#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

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 Dr. Suresh Muthukumaraswamy https://profiles.auckland.ac.nz/sd-muthu completed his PhD in Psychology at the University of Auckland in 2005 after which he joined the newly established Cardiff University Brain Research Imaging Centre as a postdoctoral fellow. While at Cardiff, he started research work with psychedelics in 2011 in collaboration with 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 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. At the University of Auckland, he has conducted clinical trials in depressed patients involving ketamine, scopolamine, and transcranial magnetic stimulation. 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, with his work receiving 8000+ citations. This special episode of the podcast is a live recording from an event hosted by theEdmund Hillary Fellowship http://ehf.org/ (EHF). 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, 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: media, education, cleantech, venture capital, and mental health initiatives/research just to name a few. EHF and its fellows aim to make a meaningful impact in New Zealand/Aotearoa with projects that often have global applications. Please enjoy! * [03:44] Current mental health and addiction trend lines in New Zealand. [05:37] Compounds Suresh has researched. [07:13] Does scopolamine have potential as an antidepressant? [09:55] How ketamine differs from other psychedelics. [16:20] The durability of antidepressant effects. [21:45] How Suresh picks the focus of his research (example: LSD microdosing). [24:43] Why New Zealand is unique for fostering psychedelic innovation. [31:01] How could New Zealand improve the impact of scientific research? [35:13] Inspiring research currently underway in New Zealand. [37:40] Obstacles to getting ketamine labeled as an antidepressant. [40:39] Ketamine research by University of Otago’s Professor Paul Glue. [41:48] Future studies Suresh would like to see (and their challenges). [47:25] The difficulty of applying placebo controls to psychedelic research. [54:49] Getting the public to benefit from this research in a timely manner. [58:17] Risks of microdosing and relying on unregulated supplies. [1:02:21] Open science replication crises. [1:03:56] Training clinical personnel in new science as it becomes available. [1:07:20] Where can New Zealanders access psychedelic therapy now? [1:08:25] Avoiding another 50 years of psychedelic research darkness. [1:13:08] Is any of Suresh’s research focused on addiction recovery? [1:14:08] Why women haven’t been as widely included in these studies as men. [1:15:56] Where aspiring psychedelic researchers should focus their education. [1:17:02] Red flags in the private sector. [1:20:14] Parting thoughts. * For show notes and past guests on The Tim Ferriss Show http://tim.blog/podcast, please visit tim.blog/podcast https://tim.blog/podcast/?utm_source=podcast&utm_medium=podcast&utm_campaign=podcast-description. For deals from sponsors of The Tim Ferriss Show http://tim.blog/podcast, please visit tim.blog/podcast-sponsors http://tim.blog/podcast-sponsors Sign up for Tim’s email newsletter (5-Bullet Friday) at tim.blog/friday https://go.tim.blog/5-bullet-friday-1/. For transcripts of episodes, go to tim.blog/transcripts http://tim.blog/transcripts. Discover Tim’s books: tim.blog/books http://tim.blog/books. 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Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:01Tim Ferriss?

  At this altitude, I can run flat out for a half mile before my hands start shaking.

• 0:06Speaker 01

  Can I ask you a personal question?

• 0:08Speaker 02

  Now would be an appropriate time.

• 0:12Speaker 01

  I'm a cybernetic organism, living tissue over metal endoskeleton.

• 0:24Tim Ferriss?

  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 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, clean tech, venture capital, and mental health initiatives and research, as we will hear in just a few moments. And

• 1:06Tim Ferriss?

  that's just to name a few. EHF and its fellows aim to make a meaningful 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.

• 1:25Speaker 02

  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 Ferriss. He's an EHF fellow who's an early-stage technology investor and advisor. And Tim will be interviewing Dr. Sharish, an associate professor at Auckland University. And the topic today is on mental health and breakthrough therapeutics. There'll be plenty of time for Q and A with Tom and Suresh during the 90 minute session, but nearer the end. Over to you, Tom.

• 2:01Tim Ferriss?

