Psychedelics — Microdosing, Mind Enhancing Methods, and More | The Tim Ferriss Show (Podcast)

Tim Ferriss 0:00 Optimal minimal At this altitude, I can run flat out for a half mile before my hands start to shake.

Ayelet Waldman 0:06 Can I ask you a personal question?

Matthew Johnson 0:08 Now we're just sitting at Brooklyn time.

Tim Ferriss 0:10 What if I did the opposite?

Ayelet Waldman 0:12 I'm a cybernetic organism living tissue over metal endoskeleton.

Tim Ferriss 0:16 The Tim Ferriss Show. Hello, boys and girls. This is Tim Ferriss, and welcome to a very bucolic episode. I'm sitting outside with the birds and the bees, the flowers and the trees of The Tim Ferriss Show, where it is my job to interview world-class performers or world-class experts, people who are in the top of their fields. And this episode is a panel. The panel relates to psychedelic science, and it was recorded at the 2019 Milken Institute Global Conference. And this particular panel was standing room only. There were several hundred seats all filled, and then the entire room was surrounded by people standing, which was really surprising and also encouraging to me because this is a conference comprised of primarily investors, many of the best investors and, uh, certainly most lauded and, uh, objectively in many respects, successful CEOs in the world. Very, very unusual, uh, to, to see that type of crowd in that room. And a few notes before we jump into it. It was a fantastic experience, uh, a lot more to share another time on that. Uh, we have a number of different types of participants in the panel. We have incredible scientists, we have investors, and we also have writers who have experimented with microdosing. And there are a few visuals that are referenced in the beginning, a number of slides that are presented. You don't really need the slides to understand what is being said, uh, and I'm a nerd for the science. Uh, you will be able to find those slides and links to the studies at tim.blog/podcast with all of the other links to everything mentioned in this episode. So if you go to tim.blog/podcast and search psychedelic, uh, you will certainly be able to find this episode and find all of the visual references. But you do not need them to get the gist of what is being said in the first, say, nine and a half minutes. If you want to skip directly to a first-person description of microdosing and what that is like or what it can be like, I should say, and certainly not recommending that you do anything that breaks the law wherever you happen to be. Color within the lines would be my recommendation. But if you are curious nonetheless, for informational purposes, what such an experience is like, that comes up around nine minutes and thirty seconds in. And without further ado, because I do ma- make-- Because I do make [laughs] For fuck's sake. I do make much ado about, uh, my introductions. Please enjoy this very wide-ranging and detailed conversation about psychedelics and psychedelic science. [electronic music] Thanks for coming, everyone. I'll keep my introductory remarks pretty short,

Tim Ferriss 3:25 but I'd like to begin with a show of hands. How many people here know someone who is depressed despite the fact that they take antidepressants? Anyone? All right. How many people have anyone in their lives affected by addiction, alcohol, opiate, or otherwise?

Ayelet Waldman 3:43 Right now, just two.

Tim Ferriss 3:44 All right. So the entire audience for both questions. [laughs] Uh, lest we start on a complete downer, let me give an inspirational story, and it relates to Katharine McCormick, a name not many people know. I'd recommend that everyone look her up on Wikipedia. She was born in 1875 in Michigan. She was educated at MIT as an undergrad, where she lobbied the administration to change a requirement that women wear hats with feathers because they were a fire hazard in labs, she said. Very true. So they changed that. Uh, she also inherited a good portion of the International Harvester fortune. And in 1953, she met a man named Gregory Pincus, who was developing an oral contraceptive. He had lost his funding because his backers didn't see any profit in sight, and over the subsequent years, pretty much single-handedly financed that development. And in 1957, the FDA approved the pill for menstrual disorders. So that was sort of the strategic first indication, and then later we know what happened. And the reason I bring this up is that in total, she provided two million dollars of funding. In today's dollars, it's around twenty-three million over many years. And it was an uncrowded bet through which she was able to completely bend the arc of history. And, uh, I will give some disclosures now. So in 2015, I stopped all my early-stage tech investing and redirected almost my entire focus to psychedelic science, uh, for reasons that I think will become clear in this conversation and have been very involved with both Hopkins and Imperial, uh, which has been incredibly gratifying. So with that, let me introduce our panelists. We have Christian Angermayer, Founder of Apeiron Investment Group. We have Robin Carhart-Harris, Head of Psychedelic Research, Centre for Psychedelic Research, Department of Brain Sciences, Imperial College London. Matthew Johnson, Associate Professor, Department of Psychiatry and Behavioral Sciences, Johns, uh, Johns Hopkins University School of Medicine. And Ayelet Waldman, Author of A Really Good Day, subtitle How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life. So let's begin, Matt, with, uh, some of your slides, if we can bring those up, and I'll let you take it from here.

Ayelet Waldman 6:01 Sure. Slide

Ayelet Waldman 6:02 three?

Matthew Johnson 6:03 So really important before we get into the meat of some of our other conversation is to let you know that we've been ahead a- as a field in terms of understanding, being very clear about the risks. There are downsides. So you ask any Jedi Knight about the Force, they're gonna tell you, in addition to knowing the good side, you need to be aware of the dark side and how to keep it at bay. Same thing with psychedelics. The so-called bad trip is real. There are other risks as well. But we published a paper over a decade ago that has now essentially become the bible of how to, uh, conduct these studies. It's been used by institutional review boards at a growing number of universities. And I was at the FDA last week. They are using these guidelines to evaluate novel protocols. Recently published another paper, um, assessing the abuse liability and risks of psilocybin and thoroughly reviewing the scientific literature and suggesting that if psilocybin, which is the active agent in so-called magic mushrooms, if it's approved ultimately through Phase III trials as a medicine, that it belongs in Schedule IV based on the data rather than Schedule I. So we're aware of the risks, we're paving the way, we've analyzed the data. Um, in terms of some

