The Peter Attia Drive - #182 - David Nutt: Psychedelics & Recreational Drugs

Episode Date: November 1, 2021

David Nutt is a psychiatrist and a neuroscientist at Downing College, Cambridge.  His research focuses on illicit drugs—their harm, classification, and potential for therapeutic use in psychiatry. In this episode, David discusses his framework for assessing the potential harm caused by common recreational drugs and explains how they are regulated, which is oftentimes misaligned with actual risk. He describes in detail the neurobiology, mechanisms of action, and addiction potential of alcohol, opiates, cocaine, and methamphetamine and contrasts those with psychedelics, which have been given a similar regulatory classification despite their relatively low risk of harm and their numerous potential therapeutic uses. Additionally, David explains the promise of psychedelics like ketamine, MDMA, and psilocybin for treating drug addiction and depression and discusses how political pressures have created roadblocks to future necessary research. We discuss: David’s early interest in the brain and experience in psychiatry [2:45]; David’s brief work on government drug policy in the UK [10:15]; A scale for rating the relative harm of certain drugs [13:45]; The contrast in regulation between cannabis vs. alcohol and why research on potential benefits of cannabis is lacking [19:15]; The opiate crisis and rise of fentanyl: the cause and potential solution [25:00]; The science of addiction and the potential use of psychedelics for treating drug addiction [35:00]; Cocaine: mechanisms of action and risks [41:45]; Methamphetamine and crystal meth: mechanisms of action and neurotoxicity [48:15]; How psychedelics came to be classified as schedule I drugs despite their numerous therapeutic uses [52:45]; The history of MDMA and the bad science and political forces leading to its demonization [1:08:45]; History of ketamine, medical use of esketamine, and the waning effects of psychedelics with increasing usage [1:13:30]; Psilocybin for depression: David’s promising research and the roadblocks to more robust experiments [1:20:15];More. Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/davidnutt  Subscribe to receive exclusive subscriber-only content:  https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, I'll focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain what those benefits are, or if you want to learn

more now, head over to peteratia MD dot com forward slash subscribe. Now without further delay, here's today's episode. My guess this week is Professor David Nutt. David is a psychiatrist and a neuroscientist who studies medicine at Downing College Cambridge. He completed his clinical training at Geys College in central London. David's had a lifelong interest in the brain and we discuss that in his path to where he is today. In particular, we focus on molecules, molecules that affect the brain and we break this into drugs of all sorts, but go through it in a framework that David has been an advocate of and proposed, which looks at the risk of harm to the individual by the use of drugs, the risk

to society and the potential for addiction. And we get into quite a bit of nuance around this, and we really cover a broad range of drugs. And I find this to be a very helpful discussion, because it's rather than just being sort of a moral discussion of drugs, it actually gets into the neurobiology of them, and of course, the risks. But the real focus of this discussion is actually around a class of drugs that many of you are well aware of and have a growing interest in which are these drugs referred to as psychedelics and more broadly really we get into not just psychedelics But at least in the classical sense such as psilocybin and LSD

But we talk more broadly about empathogens to sociative agents and even atypical psychedelics so the only thing I'll say about this episode that kind of bum me out is because David had a hard stop We were not able to go as long as either of us would have liked so I can say Without reservation that this will be part one of more when that second part will be I'm not sure But please be patient with us as I accept the fact that we probably only covered about a third to a half of the content that we wanted to get into. And my hope is that this wets your appetite for what will be a part two and potentially a part three. So as you're listening to this, keep us posted of your thoughts and what you would like

us to go deeper in the next time, because as I said, there's pretty much no question my mind. We will go into that. So without further delay, please enjoy my conversation with David Knight. And thank you so much for making time in your evening, my afternoon here today. Very, very much looking forward to speaking with you about a topic that I think is on a lot of people's minds lately. Well, thanks for the invite. Time looking forward to it too.

Let's start a little bit with your your background. It sounds like based on what I've read, going back to your early teen years, you've always had an interest in the brain, whether it be through the lens of neuroscience or psychiatry. What do you think sparked that interest? Well, thinking about things, I guess it was an understanding that, in come and I was probably four or five, I suddenly kind of realized that actually thinking was what actually made things make sense. And then I realized that thinking came out of the brain and I've always been fascinated by the brain. And actually I went to university to Cambridge to do brain science. I wanted to be a physiologist, you know, like Hodgkin and Huxley,

to do physiology. And then I kind of realized actually that some single cells are interesting, but you've got to put the 200 billion together and make sense of those and actually that's where then I did neurology and that got a little bit boring because it's mostly people kind of dying slowly from diseases like a mitrophic lateral sclerosis. So then I moved to psychiatry and then it became really wonderful because you see every aspect of the brain in psychiatry. Well it's so funny to say that because I'm not making this up, but this morning, my six-year-old son was in my office and we were sort of fumbling around and I have a

whole bunch of racing helmets in my office. So, he's putting them on and that got him talking about why we were in helmets to protect the brain and blah, blah, blah. And then I said, well, you want to see what he said. What does a brain look like? So, I pulled up, you know, on Google, I pulled up some images of brains, but actual anatomic images. Again, he's only six, but he's looking at this

and he's thinking, that's very unimpressive. And he sort of says, it just looks like a slimy thing. And I said, yeah, that's true. That's what it looks like. And he says, but is this where my thoughts come from? And I said, yes, that's where your thoughts are reaching. And he said, well, how? And I gotta tell you, it was very difficult

for me to explain how electrical impulses work. And of course, I'm not gonna get into action potentials and neurotransmitters, but what's funny is, it then took me down a rabbit hole of spending 30 minutes on YouTube trying to find good videos of this for kids. And if anybody can find one, please send it. But I couldn't find great videos because the videos that I found were more anatomic.

Like, this is the part of your brain that controls movement. This is where memories are stored. But he was asking a deeper question, which was, how does this blob make me think? Which it sounds like you were asking that same question as a four or five year old. But what's amusing, even more amusing, is my new book, which is coming out later this year, is called Brain and Mind, Made Simple. It won't be simple enough for a six year old unless he's very precocious, but I have written a book for the general public to try to explain

this peculiar phenomenon that how lots and lots of single nerves can actually turn into all the complexity of the different forms of consciousness and the different experiences that humans have. And at some point, and I think the point you raised is a really good moment. We really nice to then migrate that down for children, maybe as a series of comics or graphics. Because I think it is the most wonderful thing in the universe of human brain. There's an argument about it. So let's get communicating as soon as we can.

Yeah, and I do think that, like for me personally, it's not a question I ever contemplated early. So it made me very happy that he was asking this question at the age of six in a deep enough way. And look, even if the book is not written for a six-year-old, I'm sure it will help me do a better job explaining it to a six-year-old. So coming back to your career, so now you've migrated into psychiatry, which, of course, on some levels is really about understanding pathology of the mind, which is effectively what all parts of medicine are, whether it be neurology or otherwise. What were some of the first things that stuck out to you about the pathology of the mind through the lens of a psychiatrist? Well, the first patient I saw, who I was dropped into, a doctor didn't turn up, I'm a

medical student, so I'm saying, oh, please go and interview, go and clerk this new patient. So I'm sitting there, I'm talking to this person who's not making any sense whatsoever, and kept talking about the being a smell of fish in the room and rambling on about the smell. And after about an hour of trying to get some sense, I say, well, thank you, I'll just, I'll be back in a minute and I go out and I talk to the consultant. And he says, oh, wow, he's clearly psychotic. Oh, that makes a lot of sense. That's why he doesn't make sense. And that's why I understand what was going on. What was very interesting actually about that is that the relationship between temporal lobe disorders, those parts of the brain which are intimately involved

in aspects of consciousness and also smell. And there is this peculiar overlap between temporal lobe disorders where you can be psychotic but you also have these olfactory hallucinations. And that's where you had. So he was hallucinating rather than in his ears, which most people with schizophrenia do. He was hallucinating in terms of smell.

So yeah, I never forgotten that because it was just such a kind of completely bizarre experience and it made me realize I got a lot to learn, you know. Now for most people when they go into psychiatry and I'm sure this was the case with you, you spend a lot of time learning the neuropharmacology of the agents that are going to be used to help treat patients with psychiatric illness. And for many people, that's sort of where it stops. But you've also generated or developed this other interest, which is in the neuropharmacology of these regulated substances, you know, called them illegal or recreational drugs and otherwise. Where did that interest stem from?

Wow. Well, so, yes, I am a professor of neuropsychopharmacology at Imperial College London and neuropsychopharmacology is really the use of drugs to study the brain and to study the effects of treatments for brain disorders, particularly in the case of psychiatry, as psychotropic drugs. My PhD was on the GABA system, on drugs manipulating the GABA system, as an undergraduate. I think, you know, the big influence. I mean, I was extraordinary fortunate. So I'm at university in Cambridge in the 19, early 1970s, when people are discovering that the brain is a chemical organ. Up to that point, it was thought the brain was an electrical organ. Yeah, it was like a very complicated computer or, you know, some kind of complex telephone exchange. But then the concept of chemical transmission came along. And now we know that

there are at least 80 different chemicals, neurotransmitters, hormones, neurotransmitters. And seeing that transformation from electricity to chemistry may be realized, you know, the way you study the brain now is through drugs which affect the chemistry of the brain. And then these therapeutic agents, which are obviously very important, antidepressant, anti-psychotics, anti-convulsants. But then, it raises the next question, you know, but people use other drugs to change the brain. And they use them recreationally, but people use other drugs to change the brain.

