Making Sense with Sam Harris - #177 — Psychedelic Science

Episode Date: December 2, 2019

Sam Harris speaks with Roland Griffiths about the current state of research on psychedelics. They discuss the historical prohibition against their use; the clinical and scientific promise of psilocybin, mescaline, LSD, DMT, MDMA, and other compounds; the risks associated with these drugs; the role of “set and setting”; the differences between psychedelics and drugs of abuse; MDMA and neurotoxicity; experiences of unity, sacredness, love, and truth; the long-term consequences of psychedelic experiences; synthetic vs natural drugs; the prospects of devising new psychedelics; microdosing; research on psilocybin and long-term meditators; the experience of encountering other apparent beings; psilocybin treatment of addiction; and other topics. In his Afterword, Sam discusses his experience on a large dose of psilocybin—his first psychedelic experience in 25 years. If the Making Sense podcast logo in your player is BLACK, you can SUBSCRIBE to gain access to all full-length episodes at samharris.org/subscribe.

Welcome to the Making Sense Podcast. This is Sam Harris. Just a note to say that if you're hearing this, you are not currently on our subscriber feed and will only be hearing partial episodes of the podcast. Just a note to say that if you're hearing this, you are not currently on our subscriber feed and will only be hearing partial episodes of the podcast. If you'd like access to full episodes, you'll need to subscribe at SamHarris.org. There you'll find our private RSS feed to add to your favorite podcatcher, along with other subscriber-only content.

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Today I'm speaking with Roland Griffiths. Roland is a professor in the Departments of Psychiatry and Neurosciences at the Johns Hopkins University School of Medicine. His principal research focus in both clinical and preclinical laboratories has been on the behavioral and subjective effects of mood-altering drugs. He is the author of over 380 journal articles and book chapters and has trained more than 50 postdoctoral research fellows. He has been a consultant to the National Institutes of Health, to numerous pharmaceutical companies in the development of new psychotropic drugs, and as a member of the expert advisory panel on drug dependence for the World Health Organization. He's conducted extensive research with sedative hypnotics, caffeine, and

other drugs. And in 1999, he initiated a research program investigating the effects of the classic psychedelic psilocybin that included studies in healthy volunteers, in beginning and long-term meditators, and in religious leaders. And much of the resurgence in psychedelic research is certainly due to him and the work he's been spearheading at Johns Hopkins, as you'll hear. And Roland and I cover a lot of ground here with respect to the current state of research on psychedelics. We discuss the history of prohibition against their use, the clinical and scientific promise of psilocybin and mescaline and LSD and DMT and MDMA and other compounds. We talk about the risks associated with these drugs, the role of set and setting in determining

a person's experience. We talk about bad trips, the difference between psychedelics and drugs of abuse, MDMA and neurotoxicity. And we talk about the experiences people have, experiences of unity and sacredness and love and apprehensions of truth. We talk about the long-term consequences of psychedelic experience, synthetic versus natural compounds, the prospects of devising new drugs, microdosing, the research being done on psilocybin and long-term meditators, the experience of encountering other apparent beings while on these drugs, psilocybin treatment for addiction, and other topics. And in my afterword, I discuss the first psychedelic experience I've had in 25 years.

I actually took a large dose of psilocybin about a week after I recorded this conversation with Roland. So this is an unusual addendum. And while I had planned to do this for quite some time, you will notice that the timing of my conversation with Roland was certainly auspicious. And now, without further delay, I bring you Roland Griffiths. I am here with Roland Griffiths. Roland, thanks for joining me. Pleased to join you, Sam. Well, this is great. I've been wanting to talk to a scientist who has seized the moment, which seems to come around once every other generation, to study psychedelics. And you are, I think,

the most prominent person in the field at the moment. So it's really an honor to get you here. Let's just talk for a moment about your scientific background and the work you're doing at Johns Hopkins and just set the stage for this conversation. Well, Sam, first of all, let me just say I'm just delighted to join you. I'm a fan of your podcast, found it very interesting, and there's such a convergence, I feel, of my interests in this whole area and some of yours that I'm excited to talk about it. Nice. So let's see, with respect to my background, I'm trained in psychopharmacology, pharmacology and experimental psychology. I came to Hopkins in the early 1970s and have been focusing on research on psychoactive drugs, primarily drugs of abuse. And so much of my early career, both in animal research and human research, was focusing on various mood-altering psychoactive drugs, primarily those for which drug dependence is an issue and a problem. And about 25 years ago, I started a meditation practice. I'd been interested

