starting point is 00:14:11 there's both a clinical and a scientific interest there, and they're both really interesting to study, which is why I've been studying ketamine for nine or 10 years now. The clinical significance is what you mentioned before. You can take patients into the lab, patients that have had treatment-resistant depression, unremitting for years and years and years, and you can give them a ketamine infusion and they'll get this really rapid remission and symptoms. And that will manifest itself in hours.

Starting point is 00:14:41 Now, people will know ketamine is a street drug, right? And they will say, oh, well, maybe that's just because the person's high you know that they've been experiencing this intoxication so my response to that would be well actually you know if you then measure the person's depression symptoms at 24 hours after the ketamine infusion you'll see that they're still not depressed now what we know about the pharmacokinetics that's how long ketamine lasts in the body the half-life is about four hours for ketamine so at the 24 hour time point there's really no ketamine left in the body at all so ketamine's gone they haven't been high for you know 20 20 22 hours so they're not high anymore the ketamine's entirely left the body but

Starting point is 00:15:23 they're still not depressed and then what that shows is that the ketamine has changed something in their brain so there's caused some kind of functional change in the brain and that suggests and to move them from a depressed to a non-depressed state so that's really interesting that there's kind of like a switch in there that actually can be clicked and this ketamine's obviously working on some kind of target that can flick that switch and that understanding what that is scientifically is really interesting and and while other things can flick that switch they do it much slower like ssris they switch it in maybe four to six weeks or transcranial tms transcranial magnetic stimulation that might take a month to work as

Starting point is 00:16:03 well but here we can switch in a day for a scientist that's really interesting because you can run really good experiments because you no longer have to wait six weeks and all these extraneous variables that get in the way of your interpretations you can just go depressed non-depressed within a day and that leads to really tight experimental design so i want to preface what I'm about to say with the statement, which is, I know that the plural of anecdote does not equal data. Nonetheless, I do think case studies are interesting, and I can speak to one very cute example. A friend of mine in law enforcement who was suicidal, he had acute suicidal ideation. And many people in law enforcement or in the military, pilots would be another category, are very hesitant to admit to any type of mental challenges or to

Starting point is 00:16:54 seek treatment because it can result in leaves of absence and basically penalties, professionally speaking. And ketamine did exert those rapid effects. And again, not to say that this should be the expectation for every patient, but there are people who I know who go in acutely suicidal and have come out literally saying, I don't know what I was so upset about. I don't know how I was so concerned about X, Y, or Z. And what I'd love to ask you next, just again to contrast the, say, classical psychedelics, and you mentioned a number of them, which are in the, say, tryptamine class. We probably won't get into the phenethylamines and mescaline and MDA and so on, which can be very different in some of their subjective effects. But if we're looking at, say, LSD,

Starting point is 00:17:46 psilocybin, and then ketamine, if you look at the durability of some of the effects, say for antidepressant, what is your personal perspective on how they might differ in why they have durable effects? And I raise this because I was recently in a conversation with Roland Griffiths from Johns Hopkins Medicine, who's done a lot of work with psilocybin, and also John Crystal at Yale, say, have a lot to do with a change in content, meaning that people are actually able not just to suppress the symptoms of depression, but to address some of the kind of root narratives that are leading to depression. He was less sure about ketamine, and maybe there's sort of more of a mechanistic explanation like neurogenesis or increasing dendrite growth, where it's sort of

Starting point is 00:18:46 fixing the machinery so to speak on some level what are your perspectives the background to this for people is that the antidepressant response that we see to a ketamine infusion you know that will last any you know in our experiences anywhere from a day or two to a couple of weeks to a month. Whereas the data for psilocybin, that seems to indicate months, half a year, year-long antidepressant responses. But I think this kind of falls into the we don't know pile from a data perspective because the models that have been used, the experiments that have been done between ketamine versus the classical psychedelics

Starting point is 00:19:25 have been really different in terms of the therapeutic approaches tried so when people have been doing these psilocybin assisted therapies they've been wrapping around an intense amount of psychotherapy right so it's and i think it's really important for people to understand when they think about because you know you just read these headlines are you know psilocybin improved depression. Well, actually, it's not just psilocybin. It's the fact that the person's gone into this psychotherapy regimen with a therapist, and they've done hours of preparation for the experience.

Starting point is 00:19:55 The therapist has sat through them through the experience, and then they've spent hours and days on integration afterwards. So it's probably about 40 hours of psychotherapy for one one psilocybin course so it's not just the drug alone it's psyched out assisted psychotherapy now whereas the model for ketamine that's mostly been used is basically anyway it seems to be used in your flavor is that people just go into a ketamine clinic and they smash in an infusion for an hour and they go away and there hasn't really been much studies where people have actually done ketamine-assisted psychotherapy and tried to, well, what if we do wrap that similar

Starting point is 00:20:32 level? What would happen if we wrap that similar level of psychotherapeutic support around ketamine? Would that make that ketamine response now stretch out beyond two weeks to maybe a similar kind of time course. Because the people in the psilocybin world have come from that kind of more traditional psychedelic-assisted therapy world, and the people that have been studying ketamine have come from more of a kind of traditional psychiatry world. And so we haven't, we don't really, I'm not aware of any data that really has kind of tried to find them the man in the middle or or strip back psilocybin to just psilocybin which i think people would ethically struggle with trying to do that kind of experiment do you say that just because of the difficulties

Starting point is 00:21:15 that can come up in navigating that experience yeah because you know these are um so something like psilocybin is very powerful in terms of psilocybin and DMT. I see these very powerful psychological effects, and they can be destabilizing for people. So people need to be well prepared that they're going to experience very unusual, profound, potentially disturbing things. And to not provide that preparation might not be ethical to strip it back to nothing like it's done for ketamine. Right. Then there's probably a middle point where it could be stripped down to sort of the minimal viable support on the front side and then still provide the support on the post-session side. And this also highlights for me, you know, the I don't know, that we are really in a very fertile, nascent period of psychedelic research.