Matthew Johnson 7:21 of the... Now we've got the, the dark side out of the way, what's the light side? We can look at some of the efficacy data very quickly. So next slide, number four, please. We published the largest, a couple years ago, the largest study examining psilocybin in the treatment of depression and anxiety associated with a serious life-threatening cancer diagnosis. These are people that are freaked out because they're gonna die. Um, and this is essentially like the addiction work, it, it is picking up on older threads of research largely done with LSD back in the '60s. You can... I'll tell you briefly about our, our results here on the right, looking at our, at depression results on the left, and then anxiety, um, results in the right panel. The leftmost, uh, points on those figures under baseline, that's, those are the high levels that people had when they came into the, into the trial. And trust me, this is a, a clinically severe level of depression and anxiety. Post one, the next time point on both panels, the red group has received a high dose of psilocybin. This is not a microdose. This is a very large, overwhelming dose, something you don't wanna be at a concert on. You see a huge reduction into the non-clinical realm. I mean, these people are not having problems at those lower levels, uh, around, uh, eight on the scale. You do see a good reduction in the people in the blue group, and that's a group that, to this point, has essentially received a placebo. It actually is a very small dose that you could call a microdose. And this trial really just designed to serve as the comparison condition, essentially a placebo. So that's probably due to the very careful preparation, the rapport building, and also some of the so-called placebo effect. At the next time point, post two, that's a month after they've re-- everyone has received the high dose. So the people who had gotten the trivial dose at, in the first round, they have now also received a high dose. Now they have dramatically decreased their depression and anxiety, just like the group that got it a couple months before. And then the really mind-blowing thing on the last point in both panels is at six months, you see sustained reductions in depression and anxiety six months after treatment from a single high-dose session. And so in terms of depression, there's understandably a lot of excitement around ketamine, which was recently approved for the treatment of depression, in that it has immediate effe- antidepressant effects that last one to three weeks, which is wonderful. Get ready, 'cause we might be at a, an even higher plateau when it comes to sustained effects with psilocybin. Um, so I'll jump to the, the, the next slide. These, along the a- addiction angle, w- we decided to do something novel that wasn't done in the '60s. One of the interesting things is it appears that this isn't just specific to one drug or another, like methadone for opioids or nicotine replacement for smoking, but the anti-addiction effects of psychedelics seem to be broad-based. They get to the psychological meat of addiction. So why wouldn't it work for tobacco smoking, people who've tried to quit smoking? We ran a, a, a small open label pilot. We had dramatically, uh, impressive results. Um, at six months, we found that 80% of participants were biologically confirmed as smoke-free. Breath samples, urine samples, you know, we trust people, but we verify. Um, those results held up to, to 67% at a year and 60% at an average of two and a half years after their, after their, uh, target quit date. And in this study, they had three psilocybin sessions, most participants. Just to tell you how impressive these results are, the best medications we have, um, such as varenicline, which is Chantix, gets up into the range at six months at about 35%. Nicotine replacement, anywhere, depending on the study, between 10% and 25%. It was an open label study, so we had to be cautious. The, the real question is, is, does this warrant follow-up? And the answer to that is abso-freaking-lutely. And so we're in the middle of that randomized trial at this point. So this is just a taste of a, a number of trials that have gone on the, in the field. That are telling the same story that the earlier era of research from the '50s through the '70s showed, that there is huge potential of these psychedelics in treating a number of psychiatric disorders.

Tim Ferriss 12:16 Thank you, Matt.

Tim Ferriss 12:17 Uh, Ayelet, let's jump to you, uh, because I, I'd, I'd like to contrast, or maybe not contrast, but add to the scientific discussion, the personal discussion and, and your experience. Could you talk to how you ended up microdosing, what microdosing is, and what effect it had? That's a very big question, but I'll, I'll let you tackle it.

Ayelet Waldman 12:37 So microdosing is the practice of taking a sub-perceptual dose of a psychedelic drug. I mean, you can microdose anything, but in this case we're talking about psychedelics. So when I say sub-perceptual, I mean you do not trip. You do not have a hallucinatory experience. You see no kaleidoscopic colors. The idea is to take a dr- dose that you cannot perceive of any effects, but that there is something going on metabolically. So, um, I was experiencing serious depression and, uh, I had not... I had been on SSRIs, I had been on mood stabilizers, I had been on various medications, and they weren't working effectively, and so I decided to try microdosing. I had been a, a professor at UC Berkeley's Law School and taught a seminar called the Legal and Social Implications of the War on Drugs. During the course of which I read the psilocybin research. I read the research that, you know, from the very, from the 1930s on through the present day research. Um, and, um, I was... I, you know, made sure that what I was doing was safe. I made sure that the drugs that I was taking were pure. That is the most important issue. When drugs, um, are illegal, you have no guarantee that what you get when you buy from the illegal market is actually what you think you're getting. And I embarked on a 30-day experiment microdosing with LSD. So what I did was I took a one-tenth of a dose. If you wanna, say, have a hallucinatory experience at Burning Man, you're gonna take somewhere between 100 and 200 micrograms. LSD is a very potent drug, so we're not talking milligrams, we're talking micrograms. I took 10 micrograms, and I took it every three days, and the effect was profound. So the first day, I had been in a suicidal, intractable, anhedonic depression for what seemed like forever, 'cause when you're depressed, you have very little capacity to remember when you weren't depressed. And the first day I took the drug, I swallowed it early in the morning because LSD is activating and I didn't want it to interfere with my sleep, and nothing happened. So I thought, "All right. Well, this was a bust," and I got to work. And about, after about 40 minutes or so, I looked out my window and my dogwood tree was in bloom, and I had this thought, "Oh, look. The dogwood is in bloom. It's so beautiful." Now, it wasn't like the petals were bursting into color and taking off, butterflies in the sky, but I had been unable to appreciate beauty for months, and I saw it, and I understood it was beautiful, and it made me feel happy, and that was an experience that was really mind-boggling. Over the course of the next period that I was taking LSD microdoses, it wasn't like every day was a really good day, but many days were really good days. And, um, my set point of depression dramatically changed. Um, my productivity... I wasn't in it for mind enhancement, for productivity enhancement, but my productivity changed dramatically. The book that you can buy afterwards at the bookstore was, the first draft of that was written in a month. Now, I've done that before in periods of hypomania, but I had never done that in a period of productive, calm flow. Um, so, uh, I became convinced at the end of this experiment that this was a drug that had all the therapeutic benefits that are promised by SSRIs. But I often say that if those antidepressant commercials showed a fat person lying in bed not having sex, that would be a more accurate assessment of their effects than a happy lady skipping through a field of flowers, and I was a happy lady skipping through a field of flowers.

Tim Ferriss 16:30 [laughs]

Robin Carhart-Harris 16:33 [laughs]

Tim Ferriss 16:34 Yeah. That's great. That, that image is messing up my segue. Uh, but thank you. [laughs] The microgram, milligram difference is very important, so please take close note of that.