in meditation for a long time, had tried it in graduate school and found that it was extraordinarily difficult. Three minutes felt like three hours and I was a pretty rapid dropout. But about 25 years ago, I got reintroduced. I don't know what was different, but it was different. And all of a sudden, there was kind of a depth of experience that was just truly intriguing to me. that was just truly intriguing to me. I might say that my original training was in experimental analysis of behavior, Skinnerian psychology, if you will, that tends to discount the importance of subjective experience. But despite that, I thought just the basic methodology of meditation and approach appealed to me because I certainly had this strong sense that there was something to know about this kind of internal sense of subjectivity or whatever that was. And although the explanations that were given by the people in meditation didn't correspond in any sense to the neurophysiology or biology I was

learning, I was able to kind of discount that and take it as metaphor because, you know, clearly these procedures had been developed over thousands of years. And I thought to myself, surely there must be something of value. And if I can treat it as metaphor, what can I learn? And so that was my, that's how I kind of reconciled my scientific materialism worldview with what it was to learn about subjectivity. What I did have as I got involved with meditation is significant and salient experiences that got me deeply intrigued about the nature of these kinds of experiences and what the implications were and whether or not that should change some of my own priorities, how I'm spending my time. And so there was actually a period of time after that that I really contemplated dropping out of science, going off to India, as you did

for a period of time, going off and just enmeshing myself in this world of meditation and internal inquiry. So what year was it that you first got exposed to meditation? I think it was 1993. 1993. So at the time you said you considered going to India, what made that door not open for you? Well, I had this great job. I had respect and a job. I had employees here at Hopkins. If I had walked away from it, I would have dropped a lot of responsibilities. I would have left a lot of people in the lurch. and perhaps I just wasn't quite ready to make that radical change, walk away from my entire life situation. But you were getting into your graduate work in the 60s, you said. I assume this was after Timothy Leary and Richard Alpert were fired from Harvard,

and the stigma around studying psychedelics had already come crashing down. But at that point, you were not yet into meditation, right? So would you have been a candidate for somebody as someone who would have wanted to study those compounds or it just wasn't on your radar at all? See, how could one not have been curious about that? I mean, so no, I think I would have been curious, but because it wasn't a viable option and I didn't run in crowds that were deeply impressed with the effects of psychedelics, it just wasn't a particularly particularly important option for me to track. And then very early on, I ended up through good fortune making connection with several different people that really prompted me to

think about psychedelics and kind of reintroduced me to the older literature on psychedelics, with which I was kind of vaguely familiar. But even when I went off to graduate school in the late 60s, psychedelics as an area of research had just been pulled off the board. And in fact, it was a third rail for people who were interested in developing careers in psychopharmacology or pharmacology. If you expressed interest in that, it marginalized you in a way that wasn't professionally helpful. So I never really gave it any thought until I had some of these experiences, started rereading that literature, and then becoming really intrigued about whether or not the kinds of experiences that were being

described really happened. And I have to say, I went into this as a real skeptic. I was delighted with my meditation practice. I was doing that exploration. But I also was a full professor at Hopkins with an international reputation in clinical pharmacology and so thought, if anyone had a shot at getting a study approved through not only my IRB, but FDA and DEA, you know, I would have a reasonable shot at doing so. from a group called the Council on Spiritual Practices in California with Bob Jesse as leader there. And in part through reallocating funding from a grant I had from the National Institute on Drug Abuse, we undertook a study of psilocybin in healthy volunteers who had never before experienced a psychedelic. And we did the study with a positive control. It was a high dose of methylphenidate that's

Ritalin that has an onset and a duration of action pretty similar to psilocybin. And because it's a similar to psilocybin. And because it's a stimulant that produces mood-elevating effects, and because these people were naive to the effects of psychedelics, we thought it was a plausible positive control. This is a better control than was used in the famous Good Friday experiment at Harvard, where I think it was psilocybin they were given, and then I think they were given a placebo. And the difference between psilocybin and placebo is apparently fairly stark. It's very stark. They gave niacin, I believe. Oh, they did. Okay. But nonetheless, it's stark. I mean, that just produces some local flushing. And it's actually a deep problem in studying psychedelics because the very nature of their experience is to produce radical changes in the nature of subjective experience.