Starting point is 00:22:12 And even though studies were conducted much earlier, say in the 60s, they don't really meet our standards for study design that we would have today. And certainly with the imaging techniques that you have, fMRI and others that are now at hand, you can examine these tools with a set of lenses that you couldn't before. And it's really been astonishing to me to see how far very little money can go in this space compared to perhaps other areas like oncology or cardiology, for instance. Could you speak to how you pick your studies? For instance,

Starting point is 00:22:53 the LSD microdosing study, why did you choose to pursue that study? So I had returned to New Zealand in 2015 and having previously done classical side calories, I went and I started my research group here. I thought, well, we'll start with ketamine because it's approved. It'll be reasonably easy to get approval for, and no one's going to blink too many eyelids about a new guy coming into town wanting to study ketamine. The new guy coming to town wanting to do LSD is probably going to fluffle a few

Starting point is 00:23:23 more feathers around the faculty i would have thought back in those days but having sort of built a bit of a reputation i decided it was time to get back into doing some classical psychedelic research now the microdosing specifically was well no one had really looked at microdosing in a rct at that point and it's a randomized control trial randomized control trial. Randomized control trial. And I guess, should we explain what microdosing is maybe first? Why don't you explain what that is? And it also might segue into one of the design challenges,

Starting point is 00:23:56 meaning placebo control in psychedelics overall. So yes, please define microdosing. Yeah, so microdosing is when people take very low doses of psychedelics, about the 10th the dose of a big dose of when people are going to tripping. So people might trip on like 100, 150 micrograms LSD, but for microdose, they might take 10 micrograms, say. So about a 10th. And it causes, well, we don't really know exactly what it causes yet

Starting point is 00:24:25 because we haven't studied it properly, but users report that they have improved mental well-being, concentration increases. So what they do is they take these microdoses maybe every third day is the most common schedule. This was popularized by James Fadiman, who wrote a book in 2011. And it's really taken off since then. You know, like before 2011, not many people were doing it.

Starting point is 00:24:48 And there was really not much consciousness about it. But now we're seeing hundreds of thousands, probably, of people around the world now microdosing. You look at the size of the Reddit forum subscriptions just going up and up and up. So there's a huge amount of people out there micro dosing these classical psychedelics every third day many are giving up their antidepressant medications to do this but there's really no clinical trial evidence about it and not even in mental health patients just not anything now the reason that is is because if you wanted to run a proper rct proper randomized control trial of microdosing a psychedelic then you have to prescribe a class a substance a schedule one substance for people to take home and most

Starting point is 00:25:35 legal systems won't allow you to i don't think you could do that in the united states i don't think the dea is going to be very happy about. I think they might be a little grumpy about that. Yeah, yeah. And so there's not many jurisdictions where that could be done. So, however, there is one jurisdiction where it can be done legally, and that's Little Old New Zealand. So as I was, as you do every now and then, reading the Misuse of Drugs Regulations from 1977

Starting point is 00:26:02 and the Misuse of Drugs Act that goes along with it, Wakanda discovered this loophole. I don't know if you call it a loophole. We're actually, we're allowed to prescribe Class A substances. It's not ever really been done, but it's just sitting in the legislation saying that this is allowed to be done. So we engaged in a long process with the Ministry of Health and provided a legal reasoning for why this could be done. And so we did it and we applied to them and got the appropriate approvals from the ministry, various parts of the ministry to do it. we've just finished collecting data for which was to give 80 healthy volunteers a six-week LSD microdosing course to where they would take the first one in the laboratory and there are other 13 doses that were taken out in the wild as it were much like people do in real life. So let's

Starting point is 00:26:57 dig into that a little bit. So were they given the other 13 doses to take home all at once or did they come back to get one at a time or two at a time they were given packs of four four and five so we never gave them like 130 140 30 micrograms to take home so that they couldn't just stack them all up but actually you know there's a lot of like theoretical concern about this but actually to get into one of our trials participants have to do multiple screening sessions they spend hours getting scanned and having all sorts of probes attached to their body to record all their physiology getting pricked with needles and blood taken and all sorts of stuff right hours and hours there are a lot more efficient ways to get doses of lsd

Starting point is 00:27:41 oh for sure for sure yeah absolutely and we track we track every single dose was administered and video recorded by the participants and sent to us so we knew there was 100 adherence to the protocol and a part of the reason that i've been engaging with science in new zealand is precisely for this reason i I mean, you have on some levels, a very agile ecosystem compared to the United States, and you have legislation that would allow you to even consider designing a study like this. Could you speak to how New Zealand can or does foster scientific and research innovation. You could speak to certainly what you've already mentioned, any regulatory differences, but what else makes

Starting point is 00:28:31 New Zealand unique? What else could make New Zealand unique? And we can go from there. I'd love to hear what else is happening in New Zealand that you find interesting from a scientific standpoint in this domain. But let's begin with how does or how can New Zealand foster scientific and research innovation? We have a strong regulatory environment. So I'm not saying our regulatory environment is weak. It's strong, but it's capable of being agile and it's small. And we're a small country. So it's possible to just ring the person up who's involved in this, that, or the next thing. Whereas in another place, you might be trapped behind five layers of bureaucracy to these hidden figures that, you know, making decisions. In a country of five million, there's only so many people who know or are involved in these kind of decisions.

Starting point is 00:29:19 So if you are sensible and polite and appropriate, can ask questions and and get things to move so with small size i think does come agility and and i know that there are certainly pharmaceutical companies that are investing into new zealand psychedelics industry and our general medical into clinical trials here we're an attractive place to run clinical trials because also we're relatively cheap in terms of what you can get on a per dollar basis compared to what you might get in Europe or the United States. So that's attractive. We do have a good regulatory environment. In terms of how we can promote more sort of innovation, I think at the moment the government does take a reasonably hands-off approach, particularly in this area, it's taken a completely hands-off approach particularly in this area it's taken a completely hands-off approach

Starting point is 00:30:05 there's so by comparison and where we risk falling behind by comparison australia they created a 15 million dollar fund specifically for these sort of breakthrough mental health therapeutics to kind of prime the pump because you do need a certain amount of capacity you need a certain amount of infrastructure you need people so they've set that up as a pump priming exercise really to sort of provide all the capability they need so we haven't seen any signs of that yet from government that there would actually be sort of a more dedicated funding pathway now we are able to get funding but we have to go into the general pot of funding. So we have to compete with all the cancer researchers and the heart researchers, which does mean that when we do stuff and get funds, that our work has to be of very high quality because we're competing with our peers that are doing very high quality stuff. So we know when we get funded that what we're doing is rigorous.

