#182 - David Nutt: Psychedelics & Recreational Drugs

Hey everyone. Welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website and my weekly newsletter all 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 peterattiamd.com subscribe Now without further delay. Here's today's episode. My guest this week is Professor David Nutt. David is a psychiatrist and a neuroscientist who studies medicine at Downing College, Cambridge, and he completed his clinical training at Guy's College in Central London. David's had a lifelong interest in the brain and we discussed 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 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, dissociative agents, and even atypical psychedelics. So the only thing I'll say about this episode that kind of bummed 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 whets 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 in my mind we will go into that. So without further delay, please enjoy my conversation with David Nutt. Hey David, 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. I'm looking forward to it too.

Let's start a little bit with 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 understanding that when I was probably four or five, I suddenly kind of realized that actually thinking was what actually made things. Makes 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 do, 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 went to neurology. And that got a little bit boring because it's mostly people kind of dying slowly from diseases like hemotrophic 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 you say that because I'm not making this up, but this, this morning my 6 year old son was in my office and he, we were sort of fumbling around and I, I have a whole bunch of racing helmets in my office and so he's putting them on and that, that got him talking about why we're wearing 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 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, yep, 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 originate. And he said, well, how. And I got to tell you, it was very difficult for me to explain how electrical impulses work. And of course I'm not going to 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, of the different forms of consciousness and the different experiences that humans have. And at some point, and I think what, you know, the point you raise is a really good one, it'd be really nice to then to migrate that down for, for children, maybe you know, as a series of sort of comics or graphics because I think, you know, I mean it is the most wonderful thing in the universe, the human brain. There's no argument about it. So let's get communicating as soon as we can.

Yeah, and I do think that 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, the doctor didn't turn up. I'm a medical student. So I said, oh, please, go and interview. Go and Clark, 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 there 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 just have to go. 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. And I thought, oh, that makes a lot of sense. That's why he doesn't make sense. And that's why I didn't understand what was going on. So. And what was very interesting, actually about that is that the relationship between temporal lobe disorders, those. 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 what he 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've 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.

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, call 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, 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 on me, I was extraordinarily fortunate. So I'm at university in Cambridge in the 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, neurohormones. And seeing that transformation from electricity to chemistry made me realize, you know, the way you study the brain now is through drugs which affect the chemistry of the brain. And then there are these therapeutic agents which are obviously very important. Antidepressants, antipsychotics, anticonvulsants. But then it raises the next question, you know, but people use other drugs to change the brain and they use them recreationally for like, drugs like cocaine or crystal meth, or they use them to deaden 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, that was not true. They asked me to help them justify drug policy, but when I started working for them, I realized that 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. Than it is to have an evidence based one.

What year was that that you got involved in that?

Well, I started working on the principles of assessing drug harms really back in the 1990s, and it actually came with the rise of ecstasy. And people supposedly were seemingly getting harm 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 that 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 nights, 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 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 were actually forcing people to drink alcohol or pay for water in order to get hydrated after using ecstasy and that. And in fact, they were doing worse. They were turning off the taps in the they were even turning off the toilet so people couldn't drink water. So we made it law that people had to get access to water. And we also recommended a good policy would be to have chill out rooms. And of course a lot of clubs do have chill out rooms. And those just those two simple environmental approaches. Effectively, you know, very, very few deaths from ecstasies 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 follow in 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 catches cold. America defined drug policy, it started in 1934 with the, the attack on, you know, the liberalization of drinking and the attack on cannabis. And it continued. And I mean of course the big inflection was when Nixon decided that the war on drugs was actually a better vote getter than the war in 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, 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 then 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. So I started off with something somewhat similar to that. But more recently we've developed what's called multi criteria decision analysis. And it turns out 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 to 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 put it all together and then do a weighting, 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 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. And 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 and British adults drink alcohol. Pretty much every family in your country, in my country, knows someone that's been harmed by alcohol, either through themselves, getting in difficulties, having accidents, getting addicted to, or they've been harmed by other ones. Someone who's drunk, a 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 which are really 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 Britain it's one, but 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.