And they use them recreationally, for drugs like cocaine or crystal meth, or they use them to dead in pain or to get insights like psychedelics. After a while, because I've done so much research on drugs, I was asked by the British government to help them think through drug policy. Well, actually, that was not true. They asked me to help them justify drug policy. But when I started working for them, I realized that the drug policy wasn't in any way evidence-based. And when I tried to bring evidence to bear on drug policy, they sacked me. Because it's much more convenient to have a political decision-making about drugs than it is to have an evidence-based one. What year was that? But you got involved in that?

Well, I started working on the principles of assessing drug harms ready back in the 1990s. And it actually came with the rise of ecstasy, and people supposedly were seemingly getting harmed from ecstasy. And I was one of the experts who was asked by the government to come up with a policy which would reduce the harms from ecstasy. And it became very clear when we were researching those. The harms of ecstasy aren't from the drug at all. They're actually from the what you do when you're on the drug. They're either from the fact you dehydrate because you dance all night or you get hypothermic because you're in an environment where you can't cool down. And so we said, and actually we brought in a, what in legislation in Britain, which said, any club, which is serving drinks, which is where most people were going to have their

ecstasy, they're going to clubs, they must serve free water. Because what the clubs were doing, we're actually forcing people to drink alcohol or pay for water in order to get hydrated after using ecstasy. And in fact, they were doing worse. They were turning off the taps, they were even turning off the toilet so people couldn't drink water. So we've made it law that people had to get access to water. And we also recommended a good policy, which would be to have chill out rooms. And of course, a lot of clubs do have chill out rooms. a good policy would be to have chill out rooms. And of course a lot of clubs do have chill out rooms. And there was just those two simple environmental approaches effectively,

you know, very, very few deaths from ecstasy since then, until we've got to the modern day when a variety of international policies have now made ecstasy considerably more harmful than it used to be. How much did this coincide with, or following lockstep with drug policy in the United States, which really seemed to get a real boost in the arm in the early 80s? Was the UK leading or following? Oh, every country in the world follows you. The United Nations is probably still is paid for by the US, and it does what the US tells them. Every single British drug law until 2016 was made at the behest

of the Americans. So, you know, America basically, you know, they say America sneezes, the World Catch is cold. America defined drug policy. It started in 1934 with the attack on, you know, the liberalization of drinking and the attack on cannabis, and it continued. And of course, the big inflection was when Nixon decided that the war on drugs was actually a better vote-getter than the war of Vietnam. So he switched people's attention to drugs and the world has been fighting a war on drugs largely funded but certainly politically driven by America since then. So let's talk a little bit about the framework through which one can think about drugs.

I'm a framework junkie. Everything I think about whether it's how to order dinner comes down to sort of a framework. Some parameters that people might think of, how harmful is this? And again, you know, I think the goal of frameworks is to have them be as unemotional as possible and to have them whenever possible to be objective. So how harmful is something would be part of it, how addictive is something, what's the physiologic dependence. And even within harm, you could sort of talk about the harm to the individual and then the harm to society as that individual acts.

Are there any other things you would include or do those three things largely encompass what you think of as a good way to think about molecules? That is quite a succinct way. what you think of as a good way to think about molecules. That is quite a succinct way. So I started off with something somewhat similar to that. But more recently, we've developed what's called multi-cretary decision analysis. And it turns out that actually there are 16 different ways in which drugs can do harm. There are nine harms to the user,

and there are seven harms to society. And the societal harms range from international damage, you know, like the US, spraying agent orange in Colombia to kill to kill cocoa plants, through to economic damage, through to health costs, through to damage the families, et cetera. So there's seven harms to society and nine harms to the user, and each of those can, you can scale drugs on each of those 16 scales of parameters of harm. And if you do all that, and pull it all together,

and then do a waiting, because obviously not every single one of those scales is equally important. If you do all that, then you can actually very, very transparently and very reliably rate the harms of different drugs. And we've used this procedure in Britain, we've used it in Europe, and most recently in Australia, and pretty much all the drugs always rank the same in all those, you know, there's three sort of groups of Western jurisdictions. So based on that type of a framework, what are the drugs that consistently come to the top of the list in terms of harm, aggregate harm? So the most harmful drug overall in all, in Europe, in Britain and Australia is alcohol. An alcohol is the most harmful drug because it has way more social impact, more

harms to others than any other drug. And that, of course, is because it's much more widely used. You know, 80% of American adults, British adults, drink alcohol, pretty much every family in your country and my country know someone that's been harmed by alcohol, either through themselves getting a difficulty is having accidents getting addicted or they've been harmed by other ones someone who's drunk or drunk driver or someone who's drunk and violent. But if you look at the harm to the user, alcohol is not number one, alcohol is about number four.

The drugs that you're really harmed to the harmful to the user are opiates, crack cocaine and also crystal meth. That's super interesting, right? Because those drugs have very different scheduling. So heroin would be a schedule one drug, correct? Cocaine would be a schedule two drug. I guess crystal meth would be schedule one or would it be schedule two?

I'm not sure in the, in Britain it's one, but I think I'm not sure in the in Britain it's one, but I think I'm not sure in the US to be honest. And then of course alcohol is not even scheduled in that sense. It's regulated only by the age at which you can legally consume it. And also by taxation is right. So what we didn't talk about was tobacco. Does tobacco fit into this framework?

Yeah, tobacco. Yeah, we always do tobacco because tobacco is, this is an interesting paradox. When we first did this, tobacco came out in about number six or seventh. And the tobacco, anti-tobacco, they got very agitated. They say, it is the most harmful drug

because it kills more people. And we said, yeah, but that's right, it kills more people, but they often die in their 50s and 60s. Alcohol is killing people in their 20s. And that's more important, we think. Our valuation was that the harms of alcohol are considerably greater than the harms of tobacco.

And I think most people would agree that tobacco does, in the end, kill half of the people who smoke, but it does it later in life. And tobacco also causes relatively little damage to other people, unlike alcohol. This is such an interesting question, and I don't even know how one would think about it, because you could also take the flip side, which is there's probably nobody who's benefited from tobacco. I shouldn't say that.

There is a benefit to tobacco, which is that probably it helps some people calm down. It probably helps cope with nerves, but there's no moderate use of tobacco, like smoking only 10 cigarettes a day is protective or the harm doesn't really kick in until you're at a pack a day. No, that's not really true. Any amount of tobacco is going to take some toll on your pulmonary system and your cardiovascular system. Alcohol conversely, you could say, well, look, a person who drinks responsibly, who has three drinks a week, bears no cost of the consumption of alcohol from a relative standpoint. I mean, we could debate that.

I would argue that there's no dose of alcohol that's healthy, but there are probably doses that don't rise to the level of toxicity. Yet to your point, it's much easier to cross the line into acute toxicity, which also gets to another challenge here. Tobacco has no acute toxicity. It's a 100% chronic toxicity. alcohol has both acute toxicity and chronic toxicity, and it's that acute toxicity that results in incredible loss of life, both to the individual and to society. Yes. Does the framework allow you to measure these things? Yes, it does. We can give you absolute ratings and rankings

on both those variables, acute toxicity versus chronic toxicity. And of course, you know, the drugs which really do badly on both of the opiates, which could kill you instantly when you take them, but also crack kill you quite quickly over time as well. But there is another angle, and that's, I think, an important angle

which our analysis doesn't bring in because it's difficult and challenging, and I'd love to, and maybe at some point we can do this, and that's the benefits. You pointed out quite clearly, generally tobacco doesn't bring many benefits. Nicotine is a funny drug though, it's the only drug we know of

that both calms people people but also improves attention. And so there are people who smoke, you know, generally, although they're addicted, they do get a benefit at least when the nicotine's in the brain. But alcohol has a much broader kind of social, I mean, alcohol is one of the most social drugs. I mean, after ecstasy, it probably is the most social drug. And that's why people use it. So there are unquestionably psychological

or social benefits from alcohol. And that goes back to pre-Christian times. Yeah, that's right. Jesus turning water into wine at the wedding at Canine. Why? Because wine was what Jews used to celebrate weddings. And he's been used ever since. We all use it. We still use it today to celebrate. So, so, alcohol is a very powerful,

prosocial effect, which I think is why it's so widely used and why it's been, apart from that little aberration of American prohibition, why it's actually been stable in our society for many millennia. And do you think that that's the fundamental reason why despite the sort of I mean hypocrisy of it if we're going to be blunt we would

Make something like cannabis illegal while having something like alcohol be legal. Is it does it basically come down to Our social dependence on alcohol? Now that's a great question. And I think, and it's a very interesting, I haven't thought about those two in that context before, but I think it, that's a very interesting point in me, because cannabis is not a particularly social drug. So people, when they get stoned, they tend to be quieter. They're not, it's not the party drug cannabis, is it? And it might, you might be right.

It might be that people are less positive towards cannabis because it isn't so socially enabling as alcohol. That's a very interesting point. I take a different view up to now until you said that. I've taken a different viewpoint, which is that people have been very anti-canopies because the alcohol industry and the drug enforcement agency have seen cannabis is the enemy and the disinformation that's been produced, you know, the hatred of cannabis, which started with Harry Anselinger trying to keep the DEA functioning after alcohol prohibition was

disbanded. That 100 years or more, 90 years of disinformation has actually poisoned a lot of people's minds to cannabis. cannabis has been vilified and alcohol has been celebrated. I mean, he's been celebrated throughout history in terms of art and culture and music and television. You know, one of the staggering things, because of lockdown, I've been watching a lot of Netflix and I'm seeing these disclaimers at the top saying, this program contains product placement by which they mean usually, this program shows people drinking and awful lot of wine. Yeah, we've come a long way. It's an interesting point you raise.

