The Tim Ferriss Show Transcripts: Psychedelics — Microdosing, Mind-Enhancing Methods, and More (#377)

Please enjoy this transcript of a panel that I moderated in front of a standing-room-only crowd at the Milken Institute’s Global Conference 2019. It features Matthew Johnson, Principal Investigator at Johns Hopkins Psychedelic Research Unit; Ayelet Waldman, author of A Really Good Day: How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life; Robin Carhart-Harris, Head of Psychedelic Research at the Centre for Psychedelic Research, Department of Brain Sciences, Imperial College London; and Christian Angermayer, founder of Apeiron Investment Group and ATAI Life Sciences.

It includes a great overview of psychedelic science, investing opportunities, anecdotal personal benefits, legal challenges, and much more.

Transcripts may contain a few typos—with some episodes lasting 2+ hours, it’s difficult to catch some minor errors. Enjoy!

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Tim Ferriss: All right. Nice and bright house lights. I love that. 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? All right, so the entire audience for both questions.

Lest we start on a complete downer, let me give an inspirational story. 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. They changed that.

She also inherited a good portion of the International Harvester fortune. 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. Over the subsequent years, pretty much single handedly financed that development. In 1957, the FDA approved the pill for menstrual disorders. That was the strategic first indication and then later we know what happened.

The reason I bring this up is that in total, she provided $2 million in funding. In today’s dollars, it’s around 23 million over many years. It was an uncrowded bet, through which he was able to completely bend the arc of history. I will give some disclosures now. In 2015, I stopped all my early stage tech investing and redirected almost my entire focus to psychedelic science for reasons that I think will become clear in this conversation, and have been very involved with Hopkins and Imperial, which has been incredibly gratifying.

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 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, subtitle, How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life.

Let’s begin, Matt, with some of your slides. If we can bring those up, and I’ll let you take it from here.

Matthew Johnson: Sure. Slide three. Really important before we get into the meat of some of our other conversation 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 going to 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 conduct these studies. Its been used by institutional review boards at a growing number of universities. I was 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.

We’re aware of the risks, we’re paving the way, we’ve analyzed the data. 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, number four, please. We published 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 going to die.

This is essentially like the addiction work, picking up on older threads of research, largely done with LSD back in the ’60s. 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. The left most points on this figure under baseline, those are the high levels that people had when they came into the trial. 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. These people are not having problems at those lower levels around eight on the scale. You do see a good reduction in the people in the blue group. That’s a group that to this point has essentially received a placebo; what it actually is a very small dose that you could call microdose. In this trial really just designed to serve as the comparison condition, essentially a placebo.

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 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, 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. 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 that last 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. I’ll jump to the next slide. 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 tried to quit smoking.

We ran a small, open label pilot; we had dramatically impressive results. At six months, we found that 80 percent of participants were biologically confirmed as smoke free. Breath samples, urine samples. We trust people, but we verify. Those results held up to 67 percent at a year and 60 percent 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 Varenicline, which is Chantix, gets up into the range at six months at about 35 percent. Nicotine replacement anywhere, depending on the study, between 10 percent and 25 percent. It was an open label study, so we had to be cautious. The real question is: does this warrant follow-up? The answer to that is abso-freakin-lutely. We’re in the middle of that randomized trial at this point.

This is just a taste of a number of trials that have gone on 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: Thank you, Matt. Ayelet, 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. Can 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 —

Ayelet Waldman: Microdosing is the practice of taking a sub-perceptual dose of a psychedelic drug. You can microdose anything, but in this case, we’re talking about psychedelics. When I say sub-perceptual, I mean you do not trip, you do not have a hallucinatory experience. You see no kaleidoscope of colors. The idea is to take a dose that you cannot perceive of any effects, but that there is something going on metabolically.

I was experiencing serious depression. I had been on SSRIs, I had been on mood stabilizers, I had been on various medications, and they weren’t working effectively. I decided to try microdosing. 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 from the 1930s on through the present-day research.

I 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 ⁠— I embarked on a 30-day experiment, microdosing with LSD.

What I did was I took a one-10th of a dose. If you want to say, have a hallucinatory experience at 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. I took it every three days. The effect was profound. The first day, I had been in a suicidal, intractable and hedonic depression, for what seemed like forever. Because when you’re depressed, you have very little capacity to remember when you weren’t depressed.

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. I thought, “All right, well, this was a bust.” I got to work. After about 40 minutes or so, I looked out my window, and my dogwood tree was in bloom. 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. I saw it, and I understood it was beautiful, and it made me feel happy. 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. 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 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. 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 anti-depressant 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: That was great. That image is messing up my segue. But thank you. 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 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? Maybe you could also touch on the entropic brain?

