#377: Psychedelics — Microdosing, Mind-Enhancing Methods, and More

This episode features a panel that I moderated in front of a standing-room-only crowd at the Milken Institute's Global Conference 2019. http://globalconference.org/ It includes a great overview of psychedelic science, investing opportunities, anecdotal personal benefits, legal challenges, and much more. I think it’s one of the more comprehensive panels ever done on the subject. Here are the participants: Matthew Johnson https://hopkinspsychedelic.org/johnson — Principal Investigator, Johns Hopkins Psychedelic Research Unit https://hopkinspsychedelic.org/ Ayelet Waldman http://www.ayeletwaldman.com/ — Author, A Really Good Day: How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life https://www.amazon.com/gp/product/1101973722/ref=as_li_ss_tl?ie=UTF8&linkCode=ll1&tag=jhsbooks-20&linkId=728d8cb7979a13fbb95ad35fbf79ca9a&language=en_US Robin Carhart-Harris https://www.imperial.ac.uk/people/r.carhart-harris — Head of Psychedelic Research, Centre for Psychedelic Research, Department of Brain Sciences https://www.imperial.ac.uk/people/r.carhart-harris, Imperial College London Christian Angermayer https://twitter.com/c_angermayer — Founder, Apeiron Investment Group https://www.apeiron-investments.com/ and ATAI Life Sciences https://www.atai.life/ Please enjoy! *** If you enjoy the podcast, would you please consider leaving a short review on Apple Podcasts https://podcasts.apple.com/us/podcast/the-tim-ferriss-show/id863897795?mt=2/iTunes? 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Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:01Tim Ferriss?

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

• 0:06Speaker 01

  Can I ask you a personal question?

• 0:08Speaker 02

  No, it is an inappropriate time.

• 0:12Speaker 01

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

• 0:24Tim Ferriss?

  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,

• 1:09Tim Ferriss?

  because this is a conference comprised of primarily investors, many of the best investors and certainly most lauded and objectively, in many respects, successful CEOs in the world. Very, very unusual to see that type of crowd in that room. And a few notes before we jump into it. It was a fantastic experience. A lot more to share another time on that. 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.

• 1:50Tim Ferriss?

  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. And I'm a nerd for the science. 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, 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

• 2:35Tim Ferriss?

  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 30 seconds in. And without further ado, because I do make, because I do make, for fuck's sake, I do make much ado about my introductions, please enjoy this very wide-ranging and detailed conversation about psychedelics and psychedelic science.

• 3:21Tim Ferriss?

  Thanks for coming, everyone. I'll keep my introductory remarks pretty short, 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?

• 3:44Tim Ferriss?

  All right, so the entire audience for both questions. Lest we start on a complete downer, let me give an inspirational story. And it relates to Katherine 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. She also inherited a good portion of the International Harvester fortune. And in 1953, she met a man named Gregory Pinkus, who was developing an oral contraceptive.

• 4:29Tim Ferriss?

  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 $2 million of funding. In today's dollars, it's around $23 million over many years. And it was an uncrowded bet through which she was able to completely bend the arc of history. And I will give some disclosures now. So in 2015, I stopped all my early-stage tech investing and redirected almost my entire

• 5:13Tim Ferriss?

  focus to psychedelic science, for reasons that I think will become clear in this conversation, and have been very involved with both Hopkins and Imperial, 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, Center of Psychedelic Research, Department of Brain Sciences, Imperial College, London. Matthew Johnson, Associate Professor, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine. And Ayelet Waldman, author of "A Really Good Day: How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life."

• 5:53Tim Ferriss?

  So let's begin, Matt, with some of your slides, if we can bring those up. And I'll let you take it from here.

• 6:01Speaker 03

  Sure. Slide three. So, really important before we get into the meat of some of our other conversations is to let you know that we've been ahead 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 ya, 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 conduct these studies. It's been used by institutional review boards at a growing number of universities. And, I was

• 6:44Speaker 03

  at the FDA last week, they are using these guidelines to evaluate novel protocols. Recently published another paper, 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 three trials as a medicine, that it belongs in schedule four, based on the data, rather than schedule one. So, we're aware of the risks, we're paving the way, we've analyzed the data. In terms of some of the, now we've got 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

• 7:29Speaker 03

  number four, please. We published the largest, a couple of 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. And this is essentially like the addiction work, 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 results here on the right, looking at depression results on the left, and then anxiety results in the right panel.