I guess I hadn't thought of it that the EN needs a reason to exist. And therefore you need bogeymen, right? If your business is smashing bogeymen, you need bogeymen. Don't we have enough bogeymen with other drugs like heroin or methamphetamine or cocaine? Like I guess I'm confused as to, and I don't want, this is not going to be a discussion about the legalization of cannabis, because it seems to me that that train is left at the station. I'm just amazed that there was such a lack of study,

because I'll tell you where it's frustrating for me as an outsider. I have a lot of questions. My patients ask me questions, such as, if my 16-year-old son is smoking pot, is that going to have a negative consequence on his or her brain development? And I wish I could answer that question, but I can't really point to rigorous studies one way or the other. And to me, that's a failure of not having studied this drug the way we should have

been studying it for the past hundred years. Because you want to talk about a drug that probably has lots of benefits, but also potentially harms. Cannabis would be a case study in that. And I find it very frustrating as someone who prides himself in caring about data and trying to not have an emotional discussion about something that I don't have answers to those questions. And it seems like a real missed opportunity. Well, it's worse than that. I mean, the reason that the studies have not been done is because almost all the funding for that kind of research in America comes through the government through NIDA and essentially NIDA has not been funded to study the benefits of cannabis.

Even when, and this is the real missed opportunity, even when California voted to make kind of medical cannabis legal, what an opportunity. You're going to have, we know, 20 million people using it. You could have within a couple of years worked out its utility and its harms, but the federal law, because cannabis was illegal under federal law, and it still is, they could not fund research. So it's one of the many examples of the perverse negative consequences of this prohibition approach to drugs. So let's talk about a few other drugs that we haven't mentioned.

We've talked about basically things that are not particularly harmful. We've certainly talked about things that rise to the level of harm. Where do the classic psychedelics, LSD, psilocybin fit in, along with some of their more distant cousins, Iowaska, DMT, five MEO DMT? And of course, we've talked around it, but we haven't explicitly asked, where does MDMA fit on this list of harm? In the aggregate sense, according to this sophisticated model.

That's why I kind of started off talking about MDMA, because that was my first introduction to policy decisions. And when I started working for the government back in 1994, I disumed that what they told me about the harms of drugs was right. And then I discovered that when I did and my team did the more detailed and sophisticated analysis, they were completely wrong. I've been lying to.

The real paradox of doing a really in-depth, multi-crytero decision analysis is it turns out that the drugs that have been most vilified and which we've been taught are the most dangerous, turn out to be the least dangerous. So at one end of the most harmful drug is alcohol, the least dangerous. So it won into the most harmful drug, is alcohol, the least harmful drugs, the magic mushrooms, the LSD, and MDMA. So it's almost as if the whole law is completely on its head. So let's now simplify and talk about only harm to the individual. So purely physiologic risk to self. If I heard you correctly earlier, heroin and fentanyl and its cousins

occupy the top spot, correct? So aggregate greatest risk of acute and chronic mortality, yes? And then second, you're putting the cocaine derivatives and then third would be the emphetamine derivatives. So if we just look harm to the user, yes, I mean crack, okay, crystal meth probably more harmful than crack, because it lasts longer in the body and the brain. So I would generally, crystals probably a bit more harmful to the user, so it would be opioids, crystal crack.

Let's talk a little bit about mechanism of action. I'm very familiar with how opiates kill, but let's just briefly summarize it. Is it mostly the respiratory depression? Is that the fundamental issue in the short term? Yeah, it can. They kill you in overdose. Yeah, you take just too much. You know what you're taking.

Someone spiked your heroin fentanyl and you just stop breathing and you're done. Yeah, you want to talk about, you mentioned earlier, almost nobody in America doesn't know somebody whose life has been destroyed by alcohol. We're getting pretty close to that with opioids. I mean, I personally know three people, is it four? Maybe four who have lost a child or relative

to an opioid overdose. Think about that. I don't know that many people, David. It is terrifying. I'm sorry to say, guys, but you kind of got it wrong and then you got it wrong again, and you're still getting it wrong. And shall I just briefly go through that? Sure. So the fentanyl crisis is very much an American problem. And it's not just because there's obviously a lot of you, the more people there are, the more likely it is that people will die. But it's a disproportionate number of deaths. So now, I think last year more people died of opiate overdose than died in the whole of

the Vietnam War. Yeah. And last year we set here in the United States a record for the most overdose deaths ever. So it wasn't just the year of the most deaths due to COVID, but the real record, the story behind the story is the most overdoses. And the answers are complicated, and it's like a perfect storm of things going wrong. So the first perfect storm is the excessive rollout of strong morphine derivative painkillers, which were heavily promoted by some pharmaceutical companies and you all know they've been sued, et cetera. So I think the doctors also, some doctors were to blame, I mean, you know, some were clearly

over prescribing, but there's also the problem that chronic pain is very common, you know, perhaps quarter of the country have chronic pain. When doctors are faced with no treatment, no physiotherapy, you know, you know, you know, occupational, with all they had with prescription power, then they tended to veer towards prescribing opias, which are not good for chronic pain. And it's interesting also, you see the states, which had the highest prescription levels of opias for chronic pain, or the ones actually that don't have medical cannabis. Medical cannabis is the best treatment for chronic pain, better than any other drug, but if you haven't got that, then you can't have it. So that was the first thing. Big increase in prescription, partly driven inappropriately, partly out of just a concern to help chronic pain.

That's the second thing was then the rise, the dispersion of that into society, into parents, kids were taking it and taking the rots of care, parents oxycodone, and dying. So you have the crisis, you have the concern, and then you have the reaction, the reaction then was to stop prescribing.

But when you stop prescribing to someone who is dependent on an opiate, they don't, unless you provide them with something else like medical cannabis, they are in withdrawal. And so they go and get an opiate, and if you're not prescribing it, they go and get it from the black market. And then you see this complete paradox. You see this rise of heroin deaths, rise of fentanyl deaths, because that's

what the black market provides. And then you get into this really, the most damaging cycle, or part of this cycle, is the rise of fentanyl, because until there was a huge increase in black market demand from the people on oxycodone. Fentanyl wasn't a big issue, but for various international reasons, the United Nations limiting the access of heroin, the amount of of poppies it could be grown in a so-called attempt to prevent heroin misuse.

15 years ago, particularly in the Mexican cartels, realized if they couldn't make heroin because they couldn't get enough morphine, then they would make something else and they'd discovered fentanyls. And fentanyls are so much more potent, there's so much more value for money, you know, even the simplest fentanyl, fentanyl, it's 50 times more potent than heroin and twice it's cheap to make. So you don't have to be an economist to realize it's better to do that. And then you get to the super fentzino's like carfenzino, which are a thousand times over potent. It's so potent no one knows how to measure them and so you don't know how much you're giving them. So you see it's a psych... a series of mistakes which has actually just

led to this terrible tsunami of deaths. And the only way to deal with it really is to have lots of testing to allow people to take anything they've got and get it tested so they know what it is, eliminate fentanyls, and start to bring in much safer treatments for people in chronic pain, like medical cannabis. I want to talk a little bit about the opiates before we leave it and talk about a drug called Ibogane, a derivative of Iboga. You know, I have read quite a bit about it and a lot of it's anecdotal, but it seems that there's something very interesting going on there where you have this alkaloid that, while it comes with its own dangers, and it's not clear how over or understated they are, relative

to cardiac toxicity, it seems to have quite an efficacious punch when it comes to relieving people from the throes of opioid addiction. Do you have experience with it at least scientifically, if not through experimental collaboration? Well, we're in the process of trying to do a study. I would dearly love to understand the nearer science of Ibergain. And it's been difficult to do that study because of the cardiac risks. But we're in the process of working with a company that's developing a derivative of Ibergain called Noriva Gain, which may be less cardiotoxic.

And we're working with them to do some brain imaging to see whether we can... Is it a normal psychedelic or not? Because no one's ever studied it yet. But the evidence, as you see, from its use widely in some third world countries is a therapy for opioid withdrawal. So it's also licensed medicine, interestingly, in New Zealand. But they've stopped using New Zealand because of one death. Which strikes me as a little bit odd, right, when you consider. So based on some of the literature I've read,

the risk of a fatal arrhythmia might be one in a thousand. And that's depending of the literature I've read, you know, the risk of a fatal arrhythmia might be one in a thousand. And that's depending on what you're talking about. One in a thousand is an enormous risk. But if you're weighing it against a person remaining addicted to opioids, what's the natural history of that? I mean, that might be 300 out of a thousand. Yes, about that. Yeah. So do you have a sense of what the true risk of IBegane uses and how much of that risk could be mitigated if it were administered in a proper setting, which would be a setting with cardiac monitoring, for example, versus someone's house? Well, one thing's for sure, we're going to administer cardiac monitoring.

Yeah, that's a word. Yeah, exactly. So, and they're a plenty of other drugs which do have cardiac effects. And usually they're a plenty of other drugs which do have cardiac effects, and usually they're used by cardiologists. So the answer, you're right. I mean, that's why I want to study it, because if we could get more clarity on its mechanism, that I think would at least then reassure people that was a science behind it.

Because currently it's, well, you've got to West Africa, you've got to Vietnam and you get to have a game and your brain is shaken up, and you come back cured. And I think we could probably improve on that. I think there's also your point you make, doing in a hospital setting, I think makes more sense because I'm not just for safety, but also because I'm not sure it should be given during withdrawal, that's when it is being given.