  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 Mutukumara Swamy. I will here forward refer to him as Suresh. Suresh is an associate professor of psychopharmacology at the University 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 Centre as a postdoctoral fellow. While at Cardiff, he started research work with psychedelics and psychedelic compounds in 2011 in collaboration with two very well-known names, Professor David Nutt and Dr. Robin Carhart-Harris,

• 2:46Tim Ferriss?

  investigating the neuroimaging correlates of the psychedelic drug psilocybin and LSD. In 2014, Suresh received a prestigious Rutherford Discovery Fellowship and returned to the University of Auckland where he worked 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 are in understanding how therapies alter brain function and behaviour, 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,

• 3:28Tim Ferriss?

  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 micro doses of LSD on brain and cognitive function. Suresh has published 117 papers and his work has received more than 8,000 citations. Suresh.

• 3:46Tim Ferriss?

  Welcome to the session. Thanks for being here and taking the time.

• 3:48Speaker 03

  My pleasure, Tim. Nice to see you.

• 3:50Tim Ferriss?

  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.

• 4:13Speaker 03

  So New Zealand has pretty good data on this because every year, the Minister 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. So in terms of trend lines, so this is conducted every year. So in 2011, 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

• 4:56Speaker 03

  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 from the first sort of impact of 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. That just finished at the end of 2021. So that will definitely have impacted on people's mental wellbeing. So we'll expect that to go up. So it's not, it's not a good place to run. But so it's not just COVID. It's been trending up for a long time, and it's not getting any better.

• 5:38Tim Ferriss?

  And I would imagine, although I don't want to assume that the costs, and there are many different types of costs, 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 a 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.

• 6:22Speaker 03

  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 gabberergic drugs. So gabberergic drugs tend to be kind of sedative. So alcohol is a gabberergic drug, benzodiazepines, a lot of the anesthetics like propofol. So I've studied all those drugs at various times, various antiepileptic 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

• 7:07Speaker 03

  ones that probably I'm most well-known for in the public discourse, because they attract some interest, I suppose.

• 7:13Tim Ferriss?

  They catch the attention. So we're going to talk about the contrast between, say, ketamine 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?

• 7:49Tim Ferriss?

  This is a subject of interest for for research.

• 7:53Speaker 03

  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 a similar rapid antidepressant effects? 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 is 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

• 8:34Speaker 03

  different kind of receptor binding mechanism that we 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 glycopiranam, that's used a lot in surgery, that doesn't cross the blood brain

• 9:17Speaker 03

  barrier, but still is anti muscarinic, 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 describing most of the antidepressant response that we see to a placebo response. So lesson learned.

• 9:38Tim Ferriss?

  Yeah, that's fascinating. Yeah, scopolamine, I don't want to take us too off track, but has some very interesting effects on memory, or at least is thought to have some very interesting effects on producing amnesia.

• 9:49Speaker 03

  Yes, it does. Yeah.

• 9:51Tim Ferriss?

  While still having agency on some level. It's a fascinating compound. So let's jump to ketamine. Most people are 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 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 ketamine.

• 10:35Tim Ferriss?

  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 the rapid onset of some of the effects in certain subjects compared to, say, traditional or conventional SSRI's, 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.

• 11:15Speaker 03

  Maybe the easiest thing to start was with the classical psychedelics because it's relatively simple compared to ketamine. So LSD and psilocybin, 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 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. So it's a mini and complicated.

• 11:54Speaker 03

  So principally binds to antagonizes a receptor called the NMDA receptor, and that's a glutamate receptor. So glutamate is the most common 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 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. It also binds to opiate receptors and everyone

• 12:39Speaker 03

  will be familiar with opiates. And then there's other monoamine sites like that it interacts with serotonin, 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 also, most compounds exist in a left and right state. They're called recemic. So there's a left and a right state. And so there we 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

• 13:21Speaker 03

  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.

• 13:30Tim Ferriss?

  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 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?

• 13:53Speaker 03

  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, there's, there's both a clinical and a scientific interest there. And they're both really interesting study, which is why I've been studying ketamine for nine, 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

• 14:34Speaker 03

  a ketamine infusion and they'll get this really rapid remission and symptoms. And that would manifest itself in hours now. People will know ketamine as a street drug, right? And they would say, oh, well, maybe that's just because the person's high. You know, that they're experiencing this intoxication. So my response to that would be, well, actually, you know, if you then measure the person's depression symptoms at twenty four 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's about four hours for ketamine. So at the twenty four hour time point, there's really no ketamine left in the body at all.

• 15:14Speaker 03

  So ketamine's gone, they haven't been high for, you know, twenty, twenty, twenty two hours. So they're not high anymore. The ketamine's entirely left the body, but they're still not depressed. And then what that shows is that the ketamine has changed something in their brain. So this 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.