• 8:12Speaker 03

  The leftmost 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 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 want to 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, around eight on the scale.

• 8:55Speaker 03

  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, everyone has received the high dose. So, the people who had gotten the trivial dose in the first round, they have now also received a high dose. Now, they have dramatically decreased their depression and anxiety,

• 9:38Speaker 03

  just like the group that got it a couple of 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 is recently approved for the treatment of depression, in that it has immediate antidepressant effects, it lasts one to three weeks, which is wonderful. Get ready, because we might be at an even higher plateau when it comes to sustained effects with psilocybin. Um, so I'll jump to the, the next slide.

• 10:24Speaker 03

  These, along the addiction angle, 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 have tried to quit smoking. We ran a small, open-label pilot. We had dramatically impressive results. At six months, we found that 80% of participants were biologically confirmed as smoke-free.

• 11:07Speaker 03

  Breath samples, urine samples, you know, we trust people, but we verify. Those results held up to 67% at a year, and 60% at an average of two and a half years after their target quit date. In this study, they had three psilocybin sessions, most participants. Just to tell you how impressive these results are, the best medications we have, such as Verenecline, 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.

• 11:51Speaker 03

  The real question is, does this warrant follow-up? And the answer to that is abso-freakin'-lutely. And so, we're in the middle of that randomized trial at this point. So, this is just a taste of a number of trials that have gone 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.

• 12:16Tim Ferriss?

  Thank you, Matt. Ayala, let's jump to you because I'd like to contrast, or maybe not contrast, but add to the scientific discussion, the personal discussion 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 let you tackle it.

• 12:37Speaker 04

  So, microdosing is the practice of taking a subperceptual dose of a psychedelic drug. I mean, you can microdose anything, but in this case, we're talking about psychedelics. So, when I say "subperceptual," I mean, you do not trip. You do not have a hallucinatory experience. You see no kaleidoscopic colors. The idea is to take a dose that you cannot perceive of any effects, but that there is something going on metabolically. So, I was experiencing serious depression, and 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.

• 13:21Speaker 04

  I had been 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. And 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 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.

• 14:04Speaker 04

  If you want to, say, have a hallucinatory experience of Burning Man, you're going to 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, because 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.

• 14:47Speaker 04

  So I thought, alright, well, this was a bust, and I got to work. And about, after about forty 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,

• 15:27Speaker 04

  it wasn't like every day was a really good day, but many days were really good days. And my set point of depression dramatically changed. 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. So I became convinced at the end of this experiment

• 16:06Speaker 04

  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.

• 16:33Tim Ferriss?

  Yeah.

• 16:36Tim Ferriss?

  That's great. That image is messing up my segue. But thank you.

• 16:43Tim Ferriss?

  The microgram-milligram difference is very important, so please take close note of that. Robin, let's jump to you next, because I really want to get your perspective on plausible mechanisms, 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 most cases, they're sitting in your system, saturating your system, for, say, six months after the cessation of smoking. Could you talk to, based on our current understanding, based on your current research, what is happening? And maybe you could also touch on the entropic brain.

• 17:25Speaker 05

  Sure. Okay. So, the first thing to say is that these compounds are working on the serotonin system, an important brain chemical that modulates a range of different, important psychological functions. We know mood especially, but also cognition and states of consciousness. And it's a particular aspect of the serotonin system that psychedelics work on, a particular receptor subtype, it's called a serotonin 2A receptor. And we know from a broad range of different evidences that this receptor is involved in, you could summarize it as adaptability, flexibility, plasticity.

• 18:10Speaker 05

  There are a lot of these receptors in the cortex, an aspect of brain that humans have so much of. And so stimulating these 2A receptors appears to, at a higher level, have an interesting effect on the regularity and the quality of brain activity. So we can characterize conscious states in a way analogous to waves. When we record brain activity, it's very rhythmic, and as our conscious states change, that rhythmicity changes as we fall asleep. Or if we're knocked out with an anesthetic, or we suffer some kind of brain injury, you'll

• 18:52Speaker 05

  see that brain activity starts to look like sort of slow rollers on an ocean. And... Related to that, 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, that the waves look very different. You know, they're much more rapid, 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. There hasn't been a state of consciousness found that shows that increase in the richness

• 19:34Speaker 05

  or complexity of brain activity above the level of normal waking consciousness. That's a very mechanistic take on things. Another way to look at this, that's a way of characterising the acute experience. Another thing to emphasise, 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 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 depression and such like.