And I think withdraw, there are other treatments which we have given for opioid users, which have also been toxic in withdrawal. People withdraw is a serious medical problem. So they're ill, physically struggling. So I think adding a burden to someone who's in withdraw is not a sensible idea. So my thinking is that once if we can restore a sensible balance with ibogaine, we could potentially use it. But also I'm very interested in using other psychedelics, because I think the fundamental principle is likely to be the same between ibogaine or psilocybin or DMT in addictions. You disrupting these over-learned, these persistent patterns of over-attention

and over-increasing enhanced love for drugs. You can perhaps break down those habit circuits and then allow people to escape. Meaning that things like the default mode network? Yeah, that's right. So I mean, our current thinking about how psychedelics might be used in psychiatry is built from this remarkable finding that the psychedelic state is a state where you have completely disrupted the default mode network. This is the network in the brain, in which your main sense of self, the core of you is

in the default mode network. Embedded in that, of course, is whether you are dep you know, your depressive thoughts or whether you love objects, you know, you're heroin addict. Anything that's really related to you is embedded in the default mode network. If we can disrupt that with psychedelics, how innate is that versus how formed is that? The default mode network, I think, exists in children and babies and it is what you are. It is the part of the brain in brain where you encode yourself, your reference, your referential memories, your plans, your retrospect, you're looking back, looking forward, putting everything. It is where you are. We know that if you damage the frontal

part of the default mode network, your personality changes, you damage the posterior part of the default mode network. You become a very strange person who really struggles with coordination and integration. So the default network is a fundamental part of orchestrating what you are. But in that of course are all the things that you have been. So in the default network coordinates your access to good memories, to bad memories, to use of drugs, to resisting the use of, et cetera. But in a very simplistic way, that sort of current thought thinking is that some elements of the default mode become misaligned or malignantly overengaged with negative thinking

in depression or compulsive attitude to the seeking of drugs in drug use. And if we can disrupt those with psychedelics, then potentially people can kind of restore a normal balance in that network and have a more rational approach, a less determined. So the brain is kind of determining things like addiction.

And even though people don't want to use the drugs, they often find themselves doing it, even though they don't want to, because their brain is kind of driving them that way. And we're gonna come back and talk about the impact of psilocybin on the default mode network, but I guess to your point, this might be one of the ways in which I Bogane or I Boga kind of help rewire a brain for an individual who is opioid addicted, which isn't of itself kind of an interesting thing, isn't it? And that there's got to be a genetics susceptibility to this, because there are many people who take tons of opioids during, you know, say a post-operative recovery from surgery,

and, you know, they take tons of the stuff, and then when they have to stop it, they stop it, and that's the end of it, and yet there are other people for whom that's not true. So, do we have a sense of what that genetics susceptibility looks like, and is it more importantly, is it possible to predict that a priori so that we would understand,

hey, this is a person who is at such high risk for opioid dependency, that even if they have to get their wisdom teeth pulled out, we are not giving them this medication. We're gonna come up with a totally different pain management strategy. Yes, theoretically, it is unlikely to be in the genes.

Oh, well. It's probably polygenic, I'm sure. Yeah, exactly. There's unlikely to be in the genes. Oh, well. It's probably polygenic, I'm sure. Yeah, exactly. There's not going to be a gene. What do we know about why people have become addicted? Well, we know social factors are hugely important. You know, I mean, if you've seen the wire, then you know that downtown Baltimore... I lived the wire.

Well, I mean, I did my residency in Baltimore. So I took care of the patients in the wire. Yeah. It's a frightening place, isn't it? Unbelievable. The book, the corner, which the wire was based on, was the book I once I matched to do my residency in Baltimore, a friend of mine who was a year ahead of me at medical school who had already now spent a year in Baltimore. I was like, hey, do you have any advice for what I can do to kind of get ready for? Because I'm moving from Stanford to Baltimore. You can't go from the most posh place in the world to the least. His only piece of advice was he said, read the corner, because it's literally what you're going to be living in. And it will give you a great sense of empathy for the patients that you're going to be taking care of. And it's a

riveting book, which ultimately became a riveting series. Absolutely. And a couple of years ago, I was on my way to Philadelphia from Washington to give a lecture. And as we pulled out of Baltimore, I was looking out at the train window. I think you, it's like a water. Is this Hiroshima? Because the downtown board, you know, I hadn't realized quite how destroyed it had been. And if you're living there, and you've got no job, I mean, and the only thing you can do is deal drugs, you take drugs, you deal drugs. So a lot of drug use addiction comes because that's the one way people can actually achieve both the sense something that takes away the misery of their lives, but also in a way if they become drug dealers become some a role.

So coping with life stress is one reason people use drugs. But there are some people, you know, very, the rich, successful people who still use opiates and getting into problems with opiates. And I give two examples of this, two Oscar winners, Taita Moneagle, youngest ever Oscar winner, Mara's the best greatest tennis player in my career. There's maybe ever been. You know, got two wonderful kids, lives the life that everyone envies, you know, she's famous, beautiful, everything there. But when she comes out of heroin treatment, she says, the only time I felt whole was on heroin. I see that with

patients, not just heroin patients. I see that with patients not just her own patients. I see it with alcoholics. There are plenty of people for whom alcohol makes them what they want to be. Only when they're drunk that they're actually functioning normally. And why that is we don't know. And actually one of the interesting things, you know, the reason I want to study psychedelic because I'm wondering whether whether that gap that can only be filled by drugs could actually be kind of refilled or at least remodeled with psychedelics.

And then of course, there are people who use drugs to get high and then they find somehow that their brain becomes sensitized to the drug use. So that they lose control. And that's more classic with people you use cocaine or crystal. So let's talk about those two drugs just from a mechanistic standpoint and where the risk actually comes from, take your choice which one you want to start with. It's not with cocaine because that's the first, well there was several cocaine epidemics but I mean let's talk about that. Yeah, I mean cocaine, I give a lecture seven times, it was Freud right to give up on

psychopharmacology because of course, Freud was a great protagonist. Freud used cocaine himself, he thought cocaine was a very powerful drug for getting people of heroin. He got one of his his disciples off heroin by giving them cocaine. He didn't realize he cocaine also caused dependence. in fact Freud and his protegey both became cocaine dependent. That's another Hopkins linked by the way in Baltimore was the basically the father of the surgical residency in the United States and the first chief of surgery at Hopkins, William Stewart-Holstead himself became addicted to cocaine when he became obsessed with it as a

local anesthetic. And so in the in the process of experimenting with it as a local anesthetic. And so in the process of experimenting with cocaine as a local anesthetic, which of course it became a very potent and remarkable local anesthetic, he and many of his residents became cocaine addicted. It's a footnote to this story of the creation of the Great American Surgical Institute. Well, it hasn't stopped. They don't get addicted to cocaine anymore. They get addicted to remi-fentonal usually, the anesthetist. But that's another story.

Let's get back to cocaine. So I think the reason Freud went into psychology was because he got them, he can completely terrified of pharmacology, because he kind of assumed that any drug would have that problem. So you know, you can maybe get, make your cocaine credit for the development of psychoanalysis. But when we get to the modern era, you know, cocaine is the ultimate fund drug. It gives you energy and drive and an enormous sort of sense of focus and purpose and then a terrible crash. And we know that it's due to the release of dopamine and neurodren

in the brain, but it's very spiky and during the course of a binge over the weekend, you know, the brain gets perturbed and then people start to get paranoid and withdraw. And some of them will get sensitized and become addicted. And some of them will die because of course, there's a cardiac effect. And also there's this problem that if you mix cocaine and alcohol, you get a drug called coca-ethylene, which is a longer of acting and more cardiotoxic version of cocaine. You know, I have patients who, our patients are always going to disclose to us what they use.

We ask this question point blank, which recreational drugs do you use? And a number of them will say, hey, you know, two or three times a year, I use cocaine, and they want to know what I think. And again, the goal in that situation is not to come across as preachy and dogmatic, but it's to sort of have a point of view and have it be grounded. And my point of view with cocaine has always been, I don't think it's worth the risk. And I don't think it's the right kind of drug because, you know, just as much as we're now talking about a framework for drugs, I have a much simpler framework for drugs, which is, it's really only got two levers.

One is, what is the physical risk of this drug, to me as an individual? So with cocaine, what is the true risk of cardiac toxicity, what is the risk of deepening physiologic dependence over time, et cetera? And then the second component to my framework is, is this a drug that only alters your state, or does it have the potential to alter a trait? I'm borrowing that from the book called Altered Traits, which gets into this distinction. And so the idea being is, Silasibon for anybody who's ever taken it is clearly a drug that alters your state. But if it just altered your state, you probably wouldn't taken it, is clearly a drug that alters your state.

But if it just altered your state, you probably wouldn't take it, because it's really not that pleasurable. But the real benefit of is the potential to alter a trait, whether it be depression, smoking cessation, or something else. And so if a drug can only alter your state, but it has no potential to really alter your traits,

i.e., how you behave off the drug, is it worth it? And so my, the way I explain this to patients is I say, I don't think cocaine can do that. So therefore it has two strikes, it's O for two in the Peter framework. It has a physical risk that is non-trivial, and it's not going to make your life better when you're not taking it.

And therefore, I think cocaine makes no sense to take. Do you agree or disagree with that? I do very interesting analysis. I like that. I might start using it. So do you agree that basically there isn't a positive to cocaine that I'm missing? There isn't a benefit to it?

I certainly would say absolutely true for crack. For cocaine, I'm not tired of this. I mean, I think there aren't people who can use it just once or twice a year without getting into much difficulty. Provided they don't have serious cardiac problems, so I certainly wouldn't be using it at my age. But then look at, like there's the famous famous example which basically accelerated the war on drugs, was the case of Len bias in 1985. Are you familiar with the story of Len bias?

Oh, he was probably the most famous high school, pardon me, college basketball recruit. So he played basketball at the University of Maryland, a complete superstar, basically on the level of a Michael Jordan. And he was drafted by the Boston Celtics, and probably he'd gone on to play for the Boston Celtics would have altered the course of the NBA for the next 10 years. The day following the NBA draft, he was back in Baltimore, celebrating with friends. They're at a party in their dorm room.