• 15:55Speaker 03

  They switch it in maybe four to six weeks or transcranial TMS, transcranial magnetic stimulation. That might take a month to work as well. But here we can switch it in a day for a scientist. That's really interesting because you can run it 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.

• 16:21Tim Ferriss?

  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, I can speak to one very cute example, 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 seek treatment because it can result in leaves of absence and basically penalties, professionally speaking. And ketamine.

• 17:03Tim Ferriss?

  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

• 17:43Tim Ferriss?

  if we're looking at, say, LSD, 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 Cristel at Yale, who's done a lot of work with ketamine. And Roland's perspective was that he thinks a lot of the durability of antidepressant effects, six months, 12 months of follow-up, let's just say, have a lot to do with a change in content, meaning that people are actually able not just to

• 18:28Tim Ferriss?

  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 fixing the machinery, so to speak, on some level. What are your perspectives?

• 18:51Speaker 03

  The background to this for people is that the antidepressant response that we see to a ketamine infusion, that will last, in our experiences, anywhere from a day or two to a couple of weeks to a month. Whereas the data for, like, psilocybin, that seems to indicate, yeah, like, 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 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?

• 19:36Speaker 03

  So and I think it's really important for people to understand when they think about, because you know, you just read these headlines, 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, you know, with a therapist and they've done hours of preparation for the experience. 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 psilocybin course. So it's not just the drug alone, it's psychedelics assisted psychotherapy. Now, whereas the model for ketamine that's mostly been used is basically, and what seems to be using your label is that people just go into a

• 20:16Speaker 03

  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, 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

• 21:00Speaker 03

  really, I'm not aware of any data that really has kind of tried to find 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.

• 21:13Tim Ferriss?

  Do you say that just because of the difficulties that can come up in navigating that experience?

• 21:18Speaker 03

  Yeah, because you know, these are, um, so something like psilocybin is very powerful in terms of psilocybin and DMT, I'll say these are 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 be not be ethical to strip it back to nothing, like it's done for ketamine.

• 21:45Tim Ferriss?

  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, in a very fertile nascent period of psychedelic research. 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

• 22:25Tim Ferriss?

  techniques that you have, FMRI and, and others that are now at hand, you can examine these, 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, the LSD microdosing study. Why did you choose to pursue that study?

• 22:59Speaker 03

  So I had returned to New Zealand in 2015, and having previously done classical psychedelics, I went, and I started my research group here. I thought, well, this, we'll start with ketamine because it's approved, it'll be easily, 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, new guy coming to town wanting to do LSD is probably going to fluffle a few 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,

• 23:37Speaker 03

  No one had really looked at microdosing in a RCT at that point and

• 23:42Tim Ferriss?

  It's a randomized control trial.

• 23:44Speaker 03

  Randomized control trial. And I guess, should we explain what microdosing is maybe first?

• 23:49Tim Ferriss?

  Why don't you explain what that is? And it also might segue into one of the design challenges, meaning placebo control psychedelics overall. So yes, please define microdosing.

• 24:02Speaker 03

  Yeah. So microdosing is when people take very low doses of psychedelics, about the 10th the dose of a big dose of a when people are going to be tripping. So, you know, people might trip on like, you know, 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 because we haven't studied it properly, but users report that they have improved mental wellbeing, concentration increases. So what they do is they take these microdoses, maybe every third day is the most common schedule. That's called, this was popularized by James Fadiman, who wrote a book in 2011. And it's really taken off since then, you

• 24:45Speaker 03

  know, like before 2011, not many people were doing it. 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, the size of the Reddit forum subscriptions just going up and up and up. So there's a huge amount of people out there microdosing 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,

• 25:27Speaker 03

  then you have to prescribe a class A substance, a Schedule I substance for people to take home. And most legal systems won't allow you to do that. 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.

• 25:43Tim Ferriss?

  I think it'd be, I think they, they might be a little grumpy about that.

• 25:45Speaker 03

  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, read the, reading the Misuse of Drugs Regulations from 1977 and the Misuse of Drugs Act that goes along with it. We kind of discovered this loophole, I don't know if you call it a loophole, where actually we are 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

• 26:26Speaker 03

  be done. And so we did it and we applied to them and got the appropriate approvals from ministry, various parts of the ministry to do it. And that allowed us to run the study that 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.