Starting point is 00:31:01 Yeah. So good news is there are regulatory frameworks and federal funding for this type of work. Bad news, you don't have something like the NIMH, I think it's the National Institute on Mental Health in the United States, which might give grants specifically to this type of work. You have to compete against every researcher in any given medical field who is seeking funding. Yeah yeah that's right and yeah and there's actually some there's actually some data on that and actually what we've seen and not just psychedelics just mental health in general has been underfunded in new zealand for

Starting point is 00:31:35 very mental health research let alone treatment services mental health research has been underfunded in new zealand relative to the burden of disease that we see in the country so there are some parts things like neurology has been relatively speaking overfunded and we've spent a huge amount of research dollars on things like neurology and cancer and heart they've actually relative to the burden of disease they've done very well but actually mental health relative to the burden of disease we're seeing the population this can be quantified using and disability adjusted life years and you can look at research income relative to the disability adjusted life years and mental health has not been given the funding needs so there's an argument that New Zealand does need to carve

Starting point is 00:32:19 out specific not psychedelics but mental health research to make sure that we're getting that research done to serve the disability that we're seeing in the population and the health needs. Do you have something equivalent in New Zealand to breakthrough therapy designation? And I ask because the FDA here in the US has granted both psilocybin and MDMA-assisted psychotherapy, breakthrough therapy designation for depression, different types of depression, and PTSD, post-traumatic stress disorder, respectively. Do you see ways that the New Zealand government could foster innovation and more experimentation with some type of designation like that. Or, for instance, I'm sitting here in the state of Texas in the United States, which, for those who don't know,

Starting point is 00:33:11 is generally thought to be a very conservative place. But nonetheless, there was legislation recently passed both by the Republican, so let's just call it conservative, and liberal parties to get state funding set aside for psychedelic research related to veterans for instance and that was bipartisan and that will be coming online soon do you see any particular tools or approaches that new zealand might use to further foster what is i think what already is pretty vibrant ecosystem but it could certainly do quite a bit more what are your thoughts i think the latter would be the way to go so i think in terms of things like breakthrough designation we don't have we in new zealand sit at the end of the

Starting point is 00:33:56 pipeline for when treatments come because the way our treatments come is you know an international pharmaceutical company will apply for a registration here and they'll use all the data basically they've submitted to the fda so you know once i've got fda or ema approval then they might come here for approval after a few years and they bothered to put the marketing application together so we're kind of at the back end of that kind of process here and that's why we have in new zealand sadly a relatively weak pharmacopoeia where a lot of drugs that are available in the us or europe aren't available here because they're just not marketed here because we're a small market so i don't see that the that first approach work but the second approach could certainly work where you know the government sets aside and just probably

Starting point is 00:34:40 wouldn't be through legislation would direct one of its funding bodies to sort of, you know, to say, and it does this for other areas of research. It says, okay, let's fund this. Let's fund this. Things like growing up in New Zealand. So New Zealand has a really good history of funding longitudinal research. So there's the Dunedin study and the Christchurch study. And now growing up in New Zealand,

Starting point is 00:35:03 we've got really strong longitudinal studies that have been going on for like 40, 50 years that have been centrally funded. That would be a mechanism that is simply not possible in some larger places like the United States. And on some level, similar to the way that large global brands in some cases, even though you might be last in line or at the back of the line for certain types of, say, global drugs that are available elsewhere, you also have companies like, I want to say, Adidas and Nike and so on, who will actually do pilot studies and launches in New Zealand, because you have sort of all of the ingredients for English-speaking, first-world country with

Starting point is 00:36:04 incredible research faculties. And I mean, in this particular application, they're looking at commercial interest. But you can pilot and run experiments on a small or longitudinal basis that you can then apply elsewhere, which I think is incredible. So it's a huge gift that New Zealand

Starting point is 00:36:19 also has to offer the world, in a sense. Who are other scientific inspirations inside of New Zealand? Are there other scientists who you think are doing particularly interesting work, could be limited to psychedelics or adjacent compounds, or could be applied really anywhere else? Yeah. Well, New Zealand has a rich biomedical tradition. So I work in a general medical faculty. So the people sitting next to me are doing, you know, cancer research or, you know. So we have a really amazing people doing work in a place in Auckland called the Liggins Institute where they're doing work on preterm babies and they do really amazing interventional work there.

Starting point is 00:37:03 There's also really strong stroke research happening in New Zealand looking at how stroke recovery research is doing really well in New Zealand. And down in Otago, I really like the group down there that are doing in the more psychedelic space, they're doing, Paul Glue's been doing a huge amount of work with ketamine and in various ketamine analogues and different ketamine formulations that they've been working on. And so there's quite a rich group of research happening down at Otago as well. So I guess it's mostly centered around where the two medical schools are located in New Zealand,

Starting point is 00:37:37 where things are happening in the biomedical realm. What do you find interesting? Are there any particular ketamine analogs that you find interesting? And maybe you could just define what that means for a minute. And I also want to just to refer to something you mentioned earlier. You were talking about the metabolites of ketamine being bioactive or psychoactive themselves. Just for those who have a general interest in psychedelics, this is true for a lot of compounds. I mean, it's true for ibogaine and norebogaine and so on, which certainly makes them more interesting to to study but what is a ketamine analog and are there any analogs or approaches to analogs that you find particularly interesting maybe it's not an analog one of the things is

Starting point is 00:38:15 they've been i've been looking at like slow release formulations as as one way to go right to see if they and this comes back to that thorny issue about with ketamine like how important is actually having the psychedelic experience but if maybe if you could slow down the absorption of ketamine so it's not such a hit but came in slower so there's really interesting work happening with slow release formulations is a new zealand company who have been looking at that that is douglas pharmaceuticals have been looking at this kind of slow-release ketamine that's quite interesting. And then there's different companies overseas as well looking at,

Starting point is 00:38:51 and I described that left and right formation, they've been stripping ketamine to its R and S formulation. Now Janssen, as you'll be aware, they took the S part of ketamine and put that in a nasal spray so that they could... Bravado. Yes, bravado. And this is essentially a marketing exercise right like there's no it doesn't seem that it doesn't it has any more efficacy than normal kidney but it allowed them to achieve a patent on it what is the price differential i think it's something like one to five dollars generic like several