They're using cocaine. He has a sudden cardiac arrest and dies. And this really, really shocked the nation. This was a really big deal. And certainly some would argue that that only reinforced and doubled down on sort of the Nancy Reagan-esque, just say, no, mantra, which of course reinforced the war on drugs. So again, when you can have this totally, you know, the healthiest 21-year-old in the country can die, and you don't know what, you know,

the details, right? How much was he on? Was it laced with something? No, but you've got to remember that, you know, certain death in Athens, we just have the European Football Championships, and one of the star players, Erickson from Denmark, had a cardiac arrest on the pitch. So super fit athletes might be more susceptible. Yeah, particularly if they've got a big and they've got some kind of cardio, I'm happy. So yeah, athletes are paradoxically more potentially, at least as vulnerable as other people, to these effects.

So talk about methamphetamine, crystal meth, these drugs, which obviously the amazing Netflix series Breaking Bad brought everyone awareness of what these drugs are, but physiologically neurochemically. What is it that they're doing and what is the danger? Well, they're very similar to KK. I remember as a junior doctor, my very first period as a junior doctor giving methyl amphetamine intravenously to a man who had serious stasisaticus. Amphetamines were developed as a treatment for asthma. They were developed as an alternative to a fiedra.

A fiedra is a natural plant product. It was discovered to have this bronco-dilating properties back in the 1800s. There was a huge demand, the plant couldn't supply the demand, so German pharmaceutical companies went away and made a synthetic FEDRA, which they called Amphetamine, and it was used largely for the treatment of As, really to the Second World War, where people realize it could actually be used to keep soldiers awake. And it's another interesting aside,

I'm very interested in the history of drugs in war because they tell us quite a lot about the consequences of drug use. And I often give a talk. When I talk about unfetterings, I compare the allies. So the Brits and Americans, we use unfetterings' sulfate. Whereas the Germans and the Japanese thought they were really clever, because they

had this super unfettering called methane unfettering, which lasts a lot longer. But what they didn't realize was that longer is not better. And the turning point of the war was actually the North Africa campaign, when the Germans were pushed back when they got to Egypt. So, Romano was pushed back by... Romano's last day, yeah. That's right, absolutely, by the desert rats, the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the... the and the way the desert rats used to work was that they would be up all night working around the Germans harrying them blowing them up and then they go back

Are they that way they be up all night on and fetamine sulfate and then they go back in the sleep or day But the other Germans would take me thought I'm fetamine to stay up to defend themselves against the desert rats But they couldn't sleep in the daytime and eventually they became sleep deprived of paranoid. And the same with Japanese, you know, these descriptions of how the Japanese became a, had these terrible hallucin, sensory, somatic hallucinations from using large doses of crystal meth for long periods. So crystal meth is longer acting and probably more neurotoxic than I'm fencing sulfate. Talk about the neurotoxicity.

What actually happens to the person's brain? You certainly have this meme of the crystal meth user, right? No teeth, bruised, pin skinny, emaciated. But that meme doesn't actually tell me about their brain. What's actually happening to them? Well, they're certainly pushing their dopamine system to a point where it's probably depleted and that seems to then lock them into a state where they can't really function normally in the world without taking the drug.

There's also a bit less good evidence that it might also damage the dopamine pathways to the frontal cortex, which impairs the ability to make judgments to the executive function, etc. But I have to caution it. I mean, the big concern about crystal meth actually came as a result of the Japanese, after the Second World War, there were factories, crystal meth factories in Japan, there were barrels of the stuff, and there were a lot of Japanese soldiers had nothing else to do, and they used to use huge doses of crystal meth

off an intravenous tea. And the evidence for brain damage really comes from that population, they're not so much evidence from it being when it's being used, as it tends to be used now, orally, in more prolonged periods. So I'm not sure that you get a lot of what you might call cortical damage with crystal meth,

but I think it definitely does distort the dopamine pathways in your brain and will affect your motivation and your ability to sort of get up and get activated, etc. So now let's talk a little bit about these drugs that unfortunately, or they seem to have the same scheduling and therefore they're viewed by the DEA as both as dangerous in terms of harm or risk of addiction and as medically useless. Because really, that's the criteria for schedule one, right? Is high potential for addiction and no medical use. And so cocaine does not fit in schedule one, right, is high potential for addiction and no medical use.

And so cocaine does not fit in schedule one because while it is highly addictive, we at least have one appropriate medical use for it, which is, and it's a great anesthetic especially in the nose. Obviously, fentanyl is not schedule one because even though we acknowledge it's highly addictive, it has this pain-blunting effect. Remarkably, psilocybin is schedule one. MDMA is schedule one. LSD is schedule one. So let's talk about these three, which are if you believe the DEA scheduling the worst possible drugs imaginable because by definition they must have a high addiction for potential and they serve no medical benefit whatsoever.

So take them in any order you like. Well, let's take the psychedelics first because that's how it all started. I mean, these drugs were banned not because they had any negative impact. They were banned in the face of opposition. Bobby Kennedy confronted the DEA and the FDA when they said we want a ban LSD and he said hang on a second, hang on, we spent billions of dollars researching LSD up till this time and we got loads of positive results. In fact his wife was being pleased. Was he still the AG when he was having this discussion with them?

Was he still the Attorney General of the United States? No, no, no. He was, he was Secretary of State. He was about to get elected as president. Yeah, yeah, this was later on, yeah. Just before he was assassinated. Yeah, yeah, okay. And he's saying to these kind of, come on guys, you know, we've had 15 years of this remarkable research,

which we've invested in. NIH in the States funded over 130 grants to study the therapeutic use of LSD and they found it was very therapeutic and very little harms and then the DEA come and see IA come and say we've got a ban it. He's saying what you're talking about. And of course what they were talking about was the fact that the hippie movement was starting and the hippie movement was anti-the war in Vietnam and LSD was seen as fueling the hippie movement was starting and the hippie movement was anti-the war in Vietnam. And LSD was seen as fueling the hippie movement. But also worse than that, it was changing music and people were dressing differently and putting flowers in their hair

and they were sticking flowers down the guns of the soldiers. It were trying to stop them protesting the war. You know, it was changing the whole tenor of, I suppose what you might call, sort of intellectual debate in America, particularly among students. And it was seen as a real threat to the American way of doing everything, which was basically having bigger and better bombs and guns. And so LSD got banned because it was essentially changing the way people voted.

People didn't want to vote for war. But they couldn't ban it in those days. They were rules, which said basically you had to find harms, and those harms could be physical harms or they could be social harms. And it's very easy to find social harms because you just get a few editors of your national inquire or similar rags to just invent stories about the harms and the way people have been corrupted by using LSD. And it's wonderful. I mean, it's sad, but it's amusing now, but of course, very damaging. It's front covers of these magazines, when newspapers making absurd claims about LSD, usually with semi-naked women. And that was enough concern. Editors are socially concerned. Then we can ban the drug and it got banned. And once Ellis DeGott banned all the other Syritonurgic hallucinogens

that were known about at the time. And actually in America you did know about quite a lot. A lot of countries didn't know that there were more than LSD and psilocybin. So some countries didn't ban DMT or five mythoxy. But you Americans, you just banned it all because you had good scientists. So Ellis DeGott banned for political and social reasons. No, not because of any harm. If Tim Leary had not been around, would it still have been banned in your opinion? Probably not. I think the fact that he was encouraging a fundamental change in the American way of life through using drug life. I think he certainly compounded the problem. And he certainly popularized at SD and encouraged people to think differently about society.

There was a genuine fear that Americans would actually cease to want to fight wars and actually want to have peace. And that was just seen as being extremely bad for the American economy and of course the American presence in Tennessee. So prior to the scheduling of LSD, you mentioned over 130 grants had been issued to study it. This was a drug that had been manufactured in the late 1930s by the pharmaceutical company Sandos, what were some of the things that they had learned about LSD under that period of time in which it was studied rigorously? So, there were 40,000 patients studied. 1,000 papers were published, and there means analyses of many of these groups of patients,

and they discovered that it actually was very safe. If anything, it reduced suicide rates compared with non-treatment. And you've got to remember at the time in the 50s and 60s, there were very few alternatives. We had modern, so-called modern, a particularly antidepressants hadn't been really invented till the 1960s.

It was shown to be effective, and it was shown to be safe, and it didn't cause psychosis. So actually, this was the revolution, this was the beginning, the dawning of real psychiatry. Psychiatry was becoming like the rest of medicine. We had tools that we could help people with other than talking.

And in what context, David? So, would that be like a single dose of LSD combined with a prolonged period of psychotherapy during the period of time under which the individual is under the influence or did it require multiple treatments? I mean, do you have a sense of what was required for that efficacy? But it was used in two different ways. So in the states, the typical use was what how we're using it today, which is give people a bigish dose, give them a big trip, a few hour trip, and then afterwards

help them work out what the trip meant. So it was always done in the context of psychotherapy, because in those days all American psychiatrists were actually effectively, mostly Freudian analysts. So it was always done in the context of psychotherapy, it was allowed. But in Britain, we often use lower doses, and we use that repeatedly to try to break down psychological resistance to actually gauging in psychotherapy. And what was the difference in those doses, David? So the big trip dose would be how many micrograms? So for LSD would have been 100 or 125. And then for the reducing the resistance, we would say in psychotherapy, breaking down the resistance, it would be perhaps 25 micrograms.

And is 25 micrograms perceptible, or is that considered a microdermot? No, no, that's perceptible. Anything over 10 micrograms is perceptible. Even 10, a lot of people can discriminate 10, not in the scent, not because they're psychedelic, but they can feel. Something's different.