• 26:56Tim Ferriss?

  So let's 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?

• 27:05Speaker 03

  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? It's hours and hours. There are a lot more efficient ways to get doses of LSD.

• 27:42Tim Ferriss?

  Oh, for sure, for sure. Yeah, absolutely.

• 27:45Speaker 03

  And we tracked, we tracked 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.

• 27:55Tim Ferriss?

  And a part of the reason that I've been engaging with science in New Zealand is precisely for this reason. I mean, you have, on some levels, a very agile ecosystem compared to

• 28:11Tim Ferriss?

  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 New Zealand unique? What else could make New Zealand unique? And we can go from there. I would 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?

• 28:50Speaker 03

  We have a strong regulatory environment. So I'm not saying our regulatory environment's 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 these decisions. In a country of five million, there's only so many people who know or involved in these kind of decisions. So if you are sensible and polite and appropriate, you can ask questions and get things to move. So with small size, I think does come agility. And I know that there are certainly pharmaceutical

• 29:32Speaker 03

  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 reasonably hands-off approach, particularly in this area. It's taken a completely hands-off approach. So by comparison, and where we risk falling behind, by comparison, Australia, they created a $15 million fund specifically for these sort of breakthrough mental health therapeutics.

• 30:17Speaker 03

  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 workers are very high, has to be of very high quality, because we're competing with our peers that are, you know, doing very high quality stuff. So we know when we get funded that what we're doing is rigorous.

• 31:01Tim Ferriss?

  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.

• 31:25Speaker 03

  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 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 in the population, this can be quantified using

• 32:07Speaker 03

  disability-adjusted life years, and you can look at research income relative to disability-adjusted life years. And mental health has not been given the funding it needs. So there's an argument that New Zealand does need to carve out specific, not psychedelics, but I mean, 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.

• 32:31Tim Ferriss?

  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, is generally thought to be a very conservative place.

• 33:13Tim Ferriss?

  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 a pretty vibrant ecosystem, but it could certainly do quite a bit more? What are your thoughts?

• 33:47Speaker 03

  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 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 that's submitted to the FDA. So, you know, once they've got FDA or EMA approval, then they might come here for approval after a few years, and they've 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 pharmacopeia, where a lot of drugs that are available in the US or Europe aren't available here. Because they're just not market here because we're a small market. So I don't see

• 34:32Speaker 03

  that the that first approach work, but the second approach could certainly work where, you know, the government sets aside, probably wouldn't be through legislation, we're direct one of its funding bodies to sort of, you know, to say, and it does this for other re- areas of research, it says, okay, let's, let's fund this, let's fund this, uh, 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, we've got really strong longitudinal studies that have been going on for like forty, fifty years that have been centrally funded. That would be a mechanism that could certainly work.

• 35:14Tim Ferriss?

  Yeah, I'm, I'm very excited about New Zealand as the, the tip of the spear for studies along the lines of what you have done, you and your team have done with the LSD microdosing study, where you have the ability to pilot and innovate in a way 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

• 35:53Tim Ferriss?

  do pilot studies and launches in New Zealand, because you have sort of all of the ingredients for English-speaking, first world country with incredible research faculties. And I mean, in this particular application, they're looking at commercial interest, but you, 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 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, really

• 36:38Tim Ferriss?

  any, anywhere else?

• 36:40Speaker 03

  Yeah, well, you know, there's a, 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, um, 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. 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, 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 then various ketamine analogues that he, and different ketamine formulations that

• 37:25Speaker 03

  they've been working at. And so there's a lot of, 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 is where they're kind of, where things are happening in the biomedical realm.

• 37:40Tim Ferriss?

  What do you find interesting with, are there any particular ketamine analogues that you find interesting? And maybe you could just define what that means for a minute. And I also wanted 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 noribogaine and so on, which certainly makes them more interesting to study. But what is a ketamine analog? And are there any analogues or approaches to analogues that you find particularly interesting?

• 38:13Speaker 03

  Maybe it's not an analog. One of the things is they've been, I've been looking at like slow release formulations as, as one way to go.

• 38:19Tim Ferriss?

  Right.

• 38:20Speaker 03

  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. There's 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, 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. And so that they could, this is just.

• 39:04Tim Ferriss?