Starting point is 00:39:21 hundred dollars yeah usd something like that in new zealand there's be even bigger the differential because in new zealand racemic ketamine is uh pharmac subsidized so we can get a vial of ketamine for like twenty dollars or something but of course this bravado is like five or six thousand dollars so it's just the differences are insane. But, you know, for a clinician who may not be comfortable with prescribing ketamine off-label, because ketamine is not indicated for depression, it's an off-label treatment. And because it's a controlled substance, people, you know, there are clinicians that get, you know, antsy about that. And fair enough. But that ketamine, S-ketamine, is allowed to be prescribed on label that may make

Starting point is 00:40:07 things easier the problem with ketamine the only reason ketamine is not probably is because there's because it's a generic compound i guess this is a sort of background on how medicines get approved is you need a company to sponsor the research that goes in new zealand to go to medsafe and say look here are all our data ket Ketamine should be indicated for depression. But no company is going to do that for ketamine because it's just too expensive. And basically any generic competitor can just come and make more ketamine and sell it instead. So there's no return on investment to be had there. With intellectual property. Let's talk for a second, if you wouldn't mind expanding

Starting point is 00:40:41 on Paul Glue and his work a bit because I think some of it may give indications for other approaches that can be taken by researchers to do this type of work. Would you mind just elaborating a bit on what type of work he's doing? Yeah, so he's been looking at, he's been doing a slow release work. The other thing he's been looking at is other internalizing disorders. So he's done a lot of work looking at ketamine and anxiety disorder so and he's starting to build up quite a good evidence base that ketamine might not just have efficacy in depression but in a range of sort of ruminant internalizing disorders so i think he's done anxiety and social anxiety so ketamine is seems to have therapeutic effects beyond just the category of depression these are all kind of there's less

Starting point is 00:41:34 data on these at the moment so there's you would be even more reluctant to prescribe off-label for those things where there's a small evidence base but there is an emerging evidence space that other things and paul's definitely been contributing to that and i wanted to also for people who may not have familiarity with the odd medley of indications that psychedelics can be used for first of all i would recommend to those who haven't read it how to change your mind by michael pollan gives a pretty good overview. Some of it would be contested, like the importance of the default mode network and the downregulation of such in some of these experiences. But it would appear, and certainly I think a lot of data would support this, but the case studies themselves also would, that the, let's just say, DSM described in our parlance over here, at least, I'm not sure if you guys have an equivalent of a DSM, but for insurance reimbursement purposes, you need

Starting point is 00:42:33 an indication and a code, right? So you could have anorexia nervosa, you could have obsessive compulsive disorder, whatever the latest rephrase of that is, alcohol use disorder, right? Otherwise known as alcoholism, et cetera, et cetera. And what is plausibly the case is that these conditions actually share a lot of common DNA, so to speak, because there are certainly studies being run right now. And this is not to say that psychedelics are a panacea at all. That's not the point I'm making, but that from opiate use disorder to anorexia nervosa to OCD to chronic anxiety, there may be shared characteristics such as a rigidity in thought looping or patterning that are interrupted by these tools, which then provide a window of plasticity within which you can do very, very interesting things, which then begs the question that we were discussing a little earlier of how much the therapeutic wrapper impacts the clinical outcomes. So if you're heating up the clay, so to speak, and adding some moisture by using these compounds, who is actually molding? Is it the patient? Is it the therapist? Is it

Starting point is 00:43:44 the combination of the two? Is it the experience itself that's just bathing your neurons in various chemicals that produce dendrite growth? Part of why this whole field is so exciting to me is because there's still so many open questions, the answers to which have just supremely, potentially important ramifications. Are there any particular studies that you would like to do or see done in the near future in the next few years uh there's so you know there's endless possibilities you know like we're only at the really beginning of what we're doing right we've only been doing this stuff for like a couple of years and essentially all the stuff everything that's been done so far is essentially just elaborate pilot studies right we're just beginning to learn

Starting point is 00:44:28 and you know that's come from 50 years of prohibition where we haven't been able to do this work so you know things were looking and people will notice this might know this history that in 1960s when this research started slowing down early 1960s you know there was promising signals but everything just stopped for like almost 50 years and so we're only just you know a couple of years into like learning how to do these kind of studies again so that means that we've got a lot to learn and it's going to take a while before we figure this stuff out because studies take a long time to do and the other thing is these are really complicated interventions you know when you put them into a clinical trial and you try to work out what the hell is going on you know because

Starting point is 00:45:11 you alluded the first problem we have is diagnosis right we unlike for mental health the really thing to be aware of is unlike cardiology or cancer right we can't just like stick someone get an echocardiogram done and realize they've got some kind of thing going wrong with their heart some regurgitation or valve whatever it is or we can't measure a tumor size and no idea this is it so the physician is based entirely basically putting aside some organic issues the diagnosis is basically just subjective reports of symptoms and the diagnostic categories are completely woolly and we don't understand the biology of what's going on in terms of the diagnosis and then we have the problem that we give this intervention that we have a only a partial knowledge of what it's actually doing

Starting point is 00:45:53 in the body and then actually how we actually measure the clinical response is also kind of woolly because we have to use these kind of subjective scales you know like how are you feeling i'm feeling better okay you're feeling better so and we don't you know scales you know like how are you feeling i'm feeling better okay you're feeling better so and we don't you know which you know which if you're measuring like you know tumor size in a petri dish you know that's uh or tumor growth so we have a long way to go before to harden up the science but to answer your question more specifically the interventions themselves are really complicated we have this strong drug intervention with these therapeutic wraparounds and we have to start to systematically deconstruct what's going on there and start to

Starting point is 00:46:31 manipulate some of those factors as variables so like how much wraparound therapy do you need the question that's never really been asked is well what type of therapy do you provide or is all therapy the same or is it just actually like talking to somebody what is the actual requirements there to get because you will have no shortage of case reports like you see the people that just took cytosibine by themselves and said oh yeah i started feeling better and with no like thing not i'm not saying you should do anyone should do that by the way but just uh people report that of course at the same time people report taking cytosibine having a terrible experience and with terrible psychological shock involved afterwards.