Yeah, I feel things in this, exactly. And in the case that you describe in the UK, how many treatments at that lower level and at what interval were typically necessary to produce the benefits? Well, they'd be weekly, maybe maybe for 10, 15, 20 treatments. So it's just an unbelievable loss to this scientific community when LSD becomes scheduled. Absolutely. Perhaps the biggest loss of all is relation to alcoholism. A lot of people don't realize that there's a founder of alcoholics and non-immers, Bill Wilson.

He escaped his alcoholism. He broke free from the chains as he described it. He escaped the chains of his alcoholism through a psychedelic experience. That was before LSD. And then when LSD came along, it was legal, he tried it and he said, wow, this drug could help lots of alcoholics escape from this belief that the only thing that matters to them is alcohol. It could give them a sense that

there is more, that it is possible to change. And he was, he persuaded, or as instrumental in six trials of LSD for alcoholism that conducted in the state. So one or two doses in people with alcoholism. And a few years ago, a couple of Norwegians went back and they dug out the old data and they did it, put it through a modern meta analysis, collate all the data, you got an effect size of One which is twice that of any subsequent treatment for alcoholism LSD was a revolution in the treatment of alcoholism now In the 50 years since LSD has been banned, you know, you can make a rough Coaculation worldwide over a hundred million people have died Prematurely from alcohol use disorder.

And if LSD helped perhaps, just 10% of them, that will be 10 million lives saved. Now you ask a question, well how many lives have been saved from the ban? Well, I'm not sure at LSD. Maybe let's say globally maybe 50 lives a year, I've been saying because fewer people took it possibly. So then you say, we've got 50 years times, there's just 2,500 lives saved, and 10 million lives lost. So the equation is so balanced

against the decision that was made. It really, I think it's the worst censorship of research in the history that was made. It really, I think it's the worst censorship of research in the history of the world. And what are the typical harms of LSD? Is it basically self-harm inadvertently through people who are tripping to such an extreme level that they, you know, you hear these stories,

well, this guy thought he could fly and he jumped off a building. Sure. Well, the CIA were very good at promoting those stories, but there are, okay. Unquestionably, people do dangerous things when they're taking LSD in dangerous places, and we should mitigate against that.

And I can promise you, when we do psychedelic therapy, we lock the door so they can't judge. Okay. Okay. How many, here's a statistic in Britain, and I imagine it's even way worse in the states. Each year in Britain, probably 20 to 30 people die jumping, usually drunk from pears or break waters,

or even from hotel balconies into the swimming pool. So probably more people die each year jumping from alcohol. There's nothing of automotive accidents and liver toxicity and respiratory depression. Just the jumping. Okay, so LSD, if you take LSD, a dangerous situation with people who are also tripping and you're not got someone to look after you, then of course it's, you know, there is a risk. But when LSD was used in these 40,000 patients in hospitals, there was very little evidence of any harm at all. Okay, let's talk about its cousin, solar siren. Yes, the solar siren, of course, has been around a lot longer, solar siren is a present

in mushrooms, there are about 200 species of magic mushrooms, different ones, and different parts of the world. It was really the beginnings of the psychedelic revolution where LSD and Hoffman and Gordon Watson, the American mycologists, who discovered a tribe in Mexico that were using mushrooms for psychedelic experiences and actually went and exposed them and actually rather destroyed their culture by making it a target for tourism. So psychedelic mushrooms have been around forever because mushrooms have been around way before humans.

One of the interesting theories about Hinduism, you often wonder, you know, why do Hindu gods have so many arms? Probably because the first people that became Hindus have been using this cocktail called Soma, which of course was the term was adopted by Alders Huxley and Brave New World, but the real Soma was a powerful mixture probably of magic mushrooms of a fiedra and cannabis. You mix that a lot together. It's not surprising your elephants have five heads and four arms. So magic mushrooms have been around in many cultures for millennia. That active ingredient was discovered. The cytosybin as being the active ingredient was also discovered by Hoffman, because Watson

went in and said, why is this causing hallucinations like LSD? And he's like, oh, well, because it looks a bit like serotonin, a bit like LSD. And we've been working that with Silas and we've been working that with Silas and I've been for a number of reasons. The main one is that it doesn't have the stigma. You say LSD to a politician and they immediately turn off. LSD is a bad thing. Whereas Silas and I've been, they don't know how to say it,

they don't know what you're talking about. And how can you be worried about magic? That's only a mushroom. The second reason we started using side of cyber is because we didn't have safety, really good safety data on any of these. But we did know that in Britain, magic mushrooms were legal until 2005.

And we knew about a million young people a year were using mushrooms mushrooms and we persuaded our regulators they could let us use mushrooms because that body of evidence of safety was adequate and they said okay yeah what led to the scheduling only 15 years ago I mean what was happening that in 2005 they said we've got a ban this thing is complicated so the active ingredient silo sibin was banned in 71 alongside LSDDMT. But the mushrooms weren't banned. Why would you ban the mushrooms? They don't have much of it. And who cares if people are going to go and lie on a side of a mountain and see pretty pictures in the sky.

But what happened was that a couple of head shops in Camdentown, North London, started selling freeze-dried mushrooms. So they would concentrate the dose? Well, it's not just that. Like you could take more of it or was it just the fact that it was being sold commercially in the head shop? It could be sold in London and so no one really cares if people go and you know, line them on a hillside in Devon. That's quite fun. But if someone selling a dangerous psychedelic drug to our young people in London. The right wing press just went, eight, these were probably the same shops that sold Doc Martins, by the way,

because I know those head shops, they're very dangerous places. Yeah, absolutely. That's a, and it's a, there was a classic example of political expediency. The Tory party had lost the third election in a row to the Labour party, Tony Blair's Labour Party. They brought in a new guy called David Cameron. And David Cameron had spoken previously about, you know, he'd used drugs and he was in favour of drug reform.

But as soon as he became leader of the Tory party, he became anti-drugs because that's what he was told to do. And he saw these newspaper headlines, head shops corrupting our young people. And he started goading the Labour Party. Yeah, soft on drugs, just soft on drugs. You know, look, they're selling this illegal, the drug wasn't illegal, but the mushrooms were into illegal, but they made out they were. And Tony Blair, instead of saying, don't be stupid, he did what many liberal leaning politicians do. In fact, exemplified in your country by Clinton. Clinton was the guy that was told the Democrats had to be harder on drugs and the Republicans. And he's the guy with the

three strikes that you're in prison forever. And the same with labor. They were told, if you're not tougher on drugs or as tough as as the Tories, you're going to lose the election. So he go to Blair into making the mushrooms illegal. And he did it without consulting us and without, he actually broke the law. But we discovered that actually governments are allowed to do that. We can, even if you take them to court, they can just change the law to prove it, you know, to allow them to do what they did. So, yeah, so the mushrooms are now illegal, as well as the active ingredient.

And then MDMA itself is not really a classic psychedelic. You know, there's sort of a framework for these psychedelics where you've got the kind of the typical, the atypical, but sort of if you have sort of psilocybin LSD here, you've got MDMA here, more of an empathogen, and then you have ketamine is more of an empathogen, and then you have ketamine is more of a dissociative, and then these really atypical ones like I began, which we've already talked about. So, let's bend just a minute on MDMA, because again, I think it's one that, well, first of all, people confuse MDMA and ecstasy a little bit, and it's probably worth clarifying the

nuance is there, but also talking about the potential that it has. I've had, you know, Rick Doblin on the podcast before, so we've gone incredibly deep on the benefits of treatment for PTSD and we've talked a lot about maps. We don't need to go that deep, but just for someone who maybe hasn't heard that, what would be the overview? Well, MDMA is a great American invention. Yep.

Well, your top drug chemist, Sasha Schulgen, was interested in derivatives of emphetamines. MDMA was made, you know, back in 1904 as a possible agent for blood clotting, but never got used. And Shulgin made it in the 60s and said, wow, this drug is different from emphetamines. It's not activating, it's not driving me like emphetamines. It's actually making, it's given me a clarity of thought, but also a sense of warmness and empathy. So we gave it to his wife and she said, wow, this is a very, you know, this is empathy. This would be really useful in psychotherapy, couples

counseling, it would potentially help break down, you know, those layers of irritation and grits that build up in relationships sometimes, put people back into love. And it was widely used for about 10 years by therapists, particularly in the west coast of the states. And it was called empathy, and everything was fine. And then some smart-ass in Texas decided, this is a legal drug, and we could sell this. We can't sell our vitamins, but we can sell XSE because it's legal. But who wants a bi-exec? So they changed their name to XSE. So they didn't want to buy empathy,? So they changed their name to ecstasy. So they didn't want

a bi-emphasis, sorry, they changed their name to ecstasy. You got an amphetamine which can help keep you active, but also make you much more in love with other people. And it became widely used. What's, you know, it's the perfect drug for parties, isn't it? You've got energy, but you're also happy, you're not fighting people like when you do, if you're taking speed. And it became hugely popular and it spread into Europe. And then, of course, it just riled the right, the Puritans, it riled the right-wing press. The idea that young people could have ecstasy when, oh, the Newspaper owners couldn't even, would never had it and couldn't even remember, didn't even know what it meant. They just didn't, you had this moral outrage, which eventually got the drug banned. But again, you couldn't

in America and Britain in those days, you couldn't ban a drug just because kids liked it. You have to find evidence of harm. And some of the worst science has ever been done is the science proving or supposedly proving that MDMA is harmful. And you're culminating in that amazing experiment, it was done by Recarty, which is very embarrassing for Johns Hopkins, you know, when he claimed that taking MDMA and listening to the poaches overnight gave monkey's brain damage, and we all said, well hang on a second, none of our kids are coming out of the club's brain damage. I think your experiments are wrong, Recarty. He said, no, no, it's right.