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 interesting paradox. When we first did this, tobacco came out at about number six or seventh. And the tobacco anti tobacco brigade got really 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, that the harms of alcohol are considerably greater than the harms of tobacco. And I think most people would agree that, you know, tobacco does in the end kill half of the people who smoke, but it does it later in life, and it doesn't. 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, 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 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. Yes. We can give you absolute ratings and rankings on both of those variables. Acute toxicity versus chronic toxicity. And of course, you know, the drugs which really do badly on both are the opiates, which can kill you instantly when you take them, but also 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 you know, 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 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. 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 for sin. Well, that goes back. That goes back to pre Christian times with. Yeah, that's right. You know, you've got, you know, Jesus turning water into wine at the wedding, at canine. Why? Because wine was what the Jews used to celebrate weddings and it's been used ever since. We all use it. We still use it today to celebrate. So. So alcohol is this very powerful pro social effect, which I think is why it's so widely used and why it's been, apart from that little aberration of American prohibition, 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? Does it basically come down to. 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 that's a very interesting point you make, 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. As alcohol. That's a very interesting point. I take a different view. Up till now, until you said that, I've taken a different viewpoint, which is that people have been very anti cannabis 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 Anslinger trying to keep the DEA functioning after alcohol prohibition was disbanded, you know, that 100 years, almost 90 years of disinformation, has actually poisoned a lot of people's minds to cannabis. So cannabis has been vilified and alcohol has been celebrated. I mean, it'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, seeing these disclaimers at the top saying this program contains product placement, by which they mean usually this program shows people drinking an 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 DEA needs a reason to exist and therefore you need boogeymen. Right. If your business is smashing boogeymen, you need boogeymen. Don't we have enough boogeymen with other drugs like heroin or methamphetamine or cocaine? 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 like that train has left 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, and essentially NIDO 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 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 prohibitionist 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, ayahuasca, DMT 5 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'd assumed 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 lied to. The real paradox of doing this really in depth, multi criteria 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 harmful drugs are magic mushrooms and LSD and mdma. So there's a. 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 amphetamine derivatives.

So if we just look. Harm to the user. Yes. I mean crack cocaine, crystal meth's 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.

They kill you in overdose. You take just too much, you don't know what you're taking. Someone spiked Your heroin with fentanyl and you stop breathing and you die.

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. And 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 of you, you know, the more people there are, the more likely it is that people will die, you know, 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. 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 treatments, no physiotherapy, no occupation, with all they had was prescription pad. Then they tended to veer towards, towards prescribing opiates which are not good for chronic pain. And it's interesting also, you see the States which had the highest prescription levels of opiates for chronic pain are 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, you know, partly driven inappropriately, partly out of just a concern to help chronic pain pain. That's the second thing was then the rise the dispersion of that into, into society, into, you know, parents, kids were taking it and taking their 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 poppies it could be grown in a so called attempt to prevent heroin misuse. Fifteen years ago, particularly 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 discovered fentanyls. And fentanyls are so much more potent and there's so much more value for money, economic. You know, even the simplest fentanyl, fentanyl, it's 50 times more potent than heroin and twice as 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 fentanyls like carfentanil, which are a thousand times more potent. They're so potent no one knows how to measure them. And so you don't know how much you're giving. So we've, you know, you see it's a cycle, 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 ibogaine, a derivative of iboga. 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, that 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 nearest science of ibogaine, but it's been difficult to do that study because of the cardiac risks. So. But we are in the process of working with a company that's developing a derivative of ibogaine called noribogaine, which may be less cardiotoxic. And we're working with them to do some brain imaging to see whether we can. If it is, is it a normal psychedelic or not? Because no one's ever studied it yet. The evidence, as you see from. From it's used widely in some third world countries as a therapy for opiate withdrawals. Also a 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 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 ibogaine use is 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 a cardiac monitoring.

Yeah, of course.