Tim Ferriss 16:48 Uh, Robin, let's jump to you next because, uh, I really want to get your perspective on plausible mechanisms, f- plausible explanations for how these compounds do what they do. Because it's not as though, at least in the way they're currently administered in, in most cases, they're sitting in your system, saturating your system for, say, six months after the cessation of smoking. Uh, could you talk to, based on our current understanding, based on your current research, what is happening? And, um, maybe you could also touch on the, the entropic brain.

Robin Carhart-Harris 17:25 Sure. Okay. So the first thing to say is that these compounds are working on the serotonin system, uh, an important, um, brain chemical that modulates a range of different important, uh, psychological functions. We know, uh, mood especially, but also, uh, cognition and states of consciousness. And it, it's a particular aspect of the serotonin system that psychedelics work on. A particular receptor subtype, it's called the serotonin 2A receptor. And we know from a, a, a broad range of different evidences that this receptor is involved in, um, y- you could, um, uh, uh, summarize it as adaptability flexibility, plasticity. Um, there are a lot of these receptors in the cortex, an aspect of, of, of brain that humans have so much of. And, um, so stimulating these two A receptors a-appears to, um, at a higher level, have an interesting effect on the, um, regularity and the quality of brain activity. So we can characterize conscious states, uh, in a way ana-analogous to, um, to waves. Uh, when we record brain activity, it, it, it's very rhythmic. Um, and as our conscious states change, that rhythmicity changes as we fall asleep. Uh, or if we're knocked out with an anesthetic or we suffer some kind of brain injury, you'll see that, um, brain activity, um, starts to look like sort of slow rollers on a, on an ocean. And, um, related to that, the, the richness of conscious experience drops away. It's very predictable, very steady. There's not much going on. We know if we look at normal waking consciousness, the, the waves look very different. You know, they're much more rapid. There's, there's much more richness going on. What we've discovered with psychedelics is that that richness is enhanced further, and that was quite an interesting and novel discovery. To our knowledge, um, there hasn't been a state of consciousness found that shows that increase in the richness, uh, or complexity of brain activity above the level of normal waking consciousness. That's a very mechanistic take on things. Um, uh, another way to, to look at this, that's a way of characterizing the acute experience. Another thing to emphasize, tying this in with the therapeutic work, is that the quality of the experience that people have under psychedelics appears to predict very reliably the therapeutic, uh, outcomes. And so, you know, these really amazing findings that the drug is well washed out of the body, and yet people months on from these isolated experiences are reporting improvements in psychological wellbeing, drops in, uh, depression and such like. So what's going on there? So just quite briefly to talk about the therapeutic mechanisms and perhaps slightly frame it in a, in a slightly more, um, sort of human and, and psychological way. We can think of a range of different, um, expressions of mental suffering as being, um, underpinned by, um, biases and beliefs, whether it's in depression with negative cognitive biases, we think we are worthless and life is pointless, or it's eating disorders where we think we're ugly or overweight, uh, or obsessive compulsive disorder with those stamped in habits. Um, and so, um, th-there is this kind of commonality, this transdiagnostic commonality that, that, um, that seems to relate to a very range of, uh, broad range of different, um, psychological disorders. And what psychedelics seem to do acutely during the experience itself is they seem to relax beliefs and open a window for change, for revision. And if that opportunity is seized with the right kind of, um, psychological support, then you can work towards cultivating the r- a healthy revision of these pathological beliefs and habits.

Tim Ferriss 21:36 Thank you.

Tim Ferriss 21:37 And it, it's worth noting also for people who aren't familiar that if, if we're talking about psilocybin, which in the case of studies is synthesized, it's been used in the form of psilocybe mushrooms by, for instance, indigenous populations, including the Mazatecs in Mexico for thousands of years, one could argue very, very effectively. So th-there, there's a good question, we're not gonna dive into it right now, but as to why almost every civilization, excepting a few in Antarctica, have used psychedelic compounds. Uh, and, uh, certainly for rites of passage, but also with an objective along the lines of these enduring effects that, that you talk about. Uh, Christian, let's, let's talk about investment in this space and, and why you're involved. Uh, I know that you, uh, based on our conversation, certainly have a very sincere interest in making these compounds more widely available to people who are suffering. And your biotech company, ATAI Life Sciences, is currently one of the largest investors globally aiming to bring some of these psychedelics, including psilocybin, back into the legal realm. What prompted that and, um, how are you thinking about approaching it?

Christian Angermayer 22:46 Um, okay, let's start because you're many investors. Um, I'm a super coward. Um, until five years ago, I'm, I'm not exaggerating, I have never drank alcohol in my whole life, and I come from Bavaria in Germany, where this is like cultural, uh, actually appropriate, uh, to do so. But I, I didn't because I was super-- I was a weird kid, so I, I was super worried that, uh, my brain cells could die. Um, and, um, so I didn't drink alcohol. I've never smoked a cigarette. I've never smoked a joint. I've not- never done anything else till, like, around about six years ago, some very, very trusted friends, uh, tried to convince me of magic mushrooms, and I was like, "You're clearly insane." Yeah. "I'm never ever gonna do that." Um, till... But then I-- They told me a lot about it, actually, what, what Matt and Robin said, and s- and I do invest a lot in biotech. Actually, biotech is how I started my career. I founded a biotech company, so I was very inclined to read all the data, and the data is very compelling. So ultimately, a year later, I gave in. It was, um, to, uh, to say that as well, it was a, a jurisdiction where it's legal, um, and it was under, uh, a very guided and very, uh, well set up, protected, uh, session with a great guide. And, um, it was The single most meaningful thing I've ever done and experienced in my whole life. Full stop. There, nothing comes close, uh, to it. And, uh, which is by the way, in a lot of studies, uh, I think it's a Johns Hopkins, uh, study where I think it was 2/3 of the people rank it among the five most meaningful, uh, events in their life, among birth of a child, death of a parent. And I think 1/3 roundabout ranks it among the, the single most meaningful thing. So because I'm an entrepreneur, um, uh, I came out of the trip, um, the first thing I did, I called my parents.