Exoccurse his brain damage. And he got published in science, despite the referee said, this is gotta be wrong. And of course eventually they went back and they audited what they'd done. And instead of giving the monkeys MDMA, they give them crystal meth, which is way more toxic. That paper was recall.

I mean, he did have to pull that paper in. He didn't. No, no, he didn't retract the paper. He just put it. It was never retracted. I think you can still find it. If you look in science, you'll still find it's there. It's not struck out. I think you'll just find there's a there's a correction. Sorry, guys. This wasn't an MDMA. This was actually methamphetamine. Wow. Terrifying. So that's that So that's our answer to Andrew Wakefield for you, huh? Indeed. And it's embarrassing really because, well, for all sorts of reasons, because it's so much American science is paid by the government. Apparently, I don't know. I heard that the editor of

the magazine science was told by senators that the American Academy of Science, which runs a journal, would not get government funding if he didn't put that paper in and get it published to deter young people from using MDMA. Of course, all that happens is in the end, young people think this doesn't make sense, and then they discover they've been lied to. So are they going to listen to anything else the government tells them? Yeah. Let's talk briefly about ketamine before we come back to psilocybin, because I want to sort of double click more on psilocybin specifically for the treatment of depression, but just

to round out all of our sort of psychedelics, ketamine of course is the only drug on this list that is legal. So I believe it's a schedule three, perhaps a schedule four, used as an anesthetic typically, and it's quite dissociative. So can you talk, I guess, specifically about the use of ketamine in treatment-resistant depression, which seems to be one of the more promising areas of research? Yes, a wonderful story. And it goes back to John Crystal, who's a professor up at Yale, and he was using ketamine to model psychosis, and he was comparing ketamine and THC to model psychosis. They both produce all sorts of states of consciousness, which sort of have

some overlap with psychosis. But he noticed that afterwards his volunteers often felt better. You know, they actually came out of the ketamine experience saying, well, that was weird, but they had an improved mood. Maybe this is mood elevating. So then he and his colleagues went on to the study, yeah, ketamine elevates mood. And for a couple of days after a ketamine trip, your mood is definitely improved. And now there have been about 30 studies showing that ketamine can have a value, particularly if you add it on to other treatments of depression which have not been very successful. So if people are partially recovered, give a bit of ketamine and then mood gets better.

The problem with ketamine compared with what we're going to talk about in a minute with cytosine, and is the effect is very short lasting, it lasts only two or three days. So currently what you have now is a licensed medicine. Janssen decided to pursue this, because this was the first real breakthrough in the treatment of depression for, really for 50 years. So they, but you couldn't patent ketamine,

because ketamine was being used back in the Vietnam war as a buddy drug when people were being blown up and having it as an analgesic. So they took the enantiomer, one of the isomeras of ketamine called S, the SN SN-antium, and they're quite S-ketamine, and they formulated it for nasal inhalation, so you don't have to inject it, which is better and easier for psychiatrists. And now that's sold as a treatment, and it's called S-ketamine, it's providing. And it works, and you take it a couple of times a week, and then gradually over time,

you use, you don't, less and less as the patients recover from it. So you don't develop attack you for access to it? If you do it twice a week, you don't, no. And you are able to get patients off of it while still preserving the antidepressive benefits. That's less clear, but in some, that's true. But it does, there is an advantage of it over ketamine, ketamine clinics tend to, you have to give it intravenously or

clean as they weren't yeah, we're in for muscully, but also the problem there is that's in a ketamine is a dependence producing drug. It's a drug a recreational drug, and you know, it's relatively popular in Britain is relatively popular in China. Probably popular or some of the states. I'm not sure what the stats are. The problem is you do get tolerance, tacky for laxies if you use it regularly. So while it's relatively safe in the doses you might use, you know, maybe, you know, 500 milligrams for depression, if people are using it recreationally and taking more and more, they're getting up to grams a day and then you get into serious problems, you get bladder

problems, you get a, basically you get a severe chronic stytus which can cause bladder atrophy, needing bladder resection. And you also get a psychological state, you get a kind of you can get brain damage or at least you can get a state of severe cognitive impairment, which actually brought the mimics schizophrenia. So, so heavy use of ketamine is actually really to be avoided. And what defines that? I mean, those are very scary things you just described. Obviously, the psychiatric component much more than the urologic. What is too much? I mean, because I'll tell you, this is something I get asked a lot.

Hey, you know, I'm going to this ketamine clinic once a month. It's changing my life. You know, at what point does that become too much? Well, certainly daily use is too much. People who are addicted to ketamine are using it four or five times a day. They might be using five grams a day. That's when you get into the serious brain damage. I think twice a week, oh, I think we know from this ketamine twice a week seems to be without, I don't have any enduring problems with other.

But if you're not using the enantimer twice a week, we'll probably still produce a tacky flaxis and a diminishing return at some point. Yes, but this, one of the really interesting questions and we don't understand this, why is it that when people use ketamine and they get tacky flaxis, they can overcome it by taking more. By the way, I should explain to people

what tacky flaxis is because we're using the term without me defining it. It's of course, when the same amount of a medication produces a lesser and lesser effect or when you require more and more of a medication to produce the same effect. So for example, we don't generally get tacky phalactic to Tylenol, right? You have a seat of benefit. And if you take 500 milligrams and your head

eight goes away, you know, the next time you take 500 milligrams, it does about the same thing. So to your point, you can push the dose a little bit and stay ahead of it with ketamine. Correct. You can. You can, like heroin, like fentanyl, you can overcome the tolerance. But with psychedelics, you can't. And that's an interesting phenomenon and it's probably to do with subtle changes in the downstream mechanisms in the cells that you get an almost complete absence of effects of psychedelics after two or three doses. And do you know who told us that? The US government. So the US government were very interested in or fearful actually when psychedelics came

around in the 50s. They thought, well, maybe the Russians will be spraying LSD on our troops. So how can we protect our troops from LSD? So they started giving troops LSD to find out what the effects would be to see how they could abort them. And they discovered by the third day of giving the troops LSD. LSD had no effect anymore. Well, I didn't realize that was the case. So if you're talking 250 micrograms of LSD, at some point people are going to stop responding

to that. Yeah, but the second dose will be less than the third. If you take it every day, the second dose is way less than the first and the third. But what if you're taking it once a month, for example? No, no, no, it takes about a week to recover. The effect disappears between about one and two weeks depending on how much you take. I see. So it's not a lifelong tacky for laksas. It's very temporal.

No, some people do say, well, a lot of people say that for all drugs, the first ones are with the best. But yes. Yes. So you can't overcome the tacky for laksas for psychedelics, whereas you can with heroin and you can with ketamine. And why that is is not so clear as the way that is.

All right. Well, there's so many more questions I have about this David, but I know we have a very hard stop today. So I want to make sure we have some time to talk about your most recent work with psilocybin and depression. About three months ago, a study was published in the England Journal of Medicine. You were the senior author on that paper, I've written about it at length, which compared psilocybin to lexapro, a very, very popular, commonly used reasonably well tolerated SSRI. Do you want to just give people a quick overview of the study design and what you set out to test? Oh, be pleased to. Yes, so previously we had done a study, an open trial, we'd taken 20 people with resistant depression, we'd given them a single psilocybin trip

and found very good outcome. But effect didn't last very long, it lasted, you know, two to two months, but for many of them, the depression came back. Based on that, and also some theoretical work I don't, we've Robin Carr-Harris, who was with me at the time, he's now moved to UCSF. We came to the conclusion that psychedelics treat depression in a different way to antidepressants.

And that paper is published in general psychopharmacology, it's called a Tale of Two Receptors. It's a free download, feel free to read it because it conceptualizes that there are two ways you can lift depression. One way is with Lexipro or other similar drugs that enhance your attoning in the limbic system and there they basically block the stress response and we know that stress is a major cause of depression. You block stress induced depressive changes in that, and that allows the limbic system to recover. So it's a bit like, if you have a broken leg, you set the leg in plaster so that the bone can heal itself. SSRIs set the limbic system in plaster, so over a period of six to eight weeks,

they can heal and get you over your depression. And that's sort of a particular subtype of serotonin receptor, it's called the serotonin 1A receptor, which is in the very expressed in the limbic system. But we think psychedelics. We know psychedelics work in the cortex, and they disrupt cortical processing, and disrupt, we think, the deep, persistent, ruminations, and negative thoughts of depression. So we said, let's do a study. Well, we take the press people, we scan them with FMRI before and after, and then we see if we can, look at the brain changes are different with the esitalopram compared with the cytosybin.

Predicting that we would see cortical differences that the cortex would be changed by the cytosybin and the subcortical regions would be changed by the esotetopro. So the primary aim of the study was to see if there were differences in brain mechanisms, but of course we have to know whether there are differences in outcome. So we compared the mood-changing effects of these two drugs. But you couldn't just say, hey, you're on lexopro here, you're on cytosybin, we had to blind it.

And that's quite difficult with psychodetics. So the way we did that was to tell everyone that we're going to get cytosybing. But half the group got a low dose, a placebo dose, a 1 milligram dose, and a half got a high dose, a 25 milligram dose. But they all went through the same psychotherapy, depending, even matter what dose they got, they all got all the same preparation and, depending, no matter what dose they got, they all got all the same preparation and the psychotherapy that goes with the high dose of cytosybin.