Yeah, exactly. And there are plenty of other drugs which do have cardiac effects. 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 there was a science behind it. Because currently it's. While you go to West Africa or you go to Vietnam and you get ibogaine 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 that doing in a hospital setting I think makes more sense because 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 withdrawal just, we have, you know, there are other treatments which we have given for opiate users which have also been toxic in withdrawal. You know, people, you know, withdrawal is a serious medical problem. So you know, you know, they're ill physically and struggling. So I think adding a burden to someone who's in withdrawal is not a sensible idea. So to my thinking is that if 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 as I think the fundamental principle is likely to be the same between ibogaine or psilocybin or DMT in addictions. You're disrupting these, these overlearnt, these persistent patterns of over attention and over increase enhanced love for drugs. You can perhaps break down those habit circuits and then allow people to escape.

Meaning 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. And embedded in that of course is whether you are, you know, your depressive thoughts or whether your love objects, you know, your 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 which where you encode yourself. Your referential memories, your plans, your retrospect, you know, looking back, looking forward, putting everything, it is where you are. We know that if, you know, 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 kind of, you become a very strange person who really struggles with coordination and integration. So the default mode 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 drugs, etc. But in a very simplistic way, that sort of current thinking is that some elements of the default mode become misaligned or malignantly over engaged with negative thinking and 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, you know, a less, less constrained, less determined. So, 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 going to 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 ibogaine or iboga kind of help rewire a brain for an individual who is opioid addicted. Which is in and of itself kind of an interesting thing, isn't it, in that there's got to be a genetic susceptibility to this because there are many people who take tons of opioids during, say a post operative recovery from surgery and 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 genetic susceptibility looks like? And 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 going to come up with a totally different pain management strategy.

Yes, theoretically, it's unlikely to be in the genes.

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 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 the train window thinking, it's like a war zone. Is this Hiroshima? Because the downtown border, 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 and you deal drugs. So a lot of drug use, addiction comes because that's the one way people can actually achieve both a sense, something that takes away the misery of their lives, but also, in a way, if they become drug dealers, becomes a role. So. So coping with life stress is one reason people use drugs. But there are some people, you know, and they're very. The rich, successful people who still use opiates and get. And get into problems with opiates. And I give two examples of this. Two Oscar winners. Tatum o', Neill, youngest ever Oscar winner, marries the best, greatest tennis player 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's. 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 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, that I know the reason I want to study psychedelics, 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 who 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.

Let's start with cocaine, because that's the. That was the first. Well, there were several cocaine epidemics, but I mean, let's talk about that. Yeah, I mean, cocaine. I give a lecture seven times. 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 that cocaine also caused dependence. In fact, Freud and his protege both became cocaine dependent.

That's another Hopkins link, by the way, in Baltimore, was basically the father of the surgical residency in the United States and the first chief of surgery at Hopkins, William Stuart Halstead himself, became addicted to cocaine when he became obsessed 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 public, 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 remifentanyl, 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 there and became completely terrified of pharmacology, because he kind of assumed that any drug would have that problem. So, you know, you can maybe make it give cocaine credit for the development of psychoanalysis, but when we get to the modern era, then, you know, cocaine is the ultimate fun drug. It gives you energy and drive and an enormous sort of sense of focus and purpose. And then a terrible crash. And we now, you know, we know that that's due to the release of dopamine and noradrenaline 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 cocaethylene, which is a longer 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, 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 psilocybin, 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 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, that is how you behave off the drug, is it worth it? And so 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?

That's a very interesting analysis. I like that I might start using it. Yes.

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, absolutely True for crack, for cocaine, I'm not entirely sure. I mean, I think there are 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 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, very, very. He was the, 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 had he 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, 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, sudden death in athletes. We just had the European football championships and one of the star players, Ericsson from Denmark, had a cardiac arrest on the pitch.

So super fit athletes might be more susceptible. Yeah, yeah.