Robin Carhart-Harris: Sure. Okay. 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. Mood especially, but also cognition and states of consciousness. It’s a particular aspect of the serotonin system that psychedelics work on, in particular, receptor subtype is called serotonin 2A receptor.

We know from a broad range of different evidences that this receptor is involved in ⁠— you could summarize it as adaptability, flexibility, plasticity. There are lots of these receptors in the cortex, an aspect of the brain that humans have so much of. So stimulating these 2A receptors appears to, at a higher level have an interesting effect on the regularity and the quality of brain activity.

We can characterize conscious states in a way, not analogous to waves. When we record brain activity, it’s very rhythmic. 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 see that brain activity starts to look like slow rollers on an ocean.

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. 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.

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 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 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 outcomes.

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 well-being, drops in depression, and suchlike. So what’s going on there? Just quite briefly to talk about the therapeutic mechanisms, and perhaps, slightly, frame it in a slightly more 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.

There is this commonality, this trans-diagnostic commonality, that seems to relate to a very broad range of different psychological disorders. What psychedelics seem to do acutely during the experience itself is they seem to relax beliefs, and open a window for change, for revision. 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.

Tim Ferriss: Thank you. 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, its 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. There’s a good question, we’re not going to dive into it right now, as to why almost every civilization, excepting a few in Antarctica, have used psychedelic compounds. Certainly for rites of passage, but also with an objective along the lines of these enduring effects that you talk about.

Christian, let’s talk about investment in this space and why you’re involved. I know that you, based on our conversations, certainly have a very sincere interest in making these compounds more widely available to people who are suffering. Your biotech company, ATAI Life Sciences, is currently one of the largest investors globally aiming to bring some of the psychedelics, including psilocybin back into the legal realm. What prompted that? And how are you thinking about approaching it?

Christian Angermayer: Okay, let’s start, because you’re many investors, I’m a super coward until five years ago, I’m not exaggerating, I’ve never drank alcohol in my whole life, and I come from Bavaria in Germany, where this is culturally 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.

I didn’t drink alcohol, I’ve never smoked a cigarette, I’ve never smoked a joint. I’ve never done anything else till about six years ago, some very, very trusted friends tried to convince me of magic mushrooms. I was like, “You’re clearly insane. I’m never, ever going to do that.” 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. I was very inclined to read all the data, and the data is very compelling.

Ultimately, a year later, I gave in. To say that as well, it was a jurisdiction where it’s legal. It was under a very guided and very well set up, protected session with a great guide. It was the single most meaningful thing I’ve ever done and experienced in my whole life, full stop. Nothing comes close to it, which is by the way, in a lot of studies, I think it’s a Johns Hopkins study where I think it was two thirds of the people rank it among the five most meaningful events in their lives. From the birth of a child, death of a parent. I think one third, roundabout, ranks it among the single most meaningful thing.

Because I’m an entrepreneur, I came out of the trip, the first thing I did, I called my parents because, yeah, I realized how much I love them and I never say it. The second thing was like, this should be experienced by more people. I do think that the only way to do it ⁠— 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 unfortunately, never these drugs, these various drugs, have been brought to the FDA, or in Europe it’s called EMA life cycle, or cycle, how to approve any normal other drug you want to use for medical purposes.

I was like, “Okay, this should be done. Is anybody doing that?” I embarked on this trip in a figurative word. I’ve met great people like George, who founded Compass who had the similar thoughts that this should become a medical drug, mainly for the treating of depression and then other mental health issues. This is where we are, Compass is in phase 2B. I’m also back to the company which is bringing r-ketamine hopefully on the market, which is a subform of ketamine also for the treatment of depression. 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 been neglected over the last 30 years because the mind is a complicated thing. Pharma companies, biotech companies thought, “Okay, let’s focus on cancer, let’s focus on the more tangible illnesses.” Also, to be fair, depression, our view on depression and mental health has changed over the last decades. It’s 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.”

When people came back from the Second World War, and were showing symptoms, what we now would call it Post Traumatic Stress Disorder, people said, “Hey, get on.” I think the view 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, that whole way we live, and we have started living the last 10, 20 years, I think it’s very, very bad for the state of our mind.

This is why the numbers rise. We have 320 million people suffering from depression. These are just the official numbers, and most probably, how you say the gray number, is much higher. If you count 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. 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.

Again, let’s go back to something personal. If a person gets very depressed because somebody, loved one dies, you don’t want to take Prozac. Prozac tells you you don’t care about the deaths. You want to dissolve it and solve it in a different way. I think this is where psychedelics have a very promising path, to be a very valuable drug.