  Bravado.

• 39:05Speaker 03

  Yes, bravado. And this is essentially a marketing exercise, right? Like, there's no, it doesn't seem that it has any more efficacy than normal ketamine, but it allowed them to achieve a patent on it.

• 39:15Tim Ferriss?

  What is the price differential? I think it's something like one to five dollars, generic, like several hundred dollars.

• 39:22Speaker 03

  Yeah.

• 39:23Tim Ferriss?

  Bravado, USD, something like that.

• 39:25Speaker 03

  I mean, in New Zealand, there's be even bigger the differential because in New Zealand, resimic ketamine is 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 off-label treatment. And because it's a controlled substance, people, you know, there are clinicians that get, you know, antsy about that. And, and fair enough, but that ketamine, is ketamine, is allowed to be prescribed on label. That may make things easier.

• 40:07Speaker 03

  The problem with ketamine, the only reason ketamine is not probably is because it's a generic compound. Like, yes, this is a sort of background in how medicines get approved. Is you need a company to sponsor the research, to go to, in New Zealand, to go to Medsafe and say, look, here are all our data, 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.

• 40:38Tim Ferriss?

  With intellectual property.

• 40:39Speaker 03

  Yeah.

• 40:39Tim Ferriss?

  Let's talk for a second, if you wouldn't mind, expanding 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?

• 40:57Speaker 03

  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 disorders. So, and he's starting to build up quite a good evidence space that ketamine might not just have efficacy in depression, but in a range of sort of ruminate 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 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 smaller evidence space.

• 41:42Speaker 03

  But there is an emerging evidence space that other things in pools definitely been contributing to that.

• 41:49Tim Ferriss?

  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. You know, some of it would be contested, like the importance of the default mode network and the down regulation of such in some of these experiences. But it would appear, and certainly that 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

• 42:28Speaker 03

  We use the DSM.

• 42:29Tim Ferriss?

  For insurance, yeah, for insurance reimbursement purposes, you need a, 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

• 43:07Tim Ferriss?

  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, like, who is actually molding? Is it the patient? Is it the therapist? Is it the combination of the two? Is it the experience itself that's just bathing your neurons and various chemicals that produce dendrite growth?

• 43:52Tim Ferriss?

  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?

• 44:11Speaker 03

  There's so, 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. 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 know 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.

• 44:52Speaker 03

  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 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 realise they've got some kind of thing going wrong with their heart, some regurgitation or valv- whatever it is, or we can't measure a tumour size and oh yeah, this is it. So the physician is based entirely, basically, putting aside some

• 45:36Speaker 03

  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 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, which, you know, which if you're measuring like, you know, tumour size in a Petri dish, you know, that's, or tumour growth. So we have a long way to go to harden up the science. But to answer your question more specifically, the interventions themselves are really complicated.

• 46:21Speaker 03

  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 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 said, of people that just took side of side and by themselves and said, oh yeah, I started feeling better with no like thing. Not, I'm not saying you should do, anyone should do that, by the way, but just people will report that. Of course, at the same time, people report taking side of side and having a terrible experience and with terrible

• 47:06Speaker 03

  psychological shock involved afterwards. 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, to collect.

• 47:26Tim Ferriss?

  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 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, LD-50, so the dose at which 50% of a given subset of

• 48:11Tim Ferriss?

  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 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 and A in about five minutes.

• 48:51Tim Ferriss?

  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

• 49:20Tim Ferriss?

  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 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

• 49:57Tim Ferriss?

  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?

• 50:13Speaker 03

  For this study, we went with an inactive placebo, just because because no one had ever done LSD microdosing before. We wanted to 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 whether people are, you know, able to detect the effects, some are, some are. So we are around the threshold.

• 50:49Tim Ferriss?

  This was at around 10 micrograms?

• 50:51Speaker 03

  Yes, about 10 micrograms in male volunteers. So there's quite a heterogeneity, though, actually. 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 wanting 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, can you do it? What do people experience? If we're wanting to kind of try to fool people a bit better, then probably some kind of light placebo,

• 51:34Speaker 03

  the little bit of, I wouldn't say deception, but just ambiguity 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.

• 51:55Tim Ferriss?

  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 effectively entire class of drugs has so much trouble with placebo controls is very interesting, right? In and of itself.

• 52:21Speaker 03

  I've written a whole mess of paper out of my stomach.