Particularly if they've got, you know, if they're big and they've got to develop some kind of cardiomy. But so, so, yeah, I don't. Athletes aren't paradox, 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 cocaine. I remember as a junior doctor, my very first period as a junior doctor, giving methylamphetamine intravenously to a man who had serious status asthmaticus. Amphetamines were developed as a treatment for asthma. They were developed as an alternative to ephedra. Ephedra is a natural plant product. It was discovered to have this bronchodilating 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 ephedra which they called amphetamine. And it was used largely for the treatment of asthma, really, to the Second World War, when people realized 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 amphetamines, I compare the Allies. So the Brits and Americans, we use amphetamine sulfate, whereas the Germans and the Japanese thought they were really clever because they had this super amphetamine called methane amphetamine, 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 Rommel was pushed back by Rommel's last stand. Yeah, that's right, absolutely. By the Desert Rats, the, the, the Allied troops, the Australians. 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'd go back, they'd be up all night on amphetamine sulfate and then they go back and they sleep all day. But the Germans would take methyl amphetamine to stay up to defend themselves against the desert rats. But they couldn't sleep in the daytime and eventually they became sleep deprived and paranoid. And the same with Japanese. You know, these descriptions of how the Japanese became, had these terrible hallucinogens, sensory somatic hallucinations from using large doses of crystal meth for long periods. So crystal meth is longer acting and probably more neurotoxic than amphetamine sulfate.

Talk about the neurotoxicity, what actually happens to the person's brain. Because 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 their ability to make judgments to the executive function, etc. But I have to caution it. I mean, the, the, the big concern about crystal meth actually came as a result of the Japan, after the Second World War. There were, you know, factories, crystal meth factories in Japan. You know, there were barrels of the stuff and there were a lot of Japanese soldiers who had nothing else to do and they used to use huge doses of crystal meth, often intravenously. And, and the evidence for brain damage really comes from that population. There's not so much evidence from it being when it's being used as it tends to be used now orally without, you know, 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, and will affect your motivation and your ability to, 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 1 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 1 because even though we acknowledge it's highly addictive, it has this pain blunting effect. Remarkably. Psilocybin is Schedule 1, MDMA is Schedule 1, LSD is Schedule 1. 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 to 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 treated.

Was he still at 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 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, come on guys, we've had 15 years of this remarkable research which we've invested 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, and then the DEA come and the CIA come and say we've got to ban it. He's saying, what, what you talking about? And of course what they were talking about was, 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, 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 that were trying to stop them protesting the war. It was changing the whole tenor of, I suppose, what you might call 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. In those days there 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 Enquirer or similar rags to just invent stories about the harms and the way people have been corrupted by using lsd. And there's these wonderful. I mean it's sad, but it's amusing now, but of course very damaging. It's front covers of these magazines or newspapers making absurd claims about lsd, usually with semi naked women. And that was enough concern. If editors are socially concerned, then we can ban the drug. And it got banned and once LSD got banned, all the other serotonergic 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 there were more than LSD and psilocybin. So some countries didn't ban DMT or 5 methoxy, but you Americans, you just banned it all because you had good scientists. So LSD was banned for political and social reasons? No, not because of any harms.

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 drugs, I think he certainly compounded the problem and he certainly popularized LSD 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 internationally.

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 Sandoz. 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 have been 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 got to remember at the time in the 50s and 60s, there were very few alternatives. We hadn't modern, so called modern, 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 it was, 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's under the influence, or did it require multiple treatments? I mean, do you have a sense of what was required for that efficacy?

Well, it was used in two different ways. So in the States the typical use was how we're using it today, which is give people a biggish dose, given a big trip, 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 and 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 engaging in psychotherapy.

And what was the difference in those doses, David? So the big trip dose would be how many micrograms?

So for, for LSD it 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 micro dose 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. They can feel things different. Yeah, feel things, yeah, think.

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 and they'd be maybe for, you know, 10, 15, 20 treatments.

So it's just an unbelievable loss to the 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 the founder of Alcoholics Anonymous, 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 and 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 was it instrumental in six trials of LSD for alcoholism that were conducted in the States? 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 1, 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 calculation. Worldwide, over 100 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 the question, well, how many lives have been saved from the ban? Well, I'm not sure LSD really maybe, let's say, let's say globally, maybe, maybe 50, 50 lives a year have been saved because fewer people took it, possibly. So then you say, you know, we got 50 years times 50. There's two and a half thousand 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 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, there are, well, 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. 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 piers or breakwaters or even from hotel balconies into the swimming pool. So probably more people die each year jumping from alcohol.

It says nothing of automotive accidents and liver toxicity and respiratory depression, just the jumping.

Okay, so lsd. If you take LSD in 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, there was very little evidence of any harm at all.