And then they all got pills, but the esotalapram group got esotalapraman, the cytosybin group got the SIBO. So they're both getting two pills, one is getting a placebo plus the high dose of psilocybin, the other, yeah. And the point of that is what's called clinical equi-points. People have to believe that they're getting the best they can. And we gave them two doses of cytosybin, whether high or low, one at the starting, one after three weeks to see how long the effect would last.

And then we measured changes in in mood and we measured side effects. And we also looked at other aspects of depression, rather than just looking at depression scores, we also looked at things like wellbeing, which is a different way of looking at how people are feeling. And in the end, on the primary measure, there was no difference that cytosybin at six weeks was as good or equal to as a esitalopram, on that particular measure, which was a particular self-report measure called the quid self-report, which has been used quite extensively in research in the states, particularly in the study study.

But when we looked at all the other measures, actually, side-to-side, we did run the well. Yeah, so I want to pause on that for a sec, because I think that the paper was undersold a little bit. It read as a negative study, as opposed to a non-inferiority study. Why do you think that happened? Do you think that there was a mistake in the way that either the journal treated that or even the way you treated that as the authors? Yeah, that's a great question, a very perceptive question. That's a question I think you should ask the editors of the New England Journal. The truth was, it wasn't powered for non-inferiority.

If you want a proper non-inferiority study in psychiatry, takes 150 patients in each arm, we could never afford to do that. There's very few of them have ever been done except by, well, probably none have been done except by companies. We could not statistically do a non-inferiority study, so we had to just do a kind of comparison. And the answer was that, well, we have to, you know, you pre-specify, we pre-specify two outcomes, the quids and the well-being. And it did brilliantly on the well-being, but because that's kind of not, you know, that's sort of soft wishy-washy psychiatry, they insisted that we use the quid as the primary. Now, if you don't meet, this is a bit statistical sort of jargon, really, but if you don't meet your primary, you're not allowed to report the

secondaries. It's pureism, it's purestic statistics. But as you say, it's kind of not very intuitive because when you look at it, actually, it was very clear that they overall, many, well, there was not a single measure that favoured S. It's Hall of Ram and they were like, well, that's sort of the thing is, you know, I read the paper in great detail and my takeaway was, this is very promising because I'm very familiar with with Lexipro and I'm very familiar with its efficacy, but I'm also very familiar with its side effects and the baggage that comes with it. Most people for the listener, Lexipro is typically given at 2 doses, 10 milligrams or 20 milligrams. Going from 10 to 20, there is a so sizable increase in the efficacy, but

there's also a sizeable increase in the side effects. Many of them sexual. And when we're talking about treating young people, old people, middle-aged people, you fix their depression, but you destroy their libido, you're trading one problem for another often. And the list of patients I've taken care of who can't tolerate these drugs, despite the benefit that they're receiving from an antidepressive or anti-angiolytic standpoint, is significant. So, to me, I read that study with enormous optimism, right, which is,

if there is a way to give somebody 25 milligrams of psilocybin and get the same antidepressive benefits, but without these other side effects, this is very exciting. This needs to be explored a heck of a lot further. Do you think that the study at least accomplished that as an outcome? Yes. People have said, well, why didn't you fight back with a journal? Why didn't you demand that they were more positive? And the answer is, from my perspective, being the first ever psychedelic study in the

New England Journal of Medicine tells the world that cytosybin is a medicine. And it's as good as lexapro, and if anyone reads a paper can see that it does do better on sexual dysfunction, and it does do better on many of the other issues that lexapro is a problem with. And it fits with the theory that one of the things, it's very, the reason Nexopro and other SSRI's damp and down sexual activity is because they dampen down the limbic system, which is the part of the brain which drives those behaviors. And also people on these drugs often say, yes, I don't feel depressed anymore.

I don't cry. I don't have the distress that comes from seeing sad things on the TV. But they also say, but also I don't enjoy life as much because my pleasures are blunted. And that all fits. It's blunting the top and the bottom. Exactly. Whereas, Silasibin is stopping the thinking and allowing the rest of your brain to work normally. A word on microdosing, David, I even had to go back and do the conversion. So when I was

reading the study, I was going, wait, what is 25 milligrams of psilocybin mean? Because typically, when people are taking psilocybin, we're giving it to them in the whole mushroom, and that's typically like five grams. So of course, then I had to get really deep in the weeds and figure out which species of mushroom and what the conversion is. But the point is 25 milligrams of pure psilocybin is on par with about four to five grams of magic mushrooms and therefore it is truly a psychedelic experience. What is known about the imperceptible dose, like 100 milligrams of magic mushroom or one to two milligrams of pure psilocybin and its potential for antidepressive benefits? Well loads of people use it. Loads of people, you know, they go pick the mushrooms, they drive the mushrooms and they take them. I was talking at a festival a couple of years ago in Wales. It's got how the light gets in and it's a big intellectual music

and music festival. After my talk, a lady came up to me and she said, yeah, I've got to share you the, you know, I'm a nurse. She says, I got a kid, it's difficult. I'm not married. She says, but I got to be a remorning, you know, and I get the kid to school. I come back, she says, I'm a nurse, she says, I got a kid, it's difficult. I mean, I'm not married. She says, but I get up every morning, you know, and I get the kid to school, and I come back, she says, I have a cigarette, a cup of coffee in a mushroom, and I've been really good for the last few years. And there's a lot, anecdotally, there's a lot of numbers of people who are using mushrooms. Do they work or not?

We don't know because it's almost, the rules around these drugs, the schedule one status means that a single mushroom is just as illegal, as a bunch of mushrooms or as pure side of cybin. Four years ago, we got ethical permission to do a microdosing study with LSD, but they said, this is an illegal drug, a dangerous drug, every microdose had to be given in hospital. And then we cost it up, what it would take to buy all that time in hospitals, to do six weeks of microdose. And we couldn't afford it. And so there has never been a proper

controlled microdosing study of any repeatedly of any psychedelic. But from a mechanism of action standpoint, David, do you see a plausible path to microdosing being effective, given what you now know about microdosing? Well, it won't be as good. Obviously not a single microdose won't be remotely as good as a microdose. But say repeatedly, because I believe in your study,

they were given this microdose every two weeks, correct? Twice. Three weeks apart, twice. Yeah, that's right. But if we were given this macrodose every two weeks, correct? Twice. Three weeks apart, twice. Yeah, that's right. But if we were talking about microdosing three or four times a week at one to two milligrams, and we're talking about this type of a treatment over the course of a year, so apples to apples time wise, is there a plausibility here that you can see from a mechanism standpoint? Well, it'd be a great experiment to do.

I mean, I think it is, I mean, I think it's ethical to do that, because I think it is plausible that microdosing over a long period might do two things. I would be slightly surprised if it really elevated mood and depressed people, but it might protect people against a lowering of mood. And so one of the interesting questions, in fact, in many ways the fundamental question we have now, as a result of our two depression studies, is not that we can get bad people better. There's no question we're satisfying.

How can we keep them well? And one of the great things we know about the SSRIs is if you take them continuously, they do protect against depression. They do protect against the stresses of life-causing depression at the cost of blunting. So the question is, what could we do other than give them an SSRI after the psychodetic treatment and maybe microdosing would work? But until we get it liberated, until we get it liberating, until we get it out of schedule one and get it available, it's impossible to do those studies. Where do you think will be

the thin end of the wedge to make that happen? Obviously, Roland Griffiths has done great work at Johns Hopkins. Someone I'd like to have on the podcast as well, looking at psilocybin in end of life depression. Yes. Though I don't know where things are from a pathway perspective, there's obviously efficacy with smoking cessation and alcohol cessation and now your work with depression. Which of these will be the first domino that falls in your opinion to change the scheduling of psilocybin? I think depression, because a multi-center study

is going on in Europe and the US, the company called Compass Pathways, and they're doing a dose-finding study. They finished, they've recruited the last subject, they will get the results, hopefully, by Christmas or the new year. And that's a high dose, 25-minute-grain dose, a placebo dose, a 1-minute-grain dose like we did, and a 10-minute-grain dose in between. I think if that's positive, then the floodgates will open to their second study and also to funding of those research.

Now, compasses come under great scrutiny from some in their effort to basically do a land grab of intellectual property on a molecule that basically should be in the public domain. How do you think about that in terms of balancing the need to make something as widely available as possible to the public while at the same time needing to create an economic incentive to do so? Yes, well, of course, I have to express and I think helping them for a lot.

I mean, their compass pathways exist because of our first depression study. You know, they basically took our data and went and tried to do research with it. And they started off being a bit like maps. They started off trying to raise money by being a not-for-profit. Now, Rick Dobblin is a phenomenon, but it has taken him 25 years to raise enough money to do the maps phase three. After a year or so, Compass Pathways realized that they didn't have the resources or the skill or the personalities that Rick has.

Rick's a force of nature. He is. And they realized that they couldn't be a not-for-profit. They had to get the money for this to happen. They had to go down the more conventional route. So much as I would like it not to be the case, a reality is, if we want to see side of side with enough evidence in my lifetime

to make it a medicine, and I think that they are the people that most likely to deliver that. But on the other side, you've got Oregon. You've got Oregon, which voted in November last year, to make much rooms a medicine in two last year to make to make mushrooms a medicine in two years time. So it's actually a bit of a race now.

Does he? He's going to win. I don't know how Oregon are going to do it. I just hope they do it carefully and sensibly, but it might be that the mushroom ends up being the medicine rather than the side of Simon. It's exciting times. David, I promised you that at 6 p.m. I would draw to an end and we are at 5.59pm, so I'm going to stick to my word despite the fact that we are only halfway through what I wanted

to talk about. So I think the only logical conclusion here is that we will have to sit down and do this again if you're willing. I'd be delighted. It's been a wonderful conversation. Thank you so much. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring

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