• 52:23Tim Ferriss?

  Yeah, I mean, it's fascinating that it's so hard. Do you have any, and you don't have to give away your secrets, but anything on the shortlist for potential active placebos that you would use in such a case? Niacin?

• 52:35Speaker 03

  Niacin's not a great option. That's 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 psilocybin. But people used to use it for some reason, and I'm not sure why.

• 52:49Tim Ferriss?

  Skin flushing? I mean, maybe some type of subjective experience that people think it's doing something. It's added to a lot of dietary supplements as well.

• 52:56Speaker 03

  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 really important to prevent expectancy instances because if a person goes into a clinical trial thinking they're going to get cytosidine, they do get cytosidine and if they think it might make them better, they work out that they've had it and they go, ah, and maybe that over accentuates their clinical response, which we would call a confound. So that's potentially a problem. So, but what's important is it's not the compound itself, it's what the participant believes that they've had.

• 53:37Speaker 03

  And so it's not as much potentially around what the actual active placebo was, 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, I'm not, you know, give me another 10 to 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.

• 54:18Tim Ferriss?

  It's a really exciting time to be, for me, certainly observing, watching 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 and 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

• 55:00Speaker 02

  We do actually. Yeah, we've got heaps of questions here. What I'm going to do though, Sharice, is I'm going to start it off. First question is going to be an ask, so you can put your ask 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?

• 55:19Speaker 03

  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. Or 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 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.

• 55:58Speaker 03

  And we already are like, we're way batting above our, in terms of like us being this tiny little country that's back end of 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 few bit more push from government would potentially accelerate that and you know, and really establish us as leaders in the field.

• 56:22Tim Ferriss?

  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. So whether with you at University of Auckland or at University of Itago, 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?

• 56:55Speaker 03

  Yes, in terms of philanthropics, what the best thing is to get in touch with either myself or Paul. We don't, we're not top secret. Things and you know, there's, 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 use to then get the feasibility you need to then get a government grant to do the research.

• 57:20Tim Ferriss?

  Yep.

• 57:21Speaker 03

  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 this. 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 your grant away, right? 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 investments.

• 57:45Tim Ferriss?

  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, 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.

• 58:16Speaker 03

  Absolutely.

• 58:17Tim Ferriss?

  Now, Michelle, do you have more? I'm sure you do.

• 58:19Speaker 02

  I do, yeah. So this one, what are the risks of microdosing? So if it's patients that are diagnosed with bipolar or schizophrenia, so they're not looking for a medical advice, but just any general commentary about how safe it is it and is it dangerous?

• 58:36Speaker 03

  We have a data set that we have collected, and it's really the first data set that's been collected. And so far, we haven't seen any negative safety signs, 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, sort of could be, you know, you're heading into the unknown, I guess, is that kind of thing. So potentially, the biggest risks probably apply, actually, in the application area

• 59:18Speaker 03

  of mental health, and particularly with particular comorbid disorders. So I think it's important to tread lightly, carefully.

• 59:26Tim Ferriss?

  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 that are sometimes confused with or sold as LSD that can launch you into some very Very, at best uncomfortable and at worst very dangerous circumstances where you could be in an experience for 24 or 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 I compounds. And secondly, just because I've seen this quite a few times, we're dealing with, in the

• 1:00:09Tim Ferriss?

  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?

• 1:00:21Speaker 03

  Yep, milligrams is thousandths, yeah.

• 1:00:23Tim Ferriss?

  And microgram is a millionth of a gram? If I'm getting that right?

• 1:00:28Speaker 03

  Yep, that's right.

• 1:00:29Tim Ferriss?

  Yep, so if you're dealing with millions of a gram, even the Albert Hofmann, who's the father of LSD, I mean, went on his first famous, huge trip while bicycle riding because it 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 indeed. So I just, not to be the stern dad about it all, but felt the need to say that.

• 1:01:07Speaker 03

  These are absolutely true, that the non-physiological risks are probably far greater than the physiological risks. And even though law enforcement deals with things like schedule C, which is like cannabis relatively lightly these days, actually, they're not so forgiving with Schedule I substances. So that is important to bear in mind. And I forget often, you're absolutely right again, that's the purity of supply and dosing. I mean, I forget this because we have, I like to say, the best LSD in town in my lab, but joking aside, yeah, like illicitly obtained LSD or psilocybin could be cut with other things. It's very hard to know.