Okay, let's talk about its cousin, psilocybin.

Yes, so psilocybin of course has been around a lot longer. Psilocybin is a present in mushrooms. There are about 200 species of magic mushrooms, different ones in different parts of the world. It was, it was really the beginnings of the psychedelic revolution where LSD and Hoffman and Gordon Wasson, the American mycologist who discovered a tribe in Mexico that were using mushrooms for psychedelics experiences and, 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, this cocktail called soma, which of course was, the term was adopted by Aldous Huxley in Brave New Word. But, but the real soma was a powerful mixture probably of magic mushrooms, of ephedra 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 psilocybin as being the active ingredient was also discovered by Hoffman because Wasson went to him and said, why is this causing hallucinations like lsd? And he said, oh, because it looks a bit like serotonin, a bit like lsd. And we've been working now with psilocybin for a number of reasons. The main one is that it doesn't have the stigma. Lsd, you say LSD to a politician and they immediately turn off. You know, the LSD is a bad thing. Whereas psilocybin, they don't know how to say it, they know how to spell it, they don't know what you're talking about and who's who. How can you be worried about magic? That's only a mushroom. The second reason we started using psilocybin was 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. 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 to ban.

This thing is complicated. So the active ingredient psilocybin was banned in 71 alongside LSD, DMT, but the mushrooms weren't banned. Why would you ban the mushroom? They don't have much of it and who cares if people go on and go and lie on the side of a mountain and, you know, see pretty pictures in the sky. But what happened was that a couple of head shops in Camden Town, North London started selling freeze dried mushrooms.

So they would concentrate the dose.

Well, it's not just like you could.

Take more of it. Or was it just the fact that it was being sold commercially in the head shop?

It was sold in London and so no one really cares if people go and, you know, lie on them, you know, on a hillside in Devon. That's quite fun. But if someone's selling a dangerous psychedelic drug to our young people in London, the, the right wing press just went ape.

These were probably the same shops that sold Doc Martens, by the way, because I know those head shops, they're very dangerous places.

Yeah, absolutely, that's. And it 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, and 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 favor 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 that, yeah, soft on drugs, you're soft on drugs. You know, look, they're selling this illegal. The drug wasn't illegal, but the mushrooms weren't 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 than the Republicans. And he's the guy with the three strikes and you're in prison forever. And the same with labor. They were told, if you're not tougher on drugs or as tough as the Tories, you're going to lose the election. So he goaded 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 if you take, even if you take them to court, they can just change the law to prove it, you know, to allow them to have done what they did. So, 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, I, I, 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 as more of a dissociative, and then these really atypical ones like ibogaine, which we've already talked about. So let's spend 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 nuances there, but also talking about the potential that it has. I've had 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 Shulgin, was interested in derivatives of amphetamines. MDMA was made, you know, back in 1904 as a possible agent for blood clotting, but it never, never got used. And Shelvin made it in the, in the, in the 60s and said, wow, this drug is different from amphetamines. It's not activating, it's not, it's not driving me like amphetamines. It's actually making. It's giving me a clarity of thought, but also a sense of warmthness and empathy. So he gave it to his wife and she said, wow, this is a very. This is empathy. This would be really useful in psychotherapy and couples counseling. It would help potentially help break down, you know, those layers of irritation and grit 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, 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 amphetamines, but we can sell ecstasy because it's legal. But who wants to buy ecstasy? So they changed the name to Ecstasy. So they didn't want to buy Empathy. Sorry, they changed the 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, you know, widely used. What's, you know, it's the perfect drug for parties, isn't it? You know, you've got energy, but you're also happy. You're not fighting people like what 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 all. When the newspaper owners couldn't even had 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 had 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 culminating in that an amazing experiment that was done by Riccarti, which is really embarrassing for Johns Hopkins, you know, when he claimed that taking MDMA and listening to the podges overnight gave monkeys brain damage. And we all said, well, hang on a second, none of our kids are coming out of the clubs with brain damage. I think your experiment's wrong, Riccarti. He said, no, no, it's right. Ecstasy causes brain damage. And he got published in Science despite the fact the referee said, this is, this has got to be wrong. And of course, eventually they went back and they audited what they'd done and instead of giving the monkeys mdma, they'd given them crystal methods, which is way more toxic.