• 20:18Speaker 05

  So what's going on there? And so, just quite briefly, to talk about the therapeutic mechanisms and perhaps slightly frame it in a slightly more sort of human and psychological way. We can think of a range of different expressions of mental suffering as being underpinned by 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, or obsessive-compulsive disorder with those stamped-in habits.

• 20:59Speaker 05

  And so, there is this kind of commonality, this trans-diagnostic commonality that seems to relate to a very range of, a broad range of different 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 psychological support, then you can work towards cultivating a healthy revision of these pathological beliefs and habits.

• 21:36Tim Ferriss?

  Thank you. And it's worth noting also, for people who aren't familiar, that if we're talking about psilocybin, which, in the case of studies, is synthesized, it's been used in the form of psilocybin mushrooms by, for instance, indigenous populations, including the Moztecs in Mexico, for thousands of years, one could argue, very, very effectively. So there's a good question, we're not going to dive into it right now, but as to why almost every civilization, excepting a few in Antarctica, have used psychedelic compounds. And certainly for rites of passage, but also with an objective along the lines of these enduring effects that you talk about.

• 22:15Tim Ferriss?

  Krishnan, let's talk about investment in this space and why you're involved. I know that you, based on our conversation, certainly you 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 how are you thinking about approaching it?

• 22:46Speaker 06

  Okay, let's start, because you're many investors. I'm a super coward. Until five years ago, I'm not exaggerating, I have never drank alcohol in my whole life. And I come from Bavaria in Germany, where this is like culturally actually appropriate to do so. But I didn't, because I was a weird kid, so I was super worried that my brain cells could die. And so I didn't drink alcohol. I've never smoked a cigarette. I've never smoked a joint. I've never done anything else. Till like around about six years ago. Some very, very trusted friends tried to convince me of magic mushrooms. And I was like, "You're clearly insane." "Yeah, I'm never, ever gonna do that."

• 23:27Speaker 06

  But then, they told me a lot about it, actually, what Matt and Robin said. 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, to say that as well, it was a jurisdiction where it's legal. And it was under a very guided and very well-set-up, protected session with a great guide. And it was the single most meaningful thing I've ever done and experienced in my whole life. Full stop. Nothing comes close to it.

• 24:10Speaker 06

  And, which is, by the way, in a lot of studies, I think it's a John Hopkins study, where I think it was two-thirds of the people rank it among the five most meaningful events in their life, among birth of a child, death of a parent. And I think one-third roundabout ranks it among the single most meaningful thing. So, because I'm an entrepreneur, I came out of the trip. The first thing I did, I called my parents.

• 24:38Speaker 06

  Because, yeah, I realized how much I love them, and I never say it. And the second thing is, was like, "This should be experienced by more people." And I do think that the only way to do it, when we have a lot of anecdotal experience, like myself and like Ayala, then we have a lot of, let's call it, basic research. But 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 medical purposes. So I was like, "Okay." This should be done, is anybody doing that? And so I'm embarked on the trip, in a figuratively word,

• 25:23Speaker 06

  and met great people like George, who founded Compass, who had the similar thoughts that this should become a medical drug, mainly for treating depression and then other mental health issues. This is where we are, Compass is in phase 2B. I'm also back to company which is bringing R-ketamine, hopefully on the market, which is a sort of sub-form of ketamine, also for the treatment of depression. And we're looking on other 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 neglected,

• 26:08Speaker 06

  been neglected over the last 30 years. Because it was sort of, the mind is a complicated thing. And pharma companies, biotech companies thought, okay, let's focus on cancer, let's focus on the more tangible illnesses. And also, to be fair, depression, our fear on depression 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, when people came back from the Second World War and were showing symptoms, what we now would call post-traumatic stress disorder, people said, "Hey, get on."