Tim Ferriss: Thank you. We’re not going to probably talk about a very — specifically today — but the efficacy of MDMA for post-traumatic stress disorder is worth looking into, and is really remarkable. Both MDMA and psilocybin now have breakthrough therapy designation by the FDA, which is remarkable. If you look at the graphs, you look at the data for changes in PTSD severity from severe or extreme sentence to asymptomatic, they look very similar to the smoking cessation graphs. It’s incredible. MAPS is an organization doing great work there.

Ayelet Waldman: Tim, can I add a point to that? 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 smoke, I don’t like to smoke weed. Sometimes I take CBD because you can’t get a macho without it nowadays. But I don’t like to experience any ⁠— I like my mind to be sharp at all times.

But because I was teaching one of the first sort of people who popularized MDMA, Sasha Shulgin, a chemist in Berkeley, used to lecture to my class. Sasha and his wife Ann, who was a therapist, convinced me to try MDMA, which is ecstasy, with my husband as a tool of marital therapy. 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.

We have four kids, we have a lot of stress. But what MDMA does and why it’s relevant, I think, to PTSD is it’s somehow and these guys could 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 negative emotional content.

In the context of something that isn’t PTSD, but it’s rather the mundane PTSD of a long marriage, it allows you to talk about your issues, but from a place of connection and love. 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. That sustains, that one experience will sustain for as long as two years. It’s really remarkable.

Tim Ferriss: Thank you. Not to delve too much into any current use wouldn’t want to implicate anyone. But MDMA’s worth taking a very close look at. There are risks associated with some of these —

Ayelet Waldman: Unlike LSD.

Tim Ferriss: Yeah. 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 cardiac risk in some patients for instance. What is it, methylenedioxy-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. In the case of ketamine, some addictive potential, which I’ve certainly seen and even experienced. Psychonauts, you have to be careful with how it’s administered.

I won’t talk too much about this, but the toxicity profile of many of the classic psychedelics like psilocybin, it is remarkably appealing. Would you mind, Matt, just speaking to the potential toxicity of say psilocybin. Also, could you speak to, 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?

Matthew Johnson: Sure. 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 say it about caffeine, aspirin. Most drugs, you can’t, just take 10 times an effective dose and expect to live or to be undamaged.

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. These are very 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. In clinical research, we prefer to use 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. It was overplayed in the propaganda, the late ’60s about falling from heights, it has happened. They’re very intoxicating drugs. Far more people have fallen from heights when they’re drunk. But nonetheless, it happens.

In terms of public health, this ranks lowest amongst all the other major legal and illegal drugs. But nonetheless, there is a risk there. Nice thing is, you can squarely address that in clinical research and potential clinical use through preparation and monitoring. 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. Many of the 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.

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 where 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 are extremely reliable psychiatric structured screenings that can identify that small percentage of the population that has this risk. 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. 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.

Also, in the area of risk, we documented some systematic effects and 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 using it clinically. There’s a very rare thing called hallucinogen persisting perceptual disorder. Extremely rare, it tends to be ⁠— well, 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 in the older studies or the current studies.

What I’m referring to ⁠— you’ve heard of the term “flashback.” 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. It seems to be that 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 thing. You might have heard of that. That rounds out the entire sphere of known risks.

Tim Ferriss: Thank you. What about applications to say, opiate, opioid? Just, if I could add just a quick personal note. My cousin via marriage, he had a hereditary disposition to schizophrenia, and really abused LSD all throughout high school and college. 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. I’ve seen that firsthand.

Now on the flip side, I’ve also seen incredible abuse on a personal level that is representative of, I suppose, a pandemic level problem in opiate abuse. My best friend on Long Island died of fentanyl overdose. My aunt died of percocet plus alcohol not too long ago. This is something that’s touched a lot of lives in this room. Are there any potential applications you think, or is it more research we’re doing that would look at psychedelics and something like opiate or opioid addiction?

Matthew Johnson: Absolutely. It’s a very promising area. There was one study published in the early ’70s, using LSD with heroin-addicted individuals. 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. That’s part of this formula that 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. 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.

Ayelet Waldman: Especially since opioid addiction is resistant to treatment, we have medication-assisted treatments now that are more effective at keeping people resolving opioid problems. But without medication-assisted treatment, these traditional treatments that we think of like Narcotics Anonymous, they are grossly ineffective.

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. Which is why I actually hope that this crisis might enhance our receptivity to taking psychedelics down from schedule one, which means that they’re the most criminal drugs. A schedule one drug means there’s no medical use, and it’s the most illegal drug. Down to schedule four. What other drugs do you think of that we can analogize that are on schedule four?