That paper was recall. I mean, he did have to pull that paper.

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 correction. Sorry, guys, this wasn't mdma. This was actually methamphetamine. Wow, terrifying.

So that's our answer to Andrew Wakefield for you, huh?

Indeed. And it's. 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, 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 3, perhaps a Schedule 4, 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. And they both produce altered states of consciousness which sort of, you know, 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. He thought maybe this is mood elevating. So then he and his colleagues went on and they did a 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 their mood gets better. The problem with ketamine compared with what we're going to talk about in a minute with psilocybin is that 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. But you couldn't patent ketamine because ketamine was being used back in the Vietnam war as the buddy drug when people were being blown up and having it as a, use it as an analgesic. So they took the enantiomer, one of the isomers of ketamine called S, the S enantiomer and they call it S ketamine. And they formulated it for nasal inhalation so you don't have to inject it, which is better and easier for psychosis psychiatrist. And now that's sold as a, as a treatment. And it's called esketamine spravate and it works and you take it a couple of times a week and then gradually over time you use, you dose less and less as the patients recover.

So you don't develop a tachyphylaxis to.

It if you do it twice a week. You don't. No, no.

And you are able to get patients off of it while still preserving the antidepressant benefits.

That's less clear, but in some that's true. But it does have, there is an advantage of it over ketamine. Ketamine clinics tend to you.

Do they give it intravenously or intravenously?

Yeah, or intramuscularly. But also the problem there is that, you know, ketamine is a dependence producing drug. It's a drug, a recreational drug, you know, is relatively popular in Britain is relatively popular in China, probably popular also in the States. I'm not sure what the stats are. The problem is you do get tolerance tachyphylaxis 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. Basically, you get a severe chronic cystitis, 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 rather mimics schizophrenia. 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, 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?

Oh, yeah, well, certainly daily use is too much. So, I mean, people who are addicted to ketamine are using it four or five times a day. They might be using five grams a day. And that's when you get into the serious brain damage. So I think twice a week, or I think we know from esketamine, twice a week seems to be without. Doesn't have any enduring problems with.

But if you're not using the enantiomer, twice a week will probably still produce a tachyphylaxis and a diminishing return at some point.

Yes, but one of the really interesting questions, and we don't understand this, why is it that when people use ketamine and they get tachyphylaxis, they can overcome it by taking more?

By the way, I should explain to people what tachyphylaxis 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 tachyphylactic to Tylenol. Right? You have acetaminophen. If you take 500 milligrams and your headache goes away, 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. In the downstream mechanisms in the cells that, you know, you get almost complete absence of effects of. Of psychedelics after two or three doses. And you know who told us that?

No.

The U.S. government. So the U.S. 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. 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. The second dose will be less than the first. 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 tachyphylaxis, it's very temporal.

No. Although some people do say. Well, a lot of people say that for all drugs, that the first one's always the best, but yes, yes. So you can overcome the tachyphylaxis with psychedelics, whereas you can with heroin and you can with ketamine. And. And why that is? We're not so clear as to why 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 New 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, I'd 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 one to two months. But for many of them, the depression came back. Based on that and also some theoretical work I'd done with Robin Carhartt 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 Journal of 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 a, with, with Lexapro or other similar drugs that enhance serotonin 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 system and that allows the limbic system to recover. So that 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 through a particular subtype of serotonin receptors called the serotonin 1A receptor, which is 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 where we take depressed people, we scan them with FMRI before and after, and then we see if we can look at the. If the brain changes are different with the escitalopram compared with the psilocybin, predicting that we would see cortical differences, that the cortex would be changed by the psilocybin and the subcortical regions would be changed by the ss. 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, here you're on Lexapro, here you're on psilocybin. We had to blind it. And that's quite difficult with psychedelics. So the way we Got we did that was to tell everyone they were going to get psilocybin. But half the group got a low dose, a placebo dose, a 1 milligram dose and half got a high dose, a 25 milligram dose. But they all went through the same psychotherapy, depending. It didn't matter what dose they got. They all got all the same preparation and the psychotherapy that goes with a high dose of psilocybin. And then they all got pills, but the escitalopram group got escitalopram and the psilocybin group got placebo.