• 26:50Speaker 06

  So I think the fear on mental health has changed over the last 20 years. 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 the state of our mind. Yeah, and this is why the numbers rise. We have 320 million people. Suffering from depression. And these are just the official numbers and most probably the, how you say, the gray number is watch higher.

• 27:32Speaker 06

  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 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, if a person gets very depressive because somebody loved one dies, you don't want to take Prozac and Prozac tells you, you don't care about the death. You want to sort of dissolve it and solve it in a, in a different way. And I think this is where psychedelics have a very promising path to be a very valuable drug.

• 28:14Tim Ferriss?

  Thank you. And 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 and is, is really remarkable. Both MDMA and psilocybin now have breakthrough therapy designation by the FDA, which is remarkable. And if you look at the graphs, you look at the data 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.

• 28:51Speaker 04

  Um, Tim, can I add a point to that?

• 28:53Tim Ferriss?

  Yeah.

• 28:54Speaker 04

  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 don't, I don't smoke. I don't like to smoke weed. Sometimes I take CBD because, you know, you can't get a macho without it nowadays. Um, but, uh, I don't like to experience any hallucin- I, I, I like my mind to be sharp at all times. But, um, uh, because I was teaching that one of the first sort of people who popularized MDMA, Sasha Shulgin, a chemist in Berkeley, used to lecture to my class and Sasha and his wife, Anne, who was a therapist, convinced me to, um, try MDMA, which is ecstasy, with my husband as a tool of marital therapy.

• 29:38Speaker 04

  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. But the, what MDMA does, and why it's relevant, I think, to PTSD, is it somehow, and these guys can probably talk more accurately to it, it disconnects the emotional experience from the memory, which allows you to 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,

• 30:23Speaker 04

  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.

• 30:49Tim Ferriss?

  Thank you. Yeah, it's, not to delve too much into any current use, wouldn't want to implicate anyone. But MDMA is worth taking a very close look at. There are risks associated with some of these compounds.

• 31:00Speaker 04

  Yes, unlike LSD.

• 31:01Tim Ferriss?

  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, say, cardiac risk in some patients, for instance, since it is, what is it, methyldioxy, methamphetamine, there is that. I might be getting the chemical name wrong. But then you have risks with, say, certain other promising psychedelics. Ibogaine for potentially opiate addiction, which I want to ask you about. 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, I won't talk too much about this,

• 31:43Tim Ferriss?

  but the toxicity profile of many of the classic psychedelics like psilocybin is remarkably appealing. Would you mind, Matt, just speaking to the toxicity, or potential toxicity of, say, psilocybin? And also, could you speak to...

• 32:04Tim Ferriss?

  Based on what you've seen with tobacco and other forms of addiction, if you think there might be applications to, say, opiate or opioid addiction?

• 32:13Speaker 03

  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, not even a potential mechanism for neurotoxicity. That's pretty freakish. Cannabis is similar. You'd be hard-pressed to find anything sold over the counter at CVS/Walgreens that you could say this about. You can't say it about caffeine, aspirin.

• 32:56Speaker 03

  Most drugs, you can't just take 10 times an effective dose and expect to live or to be undamaged. So remarkably freakishly robustly safe at the physiological level. I would never say any drug is safe, period. It depends on what area of risk you're talking about. So, these are very, at sufficient doses, 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."

• 33:39Speaker 03

  In clinical research, we refer to these as "clinical experiences," as "challenging," I'm sorry, "challenging experiences," because in fact, they can be very 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, and it's certainly a small minority, but sometimes, 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, it has happened. They're very intoxicating drugs. Far more people have fallen from heights

• 34:19Speaker 03

  when they're drunk, but nonetheless, it has, it happens. So, 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 through preparation and monitoring. It's never, it's not take two and call me in the morning, follow-up care. The other major area of risk with these classic psychedelics is only applicable to 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

• 35:03Speaker 03

  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 Sid Barrett, the original singer of Pink Floyd. And in the earlier era of clinical research with LSD, with thousands and thousands of participants, the only people that had prolonged psychiatric reactions beyond the time course of the drug 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. There

• 35:45Speaker 03

  are extremely reliable psychiatric structured screenings that can identify that small percentage of the population that has this risk. And then it does modestly raise blood pressure, so we can't 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.