So blinding is deeply embedded in this area as a methodological problem. But we also bent over backwards. We gave people instructions that were misleading with respect to all the drug conditions that could be administered. They were told that they could receive up to, I think it was 13 different psychoactive compounds. They were told they'd have two or three sessions, at least one of which would include a moderately high dose of psilocybin. But in fact, all we were comparing is methylphenidate and psilocybin under conditions that blurred those effects. And some people got two doses of methylphenidate and only subsequently got psilocybin. And then the other kind of tricky

thing we did is we kept our guide staff, their clinical staff, completely blind to the design. So they didn't know the design either. And under those conditions, it was remarkable that, well, what wasn't remarkable is when you give, oh, well, let me just describe this, the setup. So the setup, which is really built on work that was done in the 50s and 60s to presumably optimize psychedelic experiences for meaningful effects is one in which rapport and trust is developed with the volunteer through about eight hours of contact prior to the first session. And then sessions are comprised of coming in to a living room-like environment. The volunteer is with two people with whom he or she has spent eight hours reviewing kind of life situation. They come in, they have a low-fat breakfast.

They take a capsule. They have a low-fat breakfast. They take a capsule. We give psilocybin in the form of a capsule, although psilocybin is the active ingredient in the magic mushroom. This is synthesized psilocybin. They take a capsule, and we ask them to lay on a couch,

use eye shades and headphones through which they listen to a program of music. And the instruction is to pay attention to your inner experience. This is not a therapeutic talk guided session per se. This is an opportunity to, we would say, explore the nature of mind as it comes forth. And so that's the basic setup. Not surprisingly, what happens is what we would have expected to happen based on everything we know about psychedelics. There are changes in visual perceptual phenomena, kind of illusions. There's changes in emotionality, both positive and negative, fearful, changes in cognitive processes.

But what was of interest to me, having gotten interested in meditation and spiritual experience, was the extent to which these experiences read out as similar to mystical-type experiences that have been reported by mystics and religious figures throughout the ages. And as you mentioned, there was a very nice study done at Harvard back in the 1960s that seemed to show that in the 1960s that seemed to show that psilocybin given to seminary students produced some of these kinds of effects that, although the methodology of that study lacked a number of features that we were able to correct for. I mean, it was a group study. It might be that the investigators were using their own supply of psilocybin. Well, they did. They were dosing right along with the volunteers, and the whole thing was

done as a group. It was not as methodologically tight as what we would have expected today. That's one approach to blinding that you can take. Just take the drug along with everybody, then you lose track of who's in which condition. So I want to get into discussing these various compounds and the clinical applications and their different spectrum of effects. But before we do, I just want to give a plug for the center that you're currently running at Johns Hopkins, and if you can just describe what's happening there. And I should say that you and I were put together by my friend Tim Ferriss, who I think has recently put his shoulder to the wheel in helping to raise money for your center. And Tim has found psychedelics have been incredibly helpful

to him of late, and I'm very grateful for him for putting us together. Yeah, and we're grateful to him and a number of the other philanthropists, including the Stephen and Alexandra Cohen Foundation, for funding what amounts to the first center for psychedelic studies. It's actually called the Center for Psychedelic and Consciousness Research to be established in the United States. And we're deeply grateful for the support that amounted to $17 million for us to extend and expand our program. So we have been doing research now with psychedelics that started with that first study I mentioned comparing psilocybin and methamphetamine, and that started in about 2000. So we've been at this for 20 years, but there's been virtually no funding or just very little funding at the federal level for this kind of research. So it's all been

philanthropic. And we've just been doing it with nickels and dimes and bootlegging time and good will from other kinds of projects to support this. And so this establishment of the center really allows us to put our shoulders to the wheel. And I'm grateful to have a whole set of very competent colleagues here at Johns Hopkins, Matt Johnson and Fred Barrett and Albert Garcia-Romeo and Natalie Lucason, all of whom are deeply interested in this area. And with the funding of this, we can devote full-time effort to these projects. And what we're envisioning is that funding at the federal level will be forthcoming. It's still going to take a little bit of time, but the results that we're seeing are just so promising on any number of domains, be it therapeutic or neuroscience, that I think that federal agencies, NIH in particular, will

have to get into the game. I think the development of the center and contributions made by Tim Ferriss have been integral in terms of making that happen. Nice, nice. So I guess I want to say a few more words about the context that you're working in. We've been alluding to this, but we really have lost a full generation, if not a generation and a half, of research on these compounds because of the backlash that occurred against their, you know, fairly indiscriminate use in the 60s. And what happened is there were thousands of papers being written in the, I guess, the 40s and the 50s and early 60s on the effects of LSD and mescaline and psilocybin and their clinical promise and their promise for