• 1:01:47Speaker 03

  But we do have drug checking services in New Zealand that can provide that kind of information though.

• 1:01:53Tim Ferriss?

  And I'll just actually, that's a really good point to just add one thing to, which is in the US, 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.

• 1:02:22Speaker 02

  There's a few people in the audience, Suresh, that are doing studies themselves in, say, Toronto and the US. And one of them's about, the question's about open science. So what are your thoughts about open science replication crisis? Will you be sharing your data or will you be keeping it private?

• 1:02:39Speaker 03

  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...

• 1:02:49Tim Ferriss?

  Suresh, could you define that just for people listening who are not familiar?

• 1:02:53Speaker 03

  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 preregistration, 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. So, 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 you, for example, you're doing industry funded work where that's not possible because that's intellectual property of, of said company. So, you know, I'm generally in favor, but I think we do end up with open science of having a lot of data in the world, but no interpretive framework.

• 1:03:38Speaker 03

  We can all do thousands of experiments and release terabytes and petabytes of data into the world with, of 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.

• 1:03:56Speaker 02

  Now we'll shift to a training question. So anticipating legislation change and increasing access to psychedelic assisted psychotherapy, how do we prepare the workforce and to be able to provide this? So what training pathways exist already for psychologists, clinical, social workers to upskill and become involved?

• 1:04:18Speaker 03

  This is a big controversy. I mean, Tim, do you?

• 1:04:21Tim Ferriss?

  Yeah, I can take a stab. 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, you know, my foundation, so the SAI Foundation, S A I S E I foundation.org,

• 1:05:05Tim Ferriss?

  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 sort of psychiatry M D training. And people can elect to then add this type of training and qualification to their preexisting

• 1:05:47Tim Ferriss?

  track, if that makes sense, which is not to say that this should be limited to being administered by M Ds or M D 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

• 1:06:32Tim Ferriss?

  that will be faced in the 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 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

• 1:07:17Tim Ferriss?

  people can see some of them at the foundation website.

• 1:07:20Speaker 02

  And now, is there a way, this has been New Zealanders, is there a way that we can access psychedelic therapy, microdosing now, or how far off is that?

• 1:07:28Speaker 03

  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. 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 US. We have a group of MAPS trained therapists, actually in New Zealand, that could actually

• 1:08:08Speaker 03

  deliver that therapy if the data was seen to be okay and our regulator were to improve it, 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.

• 1:08:26Tim Ferriss?

  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-MEODMT, ayahuasca, and every other compound you can imagine to try to get them all dealt with in a responsible

• 1:09:06Tim Ferriss?

  way simultaneously. Now, I don't think anyone's actually going to follow that advice, but you know, I have 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

• 1:09:48Tim Ferriss?

  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 in the next six months.

• 1:10:03Speaker 03

  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 and pressing 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'd be safety issues that come up or like badly regulated things. And then all these horror stories start emerging into the popular consciousness. And then we put ourselves 50 years back in the hole 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 in the 1960s. So hopefully we can avoid that kind of issue. But I think it requires us to work diligently, honestly, and carefully.

• 1:10:48Tim Ferriss?

  I mean, not to paint a bleak picture, but it's just like, hey, I think we really want to mitigate the risk of catastrophe that then becomes a political soapbox. And then, before you know it, you have an executive order that sends 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, et cetera. 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,

• 1:11:33Tim Ferriss?

  one senator's child dies of cavalier administration of 5-MEO DMT in fill-in-the-blank location, right? Not to throw 5-MEO DMT under the bus. I think it's very interesting, but high degree of thrashing, 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, the people involved, which is why the Decisive Foundation is also involved with the Harvard Poplar Project, which is a law and policy project focused on 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

• 1:12:18Tim Ferriss?

  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 coverage has just lasted too long. And I think if we want to be strategic about it,

• 1:12:58Tim Ferriss?

  we accept and expect that on some level because inevitable with, with anything that is purported to have this much promise and certainly anything that has this much coverage. Michelle, what else do we have?

• 1:13:10Speaker 02

  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?

• 1:13:20Speaker 03

  We're starting to talk about it. We're starting to talk about a project that will be a more Maori-based intervention that will be run by Maori researchers. And we're just in the very beginning stages of starting to sketch some ideas together about how that might be done for that population and methamphetamine use or alcohol use. But 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

• 1:14:04Speaker 03

  that would be interesting for those researchers to explore.