Ayelet Waldman 24:36 [laughs]

Christian Angermayer 24:37 Um, um, because, um, yeah, I realized how much I love them, and I never say it. Um, and, uh, the second thing is, was like this should be experienced by more people. Um, and I do think that the only way to do it, when we have a lot of, we have a lot of anecdotal experience like myself and like Ayelet, and we have a lot of, let's call it basic research. But, uh, unfortunately never these drugs, these various drugs have been brought to the FDA, or in Europe it's called EMA, sort of life cycle or sort of cycle how to approve any normal other drug you wanna use for, for medical purposes. So I was like, "Okay, this should be done. Is anybody doing that?" And so I embarked on the trip in, in a, in a figuratively word, um, and, um, uh, and met great people like George, uh, who founded COMPASS, um, who had the similar thoughts that this should become a medical drug mainly for the treating, uh, for treating depression and then other mental, uh, health issues. Uh, this is where we are. Um, COMPASS, uh, is in phase 2B. Um, I'm also backed a company which is bringing R-ketamine hopefully, uh, on the market, which is a sort of sub form, um, of ketamine also for the treatment of depression. And we're looking on other, um, psychedelics or wider mental health drugs. Because I think if you look at the numbers, and again, investors are very numbers driven, the whole mental health area, I'm not just talking about psychedelics, but as well, has completely more or less neglectic, uh, been neglected over the last 30 years because it was sort of, um, com- the mind is a complicated thing. And I, pharma companies, biotech companies thought, "Okay, let's focus on cancer. Let's focus on the more tangible illnesses." And also, to be fair, um, depression, our view on depression and, and mental health has changed over the last decades. Like 50 years ago, what we now call a depression, people would have said, "Go on with your life. Go to the gym, train a little bit. Get well." Yeah. Uh, when, when people came back from the Second World War and were s- showing symptoms, what we now would call post-traumatic stress disorder, people said, "Hey, get on." Yeah. So w- I think the, the, the, the view on mental health has changed over the last 20 years. Uh, but also I think we live in a world where mental health is becoming a problem because our world where we live in is very bad for our minds, especially for young people if you look at Instagram, whatever. Yeah, that whole sort of way we live and we have started living the last 10, 20 years I think is very, very bad for our, for the state of our mind. Yeah, and this is why the numbers rise. We have 320 million people suffering, uh, from depression, and these are just the official numbers, and most probably the, the, how you say, the gray number, um, uh, is, is much higher. It became, if you count sort of the side effects, like people not showing up at work and stuff like that, it became the single most costly illness, um, in the Western world. And for like 20, 30 years, there has been no innovation, and all the drugs which are on the market are not curing, but numbing it. Yeah. And again, let's go back to something personal. Like if, if s- if, if a person gets very depressive because somebody, loved one dies, you don't wanna take Prozac, and Prozac tells you you don't care about the death. You wanna sort of dissolve it and solve it in a, in a different way, and I think this is where psychedelics have a very, uh, promising path to be a very valuable drug.

Tim Ferriss 28:14 Thank you.

Tim Ferriss 28:16 And, uh, we're not going to probably talk about it very specifically today, but the efficacy of MDMA for post-traumatic stress disorder is, is worth looking into, uh, and is, is really remarkable. Both MDMA and psilocybin now have, uh, breakthrough therapy designation by the FDA, uh, which is remarkable. And if you look at the graphs, you look at the data, uh, for changes in PTSD severity from severe or extreme symptoms to asymptomatic, they look very similar to the smoking cessation graphs. It's, it's incredible. MAPS is an organization doing great work there. Um, let-

Ayelet Waldman 28:52 Um, Tim-

Tim Ferriss 28:52 Yeah

Ayelet Waldman 28:52 ... can I add a point to that?

Tim Ferriss 28:54 Mm-hmm.

Ayelet Waldman 28:54 Is the, um... It's somewhat ironic that I'm the resident drug user because like you, Christian, I don't do drugs other than these. I j- I don't smoke. I don't like to smoke weed. Sometimes I take CBD 'cause, you know, you can't get a matcha without it nowadays. [laughs]

Tim Ferriss 29:10 [laughs]

Ayelet Waldman 29:10 Um, but, uh, uh, I don't like to experience any hallu... I, I, I like my mind to be sharp at all times. But, um, uh, because I was teaching the, one of the s- first sort of people who popularized MDMA, Sasha Shulgin, a chemist in Berkeley, used to lecture to my class. And Sasha and his wife, Ann, who was a therapist, convinced me to, um, try MDMA, which is ecstasy, with my husband as a tool of marital therapy. And we've done it every couple of years since. We have the strongest marriage of anyone I know. We're sort of famous among our friends for having an incredibly strong, solid marriage. And I do act- We have four kids. We have a lot of stress. Um, but the, what MDMA does and it, why it's relevant, I think, to PTSD is it somehow, and these guys could probably talk more accurately to it, it disconnects the c- the emotional experience from the memory, which allows you to, um, deal with the trauma of memory without the intense, overwhelming emotion, negative emotional content. So in the context of something that isn't PTSD, but it's rather like the You know, mundane PTSD of a long marriage. Um, it allows you to talk about your issues, but from a place of connection and love. So every couple of years, we spend six hours talking about everything that has come up for us from a place of absolute love and commitment, and that sustains, that one experience will sustain for as long as two years. It's really remarkable.

Tim Ferriss 30:49 Thank you. Yeah, it's-- not to delve too much into any current use, wouldn't want to implicate anyone, uh, but MDMA is w-worth taking a very close look at. Uh, there are risks associated, associated with some of these compounds.

Ayelet Waldman 31:01 Yes, unlike LSD.

Tim Ferriss 31:01 Yeah. So there are some risks associated with these compounds. These are not panaceas. They are very effective or appear to be for certain conditions. MDMA has certain, uh, say, cardiac risk in some patients, for instance, since it is, [laughs] uh, what is it? Methyl dioxymethamphetamine. Um, there's that. Uh, I might be getting the chemical name wrong. But, uh, then you have risks with, say, certain other promising psychedelics, ibogaine, for potentially opiate addiction, which I want to ask you about, uh, not specific to ibogaine. You have, in the case of ketamine, some addictive potential, which I've certainly seen in even experienced psychonauts, so you have to be careful with how it's administered. But the--

Tim Ferriss 31:41 I won't talk too much about this, but the toxicity profile of many of the classic psychedelics like psilocybin is, is remarkably, um, appealing. Uh, so would you mind, uh, Matt, just speaking to the, the toxicity or potential toxicity of, say, psilocybin? And also, w-could you, could you speak to, uh, based on what you've seen with tobacco and other forms of addiction, uh, if you think there might be applications to, say, opiate or opioid addiction?