Matthew Johnson: Oh, many of the benzodiazepines and the sleeping aids are in schedule four.

Tim Ferriss: Let me jump to Robin for a second because I think that 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 can talk to all sorts of people who’ve previously been at the head of mental health ⁠— Tom Insel and others ⁠— where you have these disorders, the psychiatric disorders, so-called disorders, that are very cleanly separate. 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. They’re all very much siloed.

Could you 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 zoom out to 30,000 feet, as you mentioned earlier, you have conditions associated with hyper rigidity. And then you have conditions associated over here, OCD, anorexia, et cetera. These are compulsive behavioral or thought patterns. Then on the other side, you have this hyper fluidity, which can be problematic, like schizophrenia. But maybe explain for folks, if possible, the current thinking around the default mode network.

Robin Carhart-Harris: Sure, yeah. 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. 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. And perhaps, to some extent, the myth that there are these crisp distinctions that have crisp underlying biomarkers. That following the classical biomedical model, we can come in with a magic bullet and solve the situation.

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. We do need some kind of major paradigm-shifting events here ⁠— a black swan event ⁠— that really changes things.

I think our collective view is that 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 entrenched ways of thinking and behaving into something broader and more open.

Default mode network is, in a sense, you could say 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. It’s a system that engages when we disengage, so to speak. Well, we disengage from attentive focus, but we enter a kind of day dreamy, 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 the kind of absolute way that guides and drives our behavior, but can be so narrowing. Ego sees narrow and short. 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 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, “Why was I squabbling with my wife or my work colleague?” It’s about seeing that bigger picture.

We’ve got this opportunity through brain imaging to start to put a bit of meat on the bone, to help lift the lid on this black box that’s 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. I think it’s useful to add that to the conversation and help ground the conversation about psychedelic therapy.

Christian Angermayer: Yes, one point, because both Ayelet and Robin just touched something important where I disagree with Ayelet and I agree with Robin, that most psychedelics, it’s not true for all of them, but are very holistic treatment. Partly the setting and the guide and however you experience it is equally important. 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. 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. It’s a different experience when you read observations of treatments of depressed people, they might go through, let’s call it catharsis or through a challenging ⁠— It might have a challenging trip. Nevertheless, the trip is healing them and the guide is very important.

This is why I just want to add that, I personally think yes, it should be available as a medical drug, this is what we’re working on. But it should be available on the professional care like with psychiatrists or in clinics, but not over the counter. Definitely not over the counter.

Ayelet Waldman: I agree with you entirely. In my book, I have a whole chapter about paradigms for decriminalization. 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. Like the Canyon Ranch of psychedelics, with 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 require that, but that is much more likely to engender a positive response.

Christian Angermayer: An interesting number is The Netherlands. It is legal, you can access psilocybin, magic mushrooms in The Netherlands, legally in coffee shops. The Netherlands has the same mental health crisis than every other country in the world. Just the fact that psychedelics are available, unfortunately, does not change the mental health crisis. It is really like the professional ⁠— if I experience it with people, like I would look at my parents or friends of 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 administrating that.

Tim Ferriss: I’d like to touch on something you said that we’ve covered in a few different ways, but offer a framing that I think is helpful. That is that, rather than think of good or bad trip, think of safe or unsafe trip. Because in many cases, the difficult experiences are when you see the truths you prefer not to see. 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.” They have to look at that hard truth. Difficult, but safe.

That depends a lot on the context, and the providers, and so on. 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. There are many different ways to approach it. 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 spa element and context around which you build a business? How do you think about that?

Christian Angermayer: Well first, it sounds maybe cheesy, I would say in English, but if you’re investing in biotech, you really want to make a difference. Because I would often take investments that 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. I think it’s a little bit the myth that everybody thinks biotech investors are eagerly 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 will make it happen. The second, the market is so huge. I said we have 320 million people, and the number is rising. I think there are more people who are not diagnosed. Even if, and I would be very, very happy if it’s a single dose of psilocybin, which is helping those people. Even if that’s the case, the market is huge.

Then you have the side business models, as Ayelet said, the spas and the clinics you can build up. Because it is all about the holistic thing. We don’t know yet. For a lot of things, we also have to say, 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, it might be, and I’m not saying that because it should be like it 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.

But there is enough business. I think in general, even if you go aside and look at a meditation app like Calm, for example. I think the whole mental well-being, like treating people who are ill, have mental health issues, but also keeping people healthy in our current environment. This will get worse.