• 1:14:08Speaker 02

  So just on that a little bit then, what about, are you including women in the studies? Or has it been mostly males?

• 1:14:13Speaker 03

  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.

• 1:14:26Speaker 03

  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 we wanted to avoid for the 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 flak for this.

• 1:14:52Speaker 03

  And I say, my response is, well, you try and like get this study approved. I've like, because I spent years aging trying to get this thing approved. So, you know, we did the best that we can while we could, and we always hope to do better. But certainly, all our other studies have included females and the next study as well, now that we've got over that first hurdle.

• 1:15:11Tim Ferriss?

  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 heterogeneous group. So definitely easier to do when you have a little bit of escape velocity after the first one or two pilots.

• 1:15:35Speaker 03

  Yeah, there's actually some interesting 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 interesting. There's potentially interesting separate studies to be done there that we have considered and will consider in the future.

• 1:15:57Speaker 02

  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?

• 1:16:04Speaker 03

  Oh, so I get this all the time from undergraduate students. I'd say, you know, the best option is just go be a medical doctor because then you can learn. But a university degree, I'm just promoting the university work because it's my employer who pays the bills. But, you know, 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 mid. 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 wanted to get into being able to prescribe or be involved in this kind of

• 1:16:48Speaker 03

  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.

• 1:17:02Speaker 02

  And just going to go into one of our corporates. So have you looked into the clinical trials of the larger public companies? So there's MindMeb, Compass, ATAI and Numerus. And do you feel there are any red flags and how these are current corporations are going about improving their respective drugs? So that's like LSD, MDMA.

• 1:17:23Speaker 03

  Yes, and I should say as a disclosure that I consult for some of these companies as a disclosure. So and actually collaborating with one of them. So my observations is that.

• 1:17:36Speaker 03

  The people that these companies are employing are really, seem to be really experienced pharmaceutical people with a lot of industry experience in pharmaceuticals and they seem to do quite a rigorous job. You know, 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, you know, the pathway is long and expensive and the intellectual property that they need to gain because of, you know, these are generic medicines is going to be an issue. But there's red flags in every areas of pharmaceutical development. Are there any more red flags in this area than there are in other parts of the pharmaceutical industry?

• 1:18:18Speaker 03

  Probably no more, no less, you know, but I'm comfortable with the gray.

• 1:18:23Tim Ferriss?

  I'll hop in with just a few things. So I would say on the, on the clinical, actual, the study side, I think preregistration is very important. But as you mentioned, Sir Ash, that doesn't apply uniquely here, but it does apply here. So preregistration, publishing your protocol ahead of time so that you can't sort of torture the, the data or, or move the goalposts and declare victory when in fact it was not a victory, I think is incredibly important. And then, you know, 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 be granted patents

• 1:19:08Tim Ferriss?

  because that is how one in a market-based economy sort of raises funds and builds companies and justifies the R and D expense. There are also obvious, relatively unhelpful, non-improvements that people 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. So I do think the IP side of things is very important to to keep an eye on.

• 1:19:51Tim Ferriss?

  And an organization that might be worth checking out is Freedom to Operate, which was created by Carrie 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, co-authored a paper on intellectual property and patents. For those who are interested, that's out of Harvard Law School.

• 1:20:14Speaker 02

  It's enough time for our questions, actually, Tim goes first.

• 1:20:19Tim Ferriss?

  All right, 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.

• 1:20:28Speaker 02

  Good. Thanks, Tim. I'll just close us off for the karikia. It's been a great session today, and then hopefully this will set you on the rest of your way. Kia tō tēm ranga muriā. O tērangi nui e tā e hō nei. O pāpanuku e tāko nei. O tā te ona a hī nei. Kōranga e tāto tāto. Te hei, mōri ora. You're the team. Thank you, kaikīte, and enjoy the rest of your evening or day.

• 1:20:57Tim Ferriss?

  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 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 to share the coolest things I've found or discovered or have started exploring over that week. 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. They get sent to me by my friends, including a lot of podcast guests.

• 1:21:40Tim Ferriss?

  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 tim.blog/friday, type that into your browser, tim.blog/friday, drop in your email and you'll get the very next one. Thanks for listening.