Starting point is 00:47:08 So we do have to start to deconstruct what's actually going on in the intervention. So these are long, complicated experiments that require a lot of people, a lot of manpower, and each intervention is really complicated. So each data point is like gold dust to collect. Yeah, absolutely. So I want to add just a little bit of commentary for people who don't have the history. So you mentioned the prohibition, meaning the banning of common use of these substances for 50 plus years. And I would say, at least when we look at the case in the United States, that it was mostly, if not entirely, for political reasons as opposed to scientific reasons. And one can really learn quite a lot about the history, including Nixon and other

Starting point is 00:47:53 colorful characters like Leary and so on and so forth. But the punishment didn't really fit the crime in the sense, and that's my perspective, that if you look at the, say, LD50, so the dose at which 50% of a given subset of the population would be expected to die of overdose for these compounds, you have incredibly high, if not unknown, ceilings for a lot of them, right? I mean, they're physiologically very innocuous compared to even something like acetaminophen, for instance, where at least in the US, I don't know about New Zealand, but the rate of ER admission, emergency room admissions for acetaminophen is through the roof. It's got to be top 10. That is not to say that there are not significant psychological

Starting point is 00:48:39 implications, particularly for those who are generally going to be excluded by study criteria like those with family history of schizophrenia. And we're going to jump into Q&A in about five minutes. But what I would like to just make note of really quickly is that I feel the LSD microdosing study that you just finished gathering data for is a really important first of its kind. And please poke holes in this if I'm getting any of it wrong for a number of different reasons, but I'd like to highlight one of them. And one of them is placebo control in psychedelic studies or studies involving psychedelics where it's incredibly difficult to have placebo controls at larger doses with something like psilocybin or LSD because it is tremendously obvious to anyone who has taken it that they've taken it. And if

Starting point is 00:49:36 they haven't taken it, it's very clear that they have not taken it. And there's going to be expectancy effects. And generally people are going to come in knowing on some level what psychedelics are or believing that they do and having done some reading and so on, right? So you have placebo effects. We won't even get into nocebo effects, which people should read up on because that's also something worth looking at. But in the case of microdosing, it seems like you really can begin to apply placebo controls and just for people listening could you describe how you thought about that and whether you decided on passive or active placebo for this study we went with an inactive placebo just because because no one ever done lsd microdosing before we wanted a

Starting point is 00:50:21 rent for in the community we wanted an inactive control so that when we looked at safety and like physiological measures of safety we had a really we've not actually done anything to these people we haven't given them any drug this is just pure so we had a very pure safety group to look at and in terms of analysts whether people are able to detect the effects, some are, some aren't. So we are around the threshold. This was at around 10 micrograms? Yes, about 10 micrograms in male volunteers. So there's quite a heterogeneity though, actually.

Starting point is 00:50:56 We saw that some participants were particularly sensitive to it and we had to reduce doses for some participants and some hardly noticed. So there's quite a variability in people's response. And that's interesting in and of itself. It suggests to me that we're probably, when we move on to the next phase and actually want to look at a clinical population and run like a, for example, a depression trial, we may need to start looking at lightly active placebos because we're now interested in the clinical outcome, not just sort of like, you do it what do people experience if we're wanting to kind of try to

Starting point is 00:51:30 fool people a bit better then probably some kind of light placebo the little bit of i wouldn't say deception but just ambiguity in in the information that we provide to participants might be enough to get us over the top in terms of blinding the study successfully unlike psychedelic studies which aren't blinded at all and this is a real methodological problem that the field has to try to conquer in some way and we're working on it i just want to jump in for a second so i would say also that the fact that placebo controls are so difficult is i don't want to say a feature and not a bug, because it does present, just from the standpoint of rigor and publication, a whole lot of challenges. But the fact that this

Starting point is 00:52:12 effectively entire class of drugs has so much trouble with placebo controls is very interesting in and of itself. I've written a whole mess of paper on this topic. Yeah, I mean, it's fascinating that it's so hard do you have any you don't have to give away your secrets but anything on the short list for potential active placebos that you would use in such a case niacin niacin is not a great option that's um yeah a vitamin so actually niacin was used in the 1960s and it's been determined even in 1960 that niacin is a poor control for societal science. But people used to use it for some reason, and I'm not sure why.

Starting point is 00:52:49 Skin flushing? Skin flushing. I mean, maybe some type of subjective experience so that people think it's doing something. Yeah. That's why it's added to a lot of dietary supplements as well. We're getting into the weeds here. But what I would say is actually what the compound is isn't as important as what the participant thinks it's going it's their belief about what they're receiving that's the important thing because blinding in clinical trials is

Starting point is 00:53:12 really important to prevent expectancy instances because if a person goes into a clinical trial thinking they're going to get cytosine and they do get cytosine and if they think it might make them better they work out that they've had it, and they go, and maybe that over-accentuates their clinical response, which we would call a compound. So that's potentially a problem. But what's important is it's not the compound itself. It's what the participant believes that they've had. And so it's not as much potentially around what the actual active placebo is,

Starting point is 00:53:42 but what you tell the participant about the active placebo and the information that you provide them because you're not trying to manipulate your physiology you're trying to manipulate their beliefs about what they're having so i think these are subtle things that we need to really think about in our experimental science you know this is why i really enjoy doing research in this area because these are fascinating problems and it's a really like fascinating area to try and work out these scientific problems i reckon we can do it i'm not you know give me another 10 or 15 years and i might give up but right now i think you know we can totally crack it if we put our brains to it as a scientific discipline it's a really exciting time to be for me certainly observing watching

Starting point is 00:54:23 to the extent that i can, supporting the ecosystem and a really exciting time for people like you to be doing the research. It's really kind of a blue sky opportunity. And the payoffs, as I think we established very early on in the conversation, are potentially huge if we look at the trend lines of various diagnoses and illnesses and the costs both on a personal level familial level and societal level so let's jump to q a at this point if that makes sense and i'll hop over to michelle to see if you have any any questions for us i think we have quite a we do actually yeah we've got heaps of questions here what i'm going to do those rushes i'm going to start it off the first question is going to be um an ask so you can put your ask

Starting point is 00:55:10 out there to the audience because someone has said is how can we speed this up what can be done to make the benefits of this coming forward a lot quicker i think you know we've got plenty of awareness around mental health generally in New Zealand. I think we haven't seen government or any signals from funders. And I think that's where we haven't really seen any kind of movement. So that's where pressure can potentially be applied. There's not much in the way of like foundational advocacy for this kind of stuff in New Zealand. There's not a huge amount of push to like make government do anything about it so I think it's probably where things can be accelerated is by trying to get government to

Starting point is 00:55:52 start paying attention and for them to take the attitude that we can be at the forefront in New Zealand we can be at the forefront of this and we already are like we're way batting above our in terms of like us being this tiny little country that's back into the world, we are batting way above our weight. And we could get onto the front of these things being introduced if they are appropriate to be introduced. But a bit more push from government would potentially accelerate that and, you know, and really establish us as leaders in the field. Suresh, just to piggyback on that, for those in the audience who might want to support in a philanthropic capacity, certainly I've been interested in the space for a long time. It's deeply affected my life and the lives of many I know. And the science is important at the end of the day to push the ball forward.