So they're both getting two pills, One is getting a placebo plus a high dose of psilocybin, the other. Yeah.

And the point of that is what's called clinical equipoise. People have to believe that they're getting the best they can. And we gave them two doses of psilocybin, whether high or low, one at the start and one after three weeks to see how long the effect would last. And then we measured changes in mood and we measured side effects. And we also looked at other aspects of. Of depression. Rather than just looking at depression and scores, we also looked at things like well being, 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 psilocybin at six weeks was as good or equal to as escitalopram 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 Star D study. But when we looked at all the other measures, actually psilocybin did rather 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 studied. So we had to just do a kind of comparison and, and the answer was that, well, we, we had to pre, we, you know, you pre specify, we pre specified 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 quids as a primary. Now when they, 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 purism, it's puristic statistics. But as you, as you say, it's kind of not very intuitive because when you look at it actually it was very clear that the overall many. Well, there was not a single measure that favored acetalofram. And they were like, well, that's, 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 Lexapro 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, Lexapro is typically given at two doses, 10 milligrams or 20 milligrams, going from 10 to 20. There is a sizable increase in the efficacy, but there's also a sizable 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 antidepressant or anti anxiolytic standpoint is significant. So to me, I read that study with enormous optimism, which is if there is a way to give somebody 25 milligrams of psilocybin and get the same antidepressant 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? Yeah.

So 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 psilocybin is a medicine and it's as good as Lexapro. And anyone who reads the paper can see that it does do better on sexual dysfunction, and it does do better on many of the other issues that Lexapro has a problem with. And it fits with the theory that one of the things. It's very. The reason lexapro and other SSRIs dampen 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. I don't. 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 with that theory.

Blunting the top and the bottom.

Exactly, Exactly. Whereas psilocybin 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 this study, I was going, wait a minute. What does 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 5 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 4 to 5 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 1 to 2 milligrams of pure psilocybin and its potential for antidepressant benefits?

Well, loads of people use it. Loads of people, you know, they go pick the mushrooms, they dry the mushrooms, and they. They take them. I'll give you. I was talking at a festival a couple of years ago in Wales. It's, you know, it's called how the Light Gets in. And it's a big intellectual music festival. And after my talk, a lady came up to me and she said, yeah, I got to share you the. You know, I'm a. 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 and a mushroom. And I've been really good for the last few years. And there's anecdotally, there's large numbers of people who are using mushrooms. Do they work or not?

It's.

We don't know because it's almost the rules around these drugs. The Schedule 1 status means that a single mushroom is just as illegal as a bunch of mushrooms or as pure psilocybin. 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 costed up what it would take to buy all that time in hospitals to do six weeks of microdosing. We couldn't afford it. And so there has never been a proper controlled microdosing study 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 macrodosing?

Well, it won't be as good, obviously not a single microdose won't be remotely as good as a macrodose.

But say repeatedly, because I believe in your study they 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 1 to 2 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, and 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 in 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 people better. There's no question with psilocybin, how can we keep them? Well, and one of the great things we know about the SSRIs is that 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 psychedelic treatment and maybe microdosing would work, but until we get it liberated, 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, 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 There's a 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 milligram dose, a placebo dose, a 1 milligram dose like we did, and a 10 milligram dose in between. I think if that's positive, then the floodgates will open to their second study and also to funding of that research.

Now, Compass has come under great scrutiny from some in their effort to, you know, 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've been helping them for a lot. I mean, that 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 Doblin is a phenomenon, but it has taken him 25 years to raise enough money to do the maps phase three. And after a year or so, Compass Pathways realized that they, they didn't have the resources or the skill or the personalities that Rick has.

Yeah, 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, you know, much as I would like it not to be the case, you know, reality is, I think if we want to see psilocybin with enough evidence in my lifetime to make it a medicine, then I think that they're most the people that are 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 mushrooms a medicine in two years time. So it's actually a bit of a race now to see who'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 psilocybin. It's exciting times, David.

I promised you that at 6pm 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.

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