Matthew Johnson 32:13 Sure. So for toxicity, we can start at the physiological level. This is true for psilocybin, LSD, dimethyltryptamine or DMT, which is in ayahuasca. There is no known lethal overdose, no dose at which there's any observable organ damage, n-not even a potential mechanism for neurotoxicity. Um, that's pretty freakish. Cannabis is similar. You'd be hard-pressed to find anything sold over the counter, um, at CVS, Walgreens, that you could say this about. You can't say it about caffeine, aspirin. Most drugs, you can't just take 10 times an effective dose and expect to live or to be un, undamaged. So remarkably, freakishly, robustly, uh, safe at the physiological level. I would never say any drug is safe, period. It dema-- It, it, it depends on what area of risk you're talking about. Um, so these are very in-- at sufficient doses, um, profoundly conscious-altering drugs, very intoxicating, if you will. When you see harms, they fall into a couple of categories. One that's applicable to anybody that takes a high enough dose is what people out there call the bad trip. In clinical research, we refer to these as clinical experiences, uh, as, as challenging, I'm sorry, challenging experiences because, in fact, they can be very, um, helpful themselves going through extremely difficult experiences. Nonetheless, we try to minimize them. But out there in the wild, so to speak, recreational use or what have you, um, and it's certainly a small minority, but sometimes, um, a, an overwhelming anxious state can lead to dangerous behavior. Someone panics, they run into traffic. You know, it was overplayed in the propaganda of the late '60s, but falling from heights, um, it has happened. They're very intoxicating drugs. Far more people have fallen from heights when they're drunk, but nonetheless, it ha- it happens. So, um, in terms of public health, this ranks lowest amongst all the other major legal and illegal drugs, but nonetheless, there is a risk there. So nice thing is you can squarely address that in clinical research and potential clinical use, um, through preparation and monitoring. It's never-- It's not take two and call me in the morning follow-up care. Um, the other major area of risk with these classic psychedelics is only applicable to a, a small percent, one or two percent of the population, who have active psychotic disorders, such as schizophrenia, or a strong signal for that predisposition. And many of the kind of urban legends we may be aware of, of folks that took too much of a trip and they never came back, it seems very convincing that those folks had a predisposition, at least such as you might be familiar with Syd Barrett, the original singer of Pink Floyd. Um, it-- And in the earlier era of clinical research with LSD, with thousands and thousands of participants, the, the only people that had prolonged psychiatric reactions beyond the time course of the drug, uh, were those individuals with that psychotic predisposition. It's also very fortunate, like the bad trip side, that we can squarely address this in clinical research and eventual clinical use. Um, there are extremely reliable psychiatric structured screenings that can identify pe-- that small percentage of the population that has this risk. And then it does modestly raise blood pressure, um, so we can't, uh, run people through the research who are at an extremely high level of cardiac risk. I mean, these are the same folks that might have a cardiac event if they go up several flights of stairs. Nonetheless, that's a real thing. Um, and, uh, also in the area of risk, we, we've documented some systematic effects in increasing the chances of a headache within the day following use. Typically, not in the severe category, nothing that we would think would prevent people from, um, using it, uh, clinically. There's a very rare thing called hallucinogen, um, uh, persisting perceptual disorder. Extremely rare. It tends to be-- Well, it's All the data show that it is ex- exclusively associated with recreational use where there's typically multiple drugs, including alcohol used, and there may be a predisposition there. It's never been observed in any of the thousands of partas- participants in the older studies or the current studies. Um, uh, so, i- in what I'm referring to are ... You've heard of the term flashback, and that can mean many things. But th- what this refers to is having persisting perceptual abnormalities that severely hamper the qu- uh, uh, quality of life, and they're very distressing for individuals. And it, it seems to be that that's ... It's probably related to a neurological susceptibility where other events, not only psychedelic drugs, but other medications, other events could probably cause the same, uh, the same thing. But you might have heard of that. That sort of rounds out the entire sphere of, of ri- the known risks.

Tim Ferriss 37:33 Thank you. And what about, uh, applications to, uh, say opiate, opioid, right? And just if I could, I'll add just a, a quick personal note. So my cousin by marriage, uh, he had a hereditary disposition to schizophrenia and really abused LSD all throughout high school and college, and it would seem that it expedited the onset of symptoms of schizophrenia. Although very likely that he was headed there already, it just hastened the path. So I've seen that firsthand. Um, and now on the flip side, I've also seen incredible abuse, uh, on a personal level that is representative of, of, I suppose a sort of pandemic level problem in opiate abuse. So my best friend on Long Island died of a fentanyl overdose. My aunt died of Percocet plus alcohol not too long ago. So this is something that's touched a lot of lives in this room. Are there any potential, uh, applications you think, or is, or research worth doing that would look at psychedelics and something like opiate or opioid addiction?

Matthew Johnson 38:36 Absolutely. It's a very promising area. There was one study published in the early '70s using LSD with heroin addicted individuals. Um, there was ... You know, we needed to do follow-up, but that was right at the point in society where the rug was pulled out from this research and the research wasn't allowed anymore. But nonetheless, there was a, a, a good initial signal of long-term success, and that's part of this formula, what I was describing earlier, this picture of broad applicability to treat addiction of various types. My colleague Peter Hendricks at University of Alabama Birmingham is, is showing, uh, initial positive results in treating cocaine addiction. Um, so opioids, um, is a, is an extremely promising, um, area to ... Something that we wanna look at. Um, it's an extremely promising area, um, particularly in the midst of what's called the opioid crisis.

Ayelet Waldman 39:32 And especially since opioid addiction is resistant to treatment. Um, you know, we have medication assisted treatments now that are more effective at keeping people off op- uh, sort of resolving opioid cris- problems. But without medication assisted treatment, opioids, you know, the, the traditional treatments that we think of like Narcotics Anonymous, they are grossly ineffective. So, um, our current opioid crisis will not resolve without wholesale accessibility of medication assisted treatments, and I believe without really evaluating the potential of psychedelic drugs. Um, which is why I actually hope that this crisis might enhance our receptivity to de- taking, um, psychedelics down from Schedule 1, which means that they're the most criminal drugs. There is no ... A Schedule drug mean, dru- Schedule 1 drug means there's no medical use, and it's the most illegal drug, down to Schedule 4. So what kind of ... What other drugs do you think of that we could analogize that are on Schedule 4?