Starting point is 00:56:40 So whether with you at University of Auckland or at University of Otago, there are some interesting things happening in New Zealand. Are there any recommendations you might have for people who would like to consider supporting philanthropically? In terms of philanthropics, the best thing is to get in touch with either myself or Paul. We're not top secret. There's plenty of mechanisms, you know, but what I would say is that certainly philanthropic money is really important. And, you know, the funding that you provided us was like essentially seed money that we could

Starting point is 00:57:15 use to then get the feasibility you need to then get a government grant to do the research, to establish, you know, to establish that, you know, we can run this trial, we can do it, because when you have nothing, you just can't get started, and you apply for a grant, and then the grant people say, well, you can't do this, you can't do that. You haven't shown us that you can do this, that, and the next thing, and then they turn you grant away, right?

Starting point is 00:57:37 So philanthropic money can also be seen as a seed, not just as you're funding the whole thing, but as a seed for future investment. Definitely. Yeah, that's so important. I just want to say it again, that not only do you sort of punch above your weight class in the research that I've seen so far, but the amount of money that you commit from a philanthropic standpoint can also have much more impact and sort of amplifying effect as a signal,

Starting point is 00:58:07 right? Because then it allows researchers to fundraise that much more easily from other sources. So the money is important, of course, but the signal is also really important. Yeah. Michelle, do you have more? I'm sure you do. I do. Yeah. So this one, what are the risks of micro dosing? So if it's patients that are diagnosed with bipolar or schizophrenia, so they're not looking for medical advice, but just any general commentary about how safe it is and is it dangerous? We have a data set that we have collected, and it's really the first data set that's been collected.

Starting point is 00:58:41 And so far we haven't seen any negative safety signs, but it's a very small data set in a been collected and so far we haven't seen any negative safety things but it's a very small data set in a very healthy population so i think potentially there are indications such as schizophrenia or bipolar where it's possibly not a good idea we know that high doses of psychedelic can trigger psychosis occasionally and cause psychological distress so i think doing this kind of on your own, particularly if you're trying to treat severe mental health disorder, could be, you know, you're heading into the unknown, I guess,

Starting point is 00:59:12 is that kind of thing. So potentially the biggest risks probably apply actually in the application area of mental health and particularly with particular comorbid disorders. So I think it's important to treat lightly, carefully. I'll add something to that really quickly, which is there are also questions of provenance and legitimacy. So there are some synthetic, well, I mean a lot of synthetic, thousands of synthetic psychedelic compounds

Starting point is 00:59:42 that are sometimes confused with or sold as LSD that can launch you into some very, at best, uncomfortable and at worst, very dangerous circumstances where you could be in an experience for 24, 48 hours. And on top of that, it's critical, I would say, to consider legal ramifications. There are legal risks if you're dealing with Schedule 1 compounds. And secondly, just because I've seen this quite a few times, we're dealing with, in the case of LSD, for instance, micrograms. Okay, so to explain what that means, Suresh, please correct me if I'm getting this wrong, but you've got, let's just say milligrams, which are a thousandth of a gram. Am I right so far? Yep. Milligrams is thousandths, yep. And microgram is a millionth of a gram? Am I right so far? Yep. Milligrams is thousands. Yep. And microgram is a millionth

Starting point is 01:00:25 of a gram. If I'm getting that right, or is that a... Yep. So if you're dealing with millionths of a gram, even the Albert Hoffman, who's the father of LSD, I mean, went on his first famous huge trip while bicycle riding because he got it on his fingers. And so you're dealing with such incredibly small quantities that the ability to misdose or to absorb it through the skin can lead to something that is most certainly not a microdosing experience. And if you're doing it without supervision and you happen to get in a car expecting it to be a microdose, for instance, that could be very, very tragic very tragic indeed so i just not to be the stern dad about it all but felt the need to know these are absolutely true that the non-physiological risks

Starting point is 01:01:10 are probably far greater than the physiological risks and even though law enforcement deals with things like schedule c class just like cannabis relatively lightly these days actually they're not so forgiving with schedule one substances so that is important to bear in mind and i forget often yeah that you're absolutely right again about the purity of supply and dosing i mean i forget this because we have i like to say the best in town in my lab but uh joking aside yeah like illicitly in pain dallas d or psilocybin could be cut with other things and it's very hard to know but we do have drug tracking services in new zealand that can provide that kind of information though and i'll just actually that's a really good point to just add one thing to which is in the us

Starting point is 01:01:57 there are services like dance safe and others that will provide drug testing kits, which is not to say I recommend illicit use of drugs, but the reality is that people are going to use what they believe certain compounds to be. And there are tools also for testing so that you try to mitigate some of the risk. There's a few people in the audience that Suresh, that are doing studies themselves in, say, Toronto and the US. And one of them's about, the question is about open science. So what are your thoughts about open science replication crisis? And will you be sharing your data or will you be keeping it private? So it depends on the study and it depends what you're trying to do. So open science is admirable and it's good, but it's not always possible depending on, you know, who's...

Starting point is 01:02:49 Suresh, could you define that just for people listening who are not familiar? So open science is essentially sort of releasing your data to the world when you have it. And it goes with another thing, which is called pre-registration, which is basically publishing your clinical trial protocols before you actually do the study. So my lab group has definitely started doing publishing clinical trial protocols before we do it. And we've done open science things. So I'm in favor of it where you can do it. But there will be times where, for example, you're doing industry-funded work where that's not possible because that's intellectual property of said company. So, you know, I'm generally in favor of it, but I think we do end up with the open science of having a lot of data in the world, but no interpretive framework.

Starting point is 01:03:37 We can all do thousands of experiments and release terabytes and petabytes of data into the world with potentially bad data which you know hasn't been collected well and just adds confusing signals to the noise so i don't know that it's a panacea for actually a deep theoretical understanding of what's going on now we're going to shift to a training question so anticipating legislation change and increasing access to psychedelic assisted psychotherapy how do we we prepare the workforce to be able to provide this? So what training pathways exist already for psychologists, clinical social workers to upskill and become involved? This is a big controversy. Yeah, I can take a stab.