• 36:11Speaker 03

  And also in the area of risk, we documented some systematic effects in increasing the chances of a headache within the day following use, typically not in a severe category, nothing that we would think would prevent people from using it clinically. There's a very rare thing called hallucinogen, persisting perceptual disorder, extremely rare, it tends to be, well, it's, all the data show that it is 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 participants

• 36:54Speaker 03

  in the older studies or the current studies. So, and what I'm referring to are, you've heard of the term flashback, and that can mean many things, but what this refers to is having persisting perceptual abnormalities that severely hamper the quality of life, and they're very distressing for individuals. And 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, same thing, but you might have heard of that. That sort of rounds out the entire sphere of known risks.

• 37:32Tim Ferriss?

  Thank you. And what about applications to, say, opiate opioid, right? And just, if I could, I'll add just a quick personal note. So, my cousin by marriage, 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. And now on the flip side, I've also seen incredible abuse on a personal level that is representative of, I suppose, a sort of pandemic level problem in opiate

• 38:15Tim Ferriss?

  abuse. So my best friend on Long Island died of 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 applications you think or research worth doing that would look at psychedelics and something like opiate or opioid?

• 38:35Speaker 03

  Absolutely, it's a very promising area. There was one study published in the early 70s using LSD with heroin addicted individuals. 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 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 showing initial positive results in treating cocaine addiction.

• 39:17Speaker 03

  So opioids is an extremely promising area, it's something that we want to look at. It's an extremely promising area, particularly in the midst of what's called the opioid crisis.

• 39:31Speaker 04

  And especially since opioid addiction is resistant to treatment, you know, we'd have medication assisted treatments now that are more effective at keeping people off, sort of resolving opioid crisis problems. But without medication assisted treatment, opioids, you know, the traditional treatments that we think of like Narcotics Anonymous, they are grossly ineffective. So 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.

• 40:11Speaker 04

  Which is why I actually hope that this crisis might enhance our receptivity to taking psychedelics down from Schedule I, which means that they're the most criminal drugs, there is no, a Schedule drug means, Schedule I drug means there's no medical use and it's the most illegal drug, down to Schedule IV. So what kind of, what other drugs do you think of that we could analogize that are on Schedule IV?

• 40:39Speaker 03

  Oh, many of the benzodiazepines and the sleeping aids are in Schedule IV.

• 40:45Tim Ferriss?

  Let me, let me jump to Robin for a second because I think that we can, we can talk about- Perhaps the broad applicability and perhaps some current diagnostic problems that we may have in psychiatry. Because if you look in the DSM, and we could talk to all sorts of people who have previously been sort of at the head of mental health, Tom Insle and others, where you have these disorders, psychiatric disorders, so-called disorders, that are very cleanly separate. Yeah. 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 side

• 41:29Tim Ferriss?

  note. Could you speak to the, explain what the default mode network is, if that's possible? Just speak to that, because part of what is fascinating to me personally is that if we kind of zoom out to 30,000 feet, as you mentioned earlier, you have this kind of, you have conditions associated with hyper rigidity, 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 hyper fluidity, which can be problematic, like schizophrenia. But could you speak to, maybe explain for folks, if possible, the current thinking around the default mode network?

• 42:09Speaker 05

  Sure, yeah. I mean, schizophrenia also, it does have that kind of chaotic component to it, but it also has a rigidity to it as well, if you think of fixed delusions. And so, this is a remarkable thing that gets kind of glossed over in psychiatry, that these diagnostic categories, while they're there, really to aid the clinician, that's one view. Another view is that they're aiding something else, perhaps drug discovery and such like. And perhaps, to some extent, a myth that there are these crisp distinctions that have crisp underlying biomarkers, that following the classical biomedical model, we can come

• 42:53Speaker 05

  in with a magic bullet and solve the situation. And if that was true, then we wouldn't be seeing 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.

• 43:16Speaker 05

  Events here, a kind of black swan event that really changes things. And, you know, I think our collective view is that psychedelics, psychedelic therapy 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, 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 behaving into something broader and more open. So the default mode network is, in a sense, you could say it's the most, it's the strongest

• 43:58Speaker 05

  candidate that we have in the brain for what you might call the biological substrate of the self or the ego. 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, internal imaginative state. But this is very much tied in with self and the narratives that we build about who we are, that we start to believe in a kind of absolute way that guides and drives our behaviour, but can be so narrowing. You know, ego sees narrow and short.