Matthew Johnson 40:40 Oh, many of the benzodiazepines-

Ayelet Waldman 40:42 Right

Matthew Johnson 40:42 ... and the sleeping aids are in Schedule 4.

Tim Ferriss 40:45 Let me, let me jump to Robin for a second because I think this, that we, we can, we can talk about perhaps the broad applicability and perhaps some current diagnostic problems that we may have in psychiatry. Uh, because if you look in the DSM, and we could talk to all sorts of people who have previously been, uh, uh, sort of at the head of mental health, Tom Insel and others, uh, where you have these disorders, these psychiatric disorders, so-called disorders that are very cleanly separate, right? You have anorexia nervosa. Anorexia has the highest mortality rate of any psychiatric disorder. Then you have OCD, then you have this, then you have that, and they're all very much siloed. Uh, could you speak to the ... Explain what the default mode network is, if that's possible. Uh, just speak to that because part of what is, um, fascinating to me personally is that if we kinda zoom out to 30,000 feet, as you mentioned earlier, you have this kind of hy- you have conditions associated with hyperrigidity, and then you have conditions associated ... Over here, OCD, anorexia, et cetera, these kind of compulsive behavioral or thought patterns, and then on the other side, you have this hyperfluidity, which can be problematic like schizophrenia, right? Could, but could you speak to, um, maybe ex- explain for folks, if possible, the, the current thinking around the default mode network?

Robin Carhart-Harris 42:09 Uh, sure, yeah. I mean, schizophrenia also, it, it does have that kind of chaotic component to it, but it also has a rigidity to it as well, if you think of, uh, fixed, uh, delusions. Um, and so, um, this is a remarkable thing that gets kind of glossed over in psychiatry that, uh, these diagnostic categories, while they're there really to aid the clinician, um- Uh, that's one view [laughs] . Another view is that they're aiding something else, perhaps drug discovery and, uh, and such like. And perhaps to some extent a myth that there are these crisp, uh, distinctions that have crisp underlying biomarkers that following the, the classical biomedical model we can come in with a magic bullet and, and solve the, solve the situation. And, and if that was true, then we wouldn't be seeing the, the mental health crisis that we're seeing at the moment. Prescription rates of psychiatric medications are going up at record levels, yet we're not chipping into the problem. So, you know, we do need some kind of major paradigm-shifting, uh, uh, event here, a kind of black swan event that, that, that really changes things. And, uh, you know, I think our collective view is that psychedelics, psychedelic therapy is, is that. It's this hybrid model that's not just a drug treatment. It's more holistic than that. It's about managing context, uh, giving a drug that produces this suppleness of mind, and then managing context to try and move people out of the kind of, you know, entrenched ways of thinking and, and, um, behaving, uh, into something, um, broader and more open. So the default mode network, uh, um, is, uh, i- in a sense you could say it's the most, um, it's the strongest candidate that we have in the brain for what you might call the biological substrate of the self or the ego. Um, it's a system that engages when we disengage, so to speak. Well, we disengage from attentive focus, but we enter a kind of daydreamy, you know, uh, internal, uh, imaginative state. Um, but, uh, this is very much tied in with, with self and, and the narratives that we build about who we are, that we start to believe in a kind of absolute way that, uh, guides and drives our behavior, but can be so narrowing. You know, ego sees narrow and short. Uh, and what you see under psychedelics is that this network breaks down. It literally, albeit temporarily, disintegrates, and people see broad, um, and, uh, they see the bigger picture analogous to the so-called overview effect, you know, that astronauts have described when they, uh, are up in space. They look, look back at the whole of the Earth, and then they can put things in perspective and think, "You know, why was I squabbling with my, uh, wife or my work colleague?" Um, and, and, you know, it's about seeing that, that bigger picture. So here, you know, we've got this opportunity through brain imaging to start to put a bit of meat on the bone, you know, to, uh, help, um, you know, lift the lid on this black box that's the brain, uh, and start to show people that this isn't magic. It might feel like magic, psychedelic therapy, but it rests very firmly on nature, on biology. Um, and I think it's useful to, to add that to the conversation and, and help kinda ground the conversation about, uh, about psychedelic

Robin Carhart-Harris 45:48 therapy.

Christian Angermayer 45:49 Yeah. So one point because both, uh, Ayelet and, uh, and Robin just, uh, touched, um, uh, something important where I disagree with Ayelet and agree with Robin that most psychedelics, it's not true for all of them, but are a very holistic treatment. So partly the setting and the guide and how the experience is equally important. So why... This is my opinion, especially, for example, on, on magic mushrooms, that yes, they should be available as a medical treatment, but not over the counter. This is nothing somebody should do alone, especially when you're depressed. And by the way, we all... I think one risk is that most people very passionately, like all of us talking of psychedelics, we're not depressed. And it's a different experience when while, when you read observations of, of treatments of depressed people, they might go through a, let's call it catharsis or to, uh, to a, a challenging... They might have a challenging trip. Nevertheless, the trip is healing them, and, and the guide is very important. So this is why I just wanna add that, yeah, uh, I personally think, yes, it should be available as a medical drug. This is what we're working on, but, uh, it should be available under professional care, like with psychiatrist or in clinics, uh, but not over the counter. Definitely not over the counter.

Ayelet Waldman 47:04 I- No, I agree with you entirely. You know, in my book I have a whole sort of chapter about paradigms for decriminalization, and, you know, my ideal paradigm for s- for psychedelic decriminalization would be, for lack of a better word, the psychedelic spa, where you would check in and get that buttressing because in all drug experiences, but particularly in psychedelics, the set and setting are, as you say, are critical. Set is what you bring to this experience, and setting is the setting in which you experience it. So like, you know, the Canyon Ranch of psychedelics with f- with, you know, licensed, trained support team. I'm not sure you have to be a therapist per se, but someone with experience and training in supporting an individual, ideally with preparation both before and after. Which is not to say that I think all people, um, require that, but that is, that is much more likely to engender a positive response.