My personal theory is that our brain has an in-built, actually resilience or an immune system, which is based on faith, love, and purpose. If you look what our world is happening, we take these three things away. Communities are dissolving, families are dissolving. You have a little bit less love in the world. Most people know that the world will look so different in 20 years that they don’t have a purpose anymore. The bus driver knows that in 20 years most likely, his bus will be driven by an artificial intelligence. Then we have a dramatic loss of faith in every sense, like religion and in any spiritual dimension. It all will make people more depressive.

Clinically said, the market is growing, so I’m not worried about how often you have to take it.

Tim Ferriss: Market is growing, for better or for worse. Matt, I’d like to come to you. First of all, just, I’ll make another personal note and try not to directly implicate myself here. My family has, on both sides, quite a bit of severe depression. Let’s 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. In the last five years, I haven’t had a single major depressive episode.

Here we are, in this panel, I’ll let you guys draw your conclusions. Not to say that that is going to be true 100 percent of the time, but given the fact that one could argue that there have been incredible advances scientifically in cardiology and neurology, all these various fields. Then you look at psychiatry and there’s been very little, 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.

I’m very, very vested in this space. Matt, the reason I want to come to you next is that you mentioned schedule one, schedule four. 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 of schedule one, which is no known medical application, high potential for abuse, among other things?” Which of course, based on the data, I disagree with. But how did that happen, and how do we get out of that?

I’ll just say one more thing, because we’re running short on time, which is, 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. How did we get to this very difficult and expensive position of operating from schedule one? How do we potentially get out?

Matthew Johnson: The quick answer is that it was really because of the association with the counterculture and everything associated with it in the late ’60s, early ’70s. I would say that the culture was essentially traumatized from that kind of early introduction of psychedelics. There were casualties when they were used broadly. There were also plenty of people who 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 drugs, the Controlled Substances Act, was being developed. There are some flaws in that system. There is no category, for example, of having no accepted medical use but mild to moderate abuse potential. You jumped from having no accepted medical use and high potential for abuse in schedule one to schedule two, something like cocaine or methamphetamine, which was schedule two as having high potential for abuse, but some accepted medical value, and those two drugs are used medically and are approved.

There’s really no framework. Now, psilocybin, the language is important here, we squarely know at every level of science, the defects in the mesolimbic brain structures involving dopamine, the epidemiology, reliable animal models of reward, we know that these aren’t drugs of addiction, solidly. But they can be drugs of abuse. That simply means used in a way that can harm you or the people around you. A couple of teenagers go out driving on mushrooms, that’s abuse. Or you get into a pattern that interferes with your family relationships, et cetera.

Again, the Controlled Substances Act is rather ambiguous; they refer to abuse potential, which can include addiction potential, but also other risks. They do have risks. You could argue they have ⁠— 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. Through judicial precedent, it became solidified. What that means is FDA approval for an indication. That’s where we’re at now. Until psilocybin is approved for an indication, it’s going to, by definition, remain in schedule one.

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

Matthew Johnson: Based on the data, the most promising indication would be depression and anxiety. You can call it psychiatric distress associated with a life-threatening cancer diagnosis. That’s what the 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, as a class, are psilocybin in the treatment of smoking cessation, as a smoking cessation medication. I showed you some data, treatment of alcoholism. A colleague, Mike Bogenschutz at NYU, has done some great work with that. Then Robin’s published work on depression outside of cancer.

All of those three things, those are published results with open label, non-randomized pilot studies. They all look very promising, but the published data hasn’t reached that level of large, randomized trials yet. All of these disorders are associated with being stuck in a narrowed mental and behavioral repertoire. 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: Thank you. Ayelet, where would you hope this field that is broadly speaking of psychedelics to look like a few years from now? Do you have anywhere you’d like to see it?

Ayelet Waldman: Because I was a lawyer and I was a criminal law professor, I think through this criminal justice lens. 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.

I don’t know about you guys, but I’ve been to these pot clubs, which are like Apple stores. The bud tenders are showing you weed that in my lifetime as a teenager in New Jersey, I never saw anything approaching. 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: Right.

Ayelet Waldman: I think we will see over the course of the next decade, and maybe even less, a shift to a medical approach. Maybe changing the schedule or maybe on a statewide basis, having this as we did with marijuana. Marijuana is still schedule one federally, it’s still a crime federally, but we have different models state by state. 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, does have great potential for medical applicability.

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. That’s the way it works in America. When there is a wave of capitalist interest, it’s a lot easier for laws to change.

Tim 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 a playing field at having a Katharine McCormick level of impact. It’s a big deal.

So, please take a look. Check out everybody on the panel. Ayelet and I will be doing a book signing over there. There are a couple of chapters in Tools of Titans on the psychedelic stuff as well. Thank you all for coming. Lady and gentlemen, thank you for coming.

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