Starting point is 01:04:22 There are a number of concurrent experiments being run. So in the United States, a lot of eyes are on Oregon. And within the state of Oregon, there will be a lot of action in the next six to 12 months looking at developing effectively a parallel structure for registering and supervising administration of psilocybin for psilocybin-assisted therapies. So that is a very live question for the state of Oregon. So I'd encourage people to watch that very closely on a political, medical level. Also, my foundation, the SciSafe Foundation, S-A-I-S-E-I Foundation.org, for people who are interested, has also participated in funding a joint program which is focused on psychiatry. And this is at Hopkins, NYU, Yale, and possibly a few other institutions. I apologize that I'm forgetting where. And I'm going to get some of the details wrong here, but in effect, a certification program is being created that can be applied into this funnel, which already exists, and that is the

Starting point is 01:05:36 sort of psychiatry MD training. And people can elect to then add this type of training and qualification to their pre-existing track, if that makes sense. Which is not to say that this should be limited to being administered by MDs or MD-PhDs. I don't think that will come close to addressing the demand and need, more importantly, the need. Forgetting about healthy normals, which is a whole separate conversation, let's just talk about people with actual sort of clinical diagnoses. I do expect that there will be similar experimentation with nursing schools. I hope there will be also experimentation within accredited social work programs for allowing social workers. But the fact of the matter, I think, is that this is one of the most challenging issues that will be faced in the

Starting point is 01:06:33 next five years, next five to 10 years, because not only is it necessary to develop a pipeline for training, but the training is extremely controversial because there are people who feel like the sacred is being secularized. And therefore, if there aren't enough legally trained, let's just say therapists or facilitators to administer these drugs, that there will be a lot of gray market and black market charlatans who are going to pop up to provide services to those in need, which will cause its own large host of problems. So it's going to be a challenging road ahead, but there are experiments being done and people can see some of them at the foundation website. And now, is there a way, this is for New Zealanders,

Starting point is 01:07:23 is there a way that we can access psychedelic therapy microdosing now or how far off is this? Certainly not now. You know, ketamine is potentially available through, there are a couple of clinics around the country offering ketamine services for those with depression. But psychedelics and microdosing are still, microdosing particularly has got a long way to go.

Starting point is 01:07:45 It's going to be two to five years. Probably it's on a three to five-year track to progress that depending on how the results look. But I think the first thing that's going to come down the pipeline, if anything, will be the MDMA-assisted therapy because that's the most advanced psychotherapy for PTSD. So it's the most advanced. That's in phase three clinical trials in the U.S. We have a group of MAPS trained therapists actually in New Zealand that could actually deliver that therapy if the data was seen to be okay and our regulator were to improve it,

Starting point is 01:08:14 which would invariably happen after FDA if that were to be approved there. So we have that, and that might be only a couple of years away. that would be the first kind of cab off the rank i think yeah and i'll just add to that that if i could make an unrealistic request of these psychedelic communities per se although with the amount of infighting that goes on it's sometimes hard to view it that way that it's really important to focus on ketamine and MDMA and getting those two right. And I think it's very risky. It's fraught with incredible risk to try to boil the ocean at once with adding in NNDMT, 5-MeO-DMT, ayahuasca, and every other compound you can imagine to try to get them all dealt with in a responsible way simultaneously. Now, I don't think anyone's actually going to follow that advice, but I have

Starting point is 01:09:12 a pretty broad spectrum of interaction with these things. And I would just say, not as an expert by any stretch, but just someone looking at the risk-benefit profiles of these things, I think a focus on ketamine and MDMA-assisted psychotherapy would go a very, very long way. And psilocybin certainly is in the works, and I think it has tremendous potential for a number of different conditions, whether that be major depressive disorder, treatment-resistant depression, alcohol use disorder, and I think many others. I mean, those are the three that are kind of furthest along. But each of these compounds has its own complexities and difficulties. And I think slow is smooth and smooth is fast with this stuff. We've just come through half a century of prohibition. We don't need to figure it all out

Starting point is 01:10:02 in the next six months. Yeah, I totally agree with that. And you know why? Because there's this massive unmet need, right, to get things out to address these things. And it's heartbreaking, impressing problem. But at the same time, you have to think, well, if these things really are effective, the last thing you want to do is like rush it and get it wrong. And then there'll be safety issues that come up or like badly regulated things and you spend all these horror stories start emerging into the popular consciousness and then we put ourselves 50 years back in the hold again so i think that's what we really need to avoid with this so treating really carefully but hopefully that won't happen because we do have a stronger regulatory environment than there was

Starting point is 01:10:39 in the 1960s so hopefully we can avoid that kind of issue. But I think it requires us back to where we were, which is not an impossibility. People might laugh about that because they feel like this isn't the 60s and the generational differences no longer exist and there's bipartisan support, etc. But politicians have certain sets of incentives. And I would really say that it is a non-zero percent chance that things get sent back to prohibition if, say, one senator's child dies of cavalier administration of 5-MeO-DMT in fill-in-the-blank location, right? Not to throw 5-MAO DMT under the bus. I think it's very interesting, but high degree of thrashing,

Starting point is 01:11:48 high percentage of thrashing within the subset of people who use it. So, you know, bad things can happen. And bad things will happen also. And I think the people involved, which is why the Adesai Sai Foundation is also involved with the Harvard Poplar Project, which is a law and policy project focused on

Starting point is 01:12:07 psychedelics, because there are going to be suicides that are attributed to psychedelics. There are going to be deaths attributed to psychedelics via accidents of various types. And this would be true with any drug used at scale. It's not specific to psychedelics. This is certainly true for SSRIs. It's true for just about every drug you can imagine, sleep medications. So it's just the law of big numbers in a sense. And I do think the community needs to be prepared for that eventuality and how to deal with it because it's going to take the culture quite a bit to metabolize that. And I do think we're going to see a, not backlash, but sort of a pendulum swing into negative coverage because the positive

Starting point is 01:12:53 coverage has just lasted too long. And I think if we want to be strategic about it, we accept and expect that on some level because inevitable with anything that is purported to have this much promise and certainly anything that has this much coverage. Michelle, what else do we have? Is your research expanding a little bit further and going into addiction, which is more dangerous and obviously deadly than depression and anxiety? Are you doing any research in that area? We're starting to talk about it. We're starting to talk about a project that will be a more Māori-based intervention that we run by Māori researchers. We're just in the very beginning stages of starting to sketch some ideas together about

Starting point is 01:13:39 how that might be done for that population in methamphetamine use or alcohol use. It's very early stages for us but definitely that's something we're not leading that we're just providing support for in terms of intellectual support and learning how to navigate the regulatory system on this stuff so that could be really interesting and there are elements of for example spirituality that have some synergy with Maori culture that would be interesting for those researchers to explore. So just on that a little bit then, what about, have you included women in the studies or has it been mostly males?