Christian Angermayer 47:59 An interesting number is The Netherlands. It is legal. You can access psilocybin, magic mushrooms, in The Netherlands legally in coffee shops, and The Netherlands have the same mental health crisis than every other country in the world. So just the fact that psychedelics are available, yeah, unfortunately do not change, um, the mental health crisis. It is really, like, the professional... And I, I, if I experience it with people, like I would look at my parents or, or, or friends who have depression, they're not making that leap. They rather go to their doctor because they trust them, and then the doctor should be the one who's also, uh, administering that.

Tim Ferriss 48:39 So I'd, I'd like to touch on something you said, uh, actually, but that we've sort of covered, uh, in a few different ways, but offer a, a framing that I think is, is helpful, and that is that rather than think of good or bad trip, think of safe or unsafe trip. Because the, in, in many cases, the, the difficult experiences are when you see the truths you prefer not to see, and you look at the behaviors that may be in your blind spot, and that can be very uncomfortable. Uh, as in the case when a smoker's like, "Wow, that's disgusting. I saw that I'm killing myself," and they have to look at that hard truth. Difficult but safe, and that depends a lot on the context and the providers and, and so on. Uh, question for you, Christian. How do you think about creating business models around compounds that can be so effective with a single dose or two doses? Uh, because I, I know you want this to be available to a great number of people. That requires a sustainable model of some type, and there are many different ways to approach it. You know, MAPS has one. Let's say a B Corp that does drug development, then there are for-profit options. Uh, how do you look out for temptations like taking something that is so effective with one or two doses and create, creating something that requires a maintenance dose multiple times a week? Is it the therapeutic wrapper, that kind of spa element and context around which you build a business? How, how do you think about that?

Christian Angermayer 50:07 Well, first, um, and meaning it sh- sounds maybe cheesy or how I say in English, but like, uh, i- if you're investing in biotech, you really wanna make a difference because I do other tech investments, and I'm always very happy about biotech because if you succeed in, uh, bringing a drug to market, you really make a, a difference in the world. So, so I think it's not-- I think this is a little bit the, the myth that everybody thinks biotech investors are like evilly plotting, um, how to make the most out of it. At least this is not how I think about it. Like, we wanna cure people, um, and, and hopefully we're gonna make that happen. Um, second, the market is so huge, meaning I, I said we have three hundred twenty million people and most-- and the number is rising, and I think there are more people who are not diagnosed. So, so even if... And I would be very, very happy if it's a single dose psilocybin, which is, uh, which is helping those people. Even if that's the case, the market is, is huge. Yeah. Then you have the, um, the side business models or the, as, as Ayelet said, the spas and the, the, the clinics you can build up, yeah, because it is all about the holistic, um, thing. And, and then even-- And we don't know yet, meaning for a lot of things we also have to say like we have very good indications, but we don't know yet what is the right dose. This is, for example, what Compass is, is trying to figure out at the moment. It might be, and I'm not saying that because it should be like commercially, but it might be that you say, "Oh, if somebody was depressed, you should do it every year again." We don't know yet. We try to figure that out. Yeah. But there is enough business, uh, and I think in general, like even if you go aside and look at meditation app like Calm, for example, like I think the, the whole mental wellbeing, like treating people who are ill, have mental health, health issues, but also keeping people healthy, yeah, in our current environment, and, and this will get worse. My personal theory is that, that our brain, uh, has like an, an inbuilt actually resilience or like a immune system, which is based on faith, um, love, and, uh, and purpose. And if you look what our world is happening, we take these three things away. Communities are dissolving. Families are dissolving. So you have cheesily said a little bit less love in the world. Yeah. Yeah. Then most people know that the world will look so different in twenty years that, uh, that they don't have a purpose anymore. The bus driver knows that in twenty years, most likely his bus will be driven by an artificial intelligence. Yeah. And, uh, and then we have a, a dramatic loss of faith in every sense, like religion and in, in any spiritual dimension, and it all will make people more depressive. So cynically said, the market is growing, so I'm not worried about, uh, about, uh, how often you have to take it.

Tim Ferriss 52:53 Okay, [laughs]

Tim Ferriss 52:54 thanks. Market is growing for better or for worse. [laughs] Uh, Matt, I'd like, I'd like to come to you. First I'll just... I'll, I'll make another personal note, uh, and, um, try not to directly implicate myself here. But-

Christian Angermayer 53:09 [laughs]

Tim Ferriss 53:10 So, uh, my family has, uh, a on both sides quite a bit of severe depression, and I would say every six months or so as an adult, I've had a major depressive episode. Almost killed myself when I was an undergrad at Princeton. I've written about that if you guys wanna check it out. Uh, in the last five years, I haven't had a single major depressive episode, and here we are on this panel. I'll let you guys draw your conclusions.

Christian Angermayer 53:32 [laughs]

Tim Ferriss 53:33 Uh, not to say that that is going to be true a hundred percent of the time, but given the fact that in... One could argue that there have been incredible advances scientifically in cardiology and neurology, all these various fields, and then you look at psychiatry and there's been very little. I mean, aside from SSRIs some time ago, and now ketamine, which is very interesting, I think, for, uh, acute suicidal ideation and chronic pain especially. Uh, but there's, there's very little that has happened. And, um, so I'm, I'm very, very vested in this space. Matt, the reason I wanted to come to you next is that you mentioned Schedule I and Schedule IV. Uh, one question that people might have on their minds is, "Well, wait a second. If these are so great, if they have such low toxicity, how did they end up in a category Schedule I?" Which is no known medical application, high potential for abuse, among other things. Which of course based on the data I disagree with, but like how did that happen and how do we get out of that? And I'll just say one more thing 'cause we're running short on time, which is, you know, my not so secret agenda is to set the conditions over the next three to five years with private philanthropy and so on, so that I can then work separately to try along with other people to help get federal funding for this stuff, which is not currently forthcoming.

Christian Angermayer 54:43 Right.

Tim Ferriss 54:43 Um, so how did we get to this very difficult and expensive position of operating from Schedule 1, and how do we potentially get out?