• 44:43Speaker 05

  And what you see under psychedelics is that this network breaks down. It literally, albeit temporarily, disintegrates and people see broad and they see the bigger picture analogous to the so-called overview effect, you know, that astronauts have described when they are up in space, they 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 wife or my work colleague? And you know, it's about seeing 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 help, you know, lift the lid on this black box that's

• 45:28Speaker 05

  the brain 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. And I think it's useful to add that to the conversation and help kind of ground the conversation about psychedelic therapy.

• 45:48Speaker 06

  Yeah, so one point, because both Ayala and Robin just touched something important, where I disagree with Ayala 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 however you experience is equally important. So why, this is my opinion, especially for example 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.

• 46:29Speaker 06

  And it's a different experience when you read observations of treatments of depressed people, they might go through, let's call it catharsis, or to a challenging, they might have a challenging trip, nevertheless, the trip is healing them and the guide is very important. So this is why I just want to add that, yeah, I personally think, yes, it should be available as a medical drug, this is what we're working on, but it should be available under professional care, like with psychiatrists or in clinics, but not over the counter, definitely not over the counter.

• 47:04Speaker 04

  No, I agree with you entirely. In my book, I have a whole sort of chapter about paradigms for decriminalization. And, you know, my ideal paradigm 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, 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, you know, licensed, trained, support team. I'm not sure you have to be a therapist per se, but someone with experience and training

• 47:44Speaker 04

  in supporting an individual, ideally with preparation both before and after. Which is not to say that I think all people require that, but that is much more likely to engender a positive response.

• 47:59Speaker 06

  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 the mental health crisis. It is really like the professional... And if I experience it with people, like, I would look at my parents or friends who have depression, they're not making that leap. They'd rather go to their doctor, because they trust them, and then the doctor should be the one who's also administering that.

• 48:38Tim Ferriss?

  So I'd like to touch on something you said, actually, but that we've sort of covered in a few different ways, but offer a framing that I think is helpful, and that is that rather than think of good or bad trip, think of safe or unsafe trip. Because the, in many cases, 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. 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 so on.

• 49:22Tim Ferriss?

  A 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, because 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 with say a B Corp that does drug development, then there are for-profit options. How do you look out for temptations like taking something that is so effective with one or two doses and 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 do you think about that?

• 50:06Speaker 06

  Well, first, and meaning it sounds maybe cheesy or I always say in English, but like if you're investing in biotech, you really want to make a difference, because I do biotech investments and I'm always very happy about biotech, because if you succeed in bringing a drug to market, you really make a difference in the world. So I think it's not, I think this is a little bit the myth that everybody thinks biotech investors are like evilly plotting how to make the most out of it. At least, this is not how I think about it. We want to cure people, and hopefully, we're going to make that happen. Second, the market is so huge, meaning I said we have 320 million people and the number

• 50:49Speaker 06

  is rising, and I think there are more people who are not diagnosed. So even if, and I would be very, very happy if it's a single-dose Tylenol, which is helping those people, even if that's the case, the market is huge, yeah. Then you have the side business models, or as I always said, the spas and the clinics you can build up, yeah, because it is all about the holistic thing. 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 trying to figure out at the moment, and it might be, and I'm not saying that because it should be like commercially, but it might be that

• 51:33Speaker 06

  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 well-being, 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 an immune system, which is based on faith, um, love and, and purpose. And if you look what our world is happening, we take these three things away.

• 52:17Speaker 06

  Communities are dissolving, families are dissolving, so you have, cheesy, they 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, and then we have 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. So Nicky said, the market is growing, so I'm not worried about, uh, about, uh, how often you have to take it.

• 52:53Tim Ferriss?

  Okay, thanks. Market is growing for better or for worse.

• 52:59Tim Ferriss?

  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, try not to directly implicate myself here, but. So 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 want to 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. 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,

• 53:44Tim Ferriss?

  in neurology, in 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 acute suicidal ideation and chronic pain especially, but there's very little that has happened. And so 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. 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?