Starting point is 01:14:13 We had this one LSD microdosing study where it was males only because we, I won't say it was pitched to warfare trying to get this trial approved, but it was. And so we just had to like take risks down as much as we could in certain places so the idea of the problem of potential pregnancy was something that we just for this stage we just wanted to avoid that as an issue and there was also menstrual cycle confounding that that we wanted to avoid for the first trial we think we've now got the steps that we need to expand for their first trial we think we've now got the steps that we need to expand in the future trials but and i've taken a lot of flack for this and

Starting point is 01:14:51 and i say well my response is well you try and like get this study approved of mine because i spent years aging trying to get this thing approved um so you know we did the best that we can while we could and we always hope to do better but certainly um all our other studies have included females and the next studies will now that we've got over that first hurdle i will also say that there are studies that have very mixed gender ratios if you look at some of the end-of-life depression end- of life, anxiety studies, say involving psilocybin, you see a much more sort of heterogeneous group. So definitely easier to do when you have a little bit of escape velocity after the first one or two pilots. Yeah, there's actually some interesting

Starting point is 01:15:36 anecdotal reports of in terms of microdosing for premenstrual dysphoric disorder. People have been using it for that and that it might affect actual menstrual cycles and menstrual cycle timing so that's actually quite an interesting there's potentially interesting separate studies to be done there that we have considered and will consider in the future so if someone's wanting to sort of get into this type of research what education do you recommend for anyone wanting to help assist oh so i get this all the time undergraduate students i'd say you know the best option is just go be a medical doctor because then you can uh you learn but uh a university degree i'm just promoting the

Starting point is 01:16:17 university of walking because it's my employer who pays the bills but uh you know for young people getting a science degree or a health sciences degree, medicine, psychology, those are, I think that's where the forefront of things will be and will be in either, in New Zealand, it's going to be basically psychiatrists and psychologists that are going to run this. I suspect that that will be where things fall. So if you want to get into being able to prescribe

Starting point is 01:16:47 or be involved in this kind of therapy, I think psychology and psychiatry and general medicine are the places to study. So all the things to do. And then there's also scientific degrees you can do, like medical sciences. Strong background in mathematics is always good. I'm just going to go into one about corporate.

Starting point is 01:17:05 So have you looked into the clinical trials of the larger public companies so there's mind med compass 80 ai and numerous and do you feel there any red flags and how these are current corporations are going about improving their respective drugs so that's like lsd m. Yes, and I should say as a disclosure that I consult for some of these companies as a disclosure and actually collaborating with one of them. So my observations is that the people that these companies are employing seem to be really experienced pharmaceutical people who have a lot of industry experience in pharmaceuticals and they seem to do quite a rigorous job. There's obviously going to be tensions there for those companies in terms of wanting to get things through reasonably speedily because they've only got so much capital. The pathway is long and expensive and the intellectual property

Starting point is 01:18:03 that they need to gain because of you know these are generic medicines is going to be an issue but there's red flags within every areas of pharmaceutical development are there any more red flags in this area than there are in other parts of the pharmaceutical industry probably no more no less you know i'm comfortable with the gray i'll hop in with just a few things so i would say on the on the clinical actual the study side i think pre-registration is very important but as you mentioned sresh that doesn't apply uniquely here but it does apply here so pre-registration publishing your protocol ahead of time so that you can't sort of torture the the data or or move

Starting point is 01:18:41 the goal posts and you know declare victory when in fact it was not a victory, I think is incredibly important. And then I recommend people take a look at, there's a journalist named Shayla Love who's done a fair amount of writing about the intellectual property battles that are ongoing in the space. And there certainly are, I believe, non-obvious innovations that should sometimes get patents for, which are obstructionist in nature and that actually gum up the works and cause problems in the ecosystem overall, especially if they use said patents to try to lock up manufacturing processes to dominate a given molecule that has existed for decades, if not millennia in some cases. So I do think the IP side of things is very important to keep an eye on. And an organization

Starting point is 01:19:52 that might be worth checking out is Freedom to Operate, which was created by Kerry Turnbull. And that is an area that will be increasingly active. Mason Marks and I Glenn Cohen, I period Glenn Cohen, C O H E N coauthored a paper on intellectual property and patents for those who are interested. That's out of Harvard law school. It's enough time for our questions. Actually team goes fast. All right.

Starting point is 01:20:19 Well, well, fantastic. Thank you so much, everybody. And thank you so much Suresh for, for making the time. I'm very excited to see what you do next. Cool. Thank you.

Starting point is 01:20:28 Good. Thanks, team. I'll just close us off with a karakia. It's been a great session today, and then hopefully this will set you on the rest of your way. Thank you. Thank you. Enjoy the rest of your evening or day. Hey guys, this is Tim again. Just one more thing before you take off. And that is Five Bullet Friday. Would you enjoy getting a short email from me every Friday that provides a little fun

Starting point is 01:21:07 before the weekend? Between one and a half and two million people subscribe to my free newsletter, my super short newsletter, called Five Bullet Friday. Easy to sign up, easy to cancel. It is basically a half page that I send out every Friday

Starting point is 01:21:21 to share the coolest things I've found or discovered or have started exploring over that week. It's kind of like my diary of cool things. It often includes articles I'm reading, books I'm reading, albums perhaps, gadgets, gizmos, all sorts of tech tricks and so on that get sent to me by my friends, including a lot of podcast guests. And these strange esoteric things end up in my field and then I test them and then I share them with you. So if that sounds fun, again, it's very short, a little tiny bite of goodness before you head off for the weekend, something to think about. If you'd like to try it out, just go to

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The Tim Ferriss Show - #619: Dr. Suresh Muthukumaraswamy — LSD Microdosing, Classical Psychedelics vs. Ketamine, Science and Speed in New Zealand, Placebo Options, and The Infinite Possibilities of Studying Mind-Altering Compounds

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