Matthew Johnson 54:54 Yeah, this-- the quick answer is that psychedel- it was really because of the association with the counterculture and everything associated with it in the late '60s, early '70s. And I would say that, that the culture was essentially traumatized from, um, that kinda early introduction, uh, of psychedelics and, and, and there were casualties when they were used broadly. There are also plenty of people said it changed their lives for the better, and they're still here to, to talk about that. Um, but this, this came about right at the time when the federal framework for controlling s- uh, scheduled drugs, the Controlled Substances Act, was being developed. And, um, there is no... There are some flaws in that system. There is no category, for example, of having, um, no accepted medical use, but mild to moderate abuse potential. Um, you know, you jump from, uh, having no accepted medical use and high potential for abuse in Schedule 1 to Schedule 2, something like cocaine or methamphetamine, which are Schedule 2, um, as, as having, uh, high, high potential for abuse, but, um, some accepted medical, uh, value, and those two drugs are used, uh, medically and are approved. Um, so there's really no framework. Now, you know, psilocybin, the language is important here. It-- we squarely know at every level of science the, the effects in the mesolimbic brain structures involving dopamine, the epidemiology, reliable animal models of reward. We know that these aren't drugs of addiction solidly. Um, but they are, they can be drugs of abuse, and that simply means used in a way that can ki- can harm you or the people around you. So, you know, a couple teenage- teenagers go out driving on mushrooms. That's abuse. Or you get into a pattern that interferes with your family relationships, et cetera. Um, so they really don't belong... And, and, and the, again, the Controlled Substances Act is, is rather ambiguous. You know, they refer to abuse potential, which can include addiction potential, but also other risks. So they do have risks. You could argue they have, uh, you know, these classic psychedelics, mild abuse potential. Um, but the other side of that is there's, there's no accepted medical value. Um, when the Controlled Substances Act was originally, um, uh, adopted, the-- it wasn't clear what that really meant, and through judicial precedent, it became solidified that, that what that means is FDA approval for an indication. So that's where we're at now. So until one of these dru- until psilocybin is approved for an indication, it's gonna, by definition, remain in Schedule 1.

Tim Ferriss 57:49 What are the most promising indications currently, or those that are furthest along?

Matthew Johnson 57:54 Based on the data, um, the most promising indication would be depression and anxiety, you could call it psychiatric distress, associated with a life-threatening cancer diagnosis. That's what the most modern, uh, most cr-- uh, advanced research with psilocybin as a therapeutic, uh, has been focused on. There's three randomized studies in that category. And then secondary to that, sort of as a class, are, um, psilocybin in the treatment of, of, uh, smoking cessation as a smoking cessation medication. I showed you some data. Treatment of alcoholism. Uh, a colleague, Mike Bogenschutz at NYU, has done some great work with that. And, and then Robin's published work on depression outside of cancer. So all of those, those three things have been, uh, those are published results with open-label, non-randomized pilot studies. So they all look very promising, but they haven't, um, gone, uh, the published data hasn't reached that level of, you know, large randomized trials yet. All of these disorders are associated with being stuck in a narrowed mental and behavioral repertoire, and as Robin suggested, I think that's why we're seeing efficacy with these nominally different disorders. Psychedelics have a way to blast one out of that narrowed mental repertoire.

Tim Ferriss 59:15 Thank you.

Tim Ferriss 59:16 Uh, Ayelet, where would you hope, what would you hope this, uh, this field that is, broadly speaking, psychedelics, to look like a few years from now? Do you have anywhere you'd like to see it?

Ayelet Waldman 59:29 Well, you know, um, because I, I went-- I was a lawyer and I, I was a criminal law professor, and so I think through this criminal justice lens. And I remember a period where decriminalization of marijuana seemed incomprehensible. When we first started working, um, and I was working with the Drug Policy Alliance on state initiatives to decriminalize marijuana, it seemed, um, remotely possible that in some very liberal states you might have a medical model, and absolutely impossible that you would ever have a recreational model. And I don't know about you guys, but I've been to these pot clubs which are like Apple stores, and the budtenders are, you know, showing you weed that, in my lifetime as a teenager in New Jersey, I never saw anything approaching. So there is a kind of, there, there, the shift is possible. I think we could see a medicalized model specifically for psilocybin. The reason that this research is happening in psilocybin and not LSD is because of the sort of fear associated with LSD. But they operate, wouldn't you say, Matt, almost identically in the brain?

Matthew Johnson 1:00:38 Right.

Ayelet Waldman 1:00:39 So I think we will see, over the course of the next decade, a sh- and maybe even less, a sh- a shift to a medical approach, maybe, maybe changing the schedule or maybe on a statewide basis having the s- as we did with marijuana. Marijuana's still Schedule 1 federally. It's still a crime federally, but we have different models state by state. Um, and, uh, I think that we are a long way from a decriminalization model for other, for drugs generally. But I do think psychedelics because of the research that these gentlemen are doing does have great potential for medical applicability. And I actually think what can drive that more effectively than anything else are the individuals in this room and others like this, which is why I'm speaking to you, and I imagine that's why Tim is here as well, and maybe the rest of the panel, because what we need is a model of investment and corporate pressure to change laws. I mean, that's the way it works in America. When there is a wave of, uh, of capitalist interest, it's a lot easier for laws to change.

Tim Ferriss 1:01:48 We are up on time. Closing comments real quickly. Check out the research. This, these are not panaceas, but they are the most exciting thing that I've been focused on for the last several years. It's worth looking at. You have a chance if you're interested in being on the playing field at having a Katherine McCormick level of impact. It's a big deal. Uh, so please take a look, check out everybody on the panel, and, uh, I, Ayelet and I will be doing book signing over there. There are a couple of chapters in Tools of Titans on the psychedelic stuff as well. And, uh, thank you all for coming. And ladies, lady and gentlemen, thank you for coming.

Ayelet Waldman 1:02:29 Thank you. [audience applauding]

Tim Ferriss 1:02:29 Hey guys, this is Tim again. Just a few more things before you take off. Number one, this is 5-Bullet Friday. Do you want to get a short email from me? Would you enjoy getting a short email from me every Friday that provides a little morsel of fun for the weekend? And 5-Bullet Friday is a very short email where I share the coolest things I've found or that I've been pondering over the week. That could include favorite new albums that I've discovered. It could include gizmos and gadgets and all sorts of weird shit that I've somehow dug up in the, uh, the world of the esoteric as I do. It could include favorite articles that I've read and that I've shared with my close friends, for instance, and it's very short. It's just a little tiny bite of goodness before you head off for the weekend. So if you want to receive that, check it out. Just go to fourhourworkweek.com. That's fourhourworkweek.com all spelled out, and just drop in your email, and you will get the very next one. And if you sign up, I hope you enjoy it.