• 54:26Tim Ferriss?

  And I'll just say one more thing, because 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. So how did we get to this very difficult and expensive position of operating from Schedule I and how do we potentially get out?

• 54:54Speaker 03

  Yeah, this, the quick answer is that psychedelics, 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 the culture was essentially traumatized from that kind of early introduction of psychedelics 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 talk about that. But this came about right at the time when the federal framework for controlling scheduled

• 55:37Speaker 03

  drugs, the Controlled Substances Act, was being developed. And there is no, there are some flaws in that system. There is no category, for example, of having...

• 55:50Speaker 03

  No accepted medical use, but mild to moderate abuse potential. You know, you jump from having no accepted medical use and high potential for abuse in Schedule I to Schedule II, something like cocaine or methamphetamine, which are Schedule II, as having high potential for abuse, but some accepted medical value, and those two drugs are used medically and are approved. So there's really no framework. Now, you know, psilocybin, the language is important here. We squarely know at every level of science, the effects in the mesolimbic brain structures

• 56:32Speaker 03

  involving dopamine, the epidemiology, reliable animal models of reward. We know that these aren't drugs of addiction, solidly. But they are, they can be, drugs of abuse. And that simply means used in a way that can harm you or the people around you. So, you know, a couple teenagers go out driving on mushrooms, that's abuse. Or you get into a pattern that interferes with your family relationships, et cetera. So they really don't belong, and again, the Controlled Substances Act is rather ambiguous. You know, they refer to abuse potential, which can include addiction potential, but also other risks. So they do have risks.

• 57:12Speaker 03

  You could argue they have, you know, these classic psychedelics, mild abuse potential. But the other side of that is there's no accepted medical value. When the Controlled Substances Act was originally adopted, it wasn't clear what that really meant, and through judicial precedent, it became solidified that what that means is FDA approval for an indication. So that's where we're at now. So until one of these drugs, until psilocybin is approved for an indication, it's going to, by definition, remain in Schedule I.

• 57:49Tim Ferriss?

  What are the most promising indications currently, or those that are furthest along?

• 57:54Speaker 03

  Based on the data, 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, most advanced research with psilocybin as a therapeutic has been focused on. There's three randomized studies in that category. And then... Secondary to that, sort of as a class, are psilocybin and the treatment of smoking cessation as a smoking cessation medication, I showed you some data, treatment of alcoholism, a colleague, Mike Boganshutz at NYU, has done some great work with that, and then Robin's published

• 58:38Speaker 03

  work on depression outside of cancer. So, all of those three things have been, those are published results with open label, non-randomized pilot studies. So, they all look very promising, but they haven't gone, 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.

• 59:15Tim Ferriss?

  Thank you. Ayala, where would you hope, what would you hope 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?

• 59:28Speaker 04

  Well, you know, because I was a lawyer and 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, and I was working with the Drug Policy Alliance, on state initiatives to decriminalize marijuana, it seemed 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 bud tenders are, you know, showing you...

• 1:00:11Speaker 04

  Weed that in my lifetime as a teenager in New Jersey, I never saw anything approaching. So there is a kind of, 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? So I think we will see over the course of the next decade, and maybe even less, a shift to a medical approach, maybe, maybe changing the schedule, or maybe on a statewide basis, having this, as we did with marijuana, marijuana is still Schedule I federally, it's still a

• 1:00:56Speaker 04

  crime federally, but we have different models state by state. And I think that we are a long way from a decriminalization model for drugs generally. But I do think psychedelics, because of the research that these gentlemen are doing, just 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.

• 1:01:39Speaker 04

  When there is a wave of capitalist interest, it's a lot easier for laws to change.

• 1:01:47Tim Ferriss?

  We are up on time, closing comments real quickly. Check out the research. 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 Catherine McCormick level of impact. It's a big deal. So please take a look, check out everybody on the panel. And 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 thank you all for coming. And ladies, lady and gentlemen, thank you for coming.

• 1:02:29Tim Ferriss?

  Hey guys, this is Tim again. Just a few more things before you take off. Number one, this is Five 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 before the weekend? And Five 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 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.

• 1:03:12Tim Ferriss?

  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.