psychopharmacology. And then the 60s happened, and that was to some degree engineered by Timothy Leary and Richard Alpert's attitude toward essentially putting this stuff in the water, which, you know, given how transformative these drugs have been for so many people, the temptation is understandable. It did seem like a sacrament had been discovered that could cure society of all of its ills. At least you could well imagine it seemed that way from the perspective of people who were finding these drugs so transformative. And so there was very little discipline around keeping these drugs merely within research channels. And then we can see

the effects with everyone growing their hair long and painting flowers on their faces and dancing in the streets. And so the backlash against all of that put these drugs on, you know, Schedule 1, and it became illegal to do research with them. And Roland, when did the total prohibition begin to lift? So the total prohibition began to lift with some early studies done by Rick Straussman, who gave DMT, dimethyltryptamine, which is chemically related to psilocybin. It's one of the active ingredients in ayahuasca, which is used in South America. And he got permission to give DMT to people who had previously used DMT. And he did that in the early 90s. Our approval was the first that FDA granted to give a reasonably high dose of a psychedelic to people who had

never before used a psychedelic. And so that we considered to be an important step and actually a breakthrough because if you're going to really evaluate the effects of these drugs, you can't introduce a selection bias of those people who have tried and want to try again, right? You have skewed the population mightily. And so we got our approval back in 2000. But you're right, you know, it's actually a very interesting story that these drugs became unavailable functionally for any human research for a period of decades. have occurred? Where has an area of really promising and interesting research been halted in its tracks with a prohibition to stop entirely? Maybe chemical warfare or germ warfare, but very possibly not. So it's actually very interesting, I think, from a history of science point of view. And it actually may speak

precisely to the power of these compounds and their effects and their potential ability to destabilize existing cultural institutions. Because if you actually think back, I mean, these drugs, psilocybin and mescaline and DMT have been used very possibly for thousands of years, but usually they're used in cultural contexts that are ritualized and control their use in a very structured manner, often for religious or divinatory or healing purposes. And so it could be that, yeah, if you let these compounds out into culture at large, they can destabilize cultural institutions. And that may be a part of what happened in the 1960s.

And that may be a part of what happened in the 1960s. So, you know, in addition to the antics of Timothy Leary and his, you know, advocacy for widespread use, you know, it interacted with an anti-establishment, anti-war movement. You know, Nixon is reported to have declared Timothy Leary at one point the most dangerous man in America. And so there was a weird convergence politically, in terms of funding, in terms of legal structure that just wiped out research. And then interestingly, that reached into the academic institutions and they bought into that. There was such a media frenzy that emphasized the potential risks of these compounds. And there really are risks. And I certainly wouldn't want anyone to misunderstand that. And there really are risks, but they certainly are not at the level that no human research should be done with them. Yeah, well, let's hit that point

of disclaimer up front. So we're going to talk about kind of two aspects of this. They're the clinical applications for addiction and depression and PTSD and end-of-life anxiety. And there's also just the fact that these drugs, as you say, many of them have millennia of usage for the betterment of already well people, right? So it's not just a matter of treating clinical issues. But we should acknowledge that not everyone should take psychedelics, and there are conditions under which it is unwise to take them. And there's a lot to talk about with respect to the set and the setting in which one uses these drugs and, you know, how to use them safely. And I want to talk about the prospect that any one of these compounds could be physically toxic. I think the data are not perhaps perfectly clear there,

but they suggest that the problem of danger here is not so much a matter of physical toxicity, but the potential that someone could have a very bad experience on one or another of these drugs, and that that is just psychologically destabilizing. And, you know, obviously, if you're not in a physical setting where, you know, you are looked over by somebody who is not on the drug with you, or maybe there's the prospect that you can wander out of your house or out into nature and do something dangerous and stupid. So feel free to sound a note of caution here, Roland, and then we'll begin talking about the different compounds and how they may be different physically and psychologically.

Yeah, good. So with respect to adverse effects, so we're able to manage this in our research setting because we very carefully screen people, we prepare them for these sessions. They're in the presence of two sitters throughout the day-long session. We meet with them after the sessions and then subsequently follow them up. And under those conditions, we actually haven't had any very significant adverse events at all. However, in absence of all those parameters, there are risks. The first and most probable one is that people will become terrified and engage in dangerous behavior. They can run out into traffic. People can jump off of cliffs or jump out of windows. It does happen. They can put themselves or others at risk, even life-threatening risk, and there are, you know, homicides and suicides that can occur. It's low probability, but it does occur. The other most salient risk and one that we protect against and for which there's

the empirical evidence is circumstantial, but it's something that we're very cautious about. The idea is that people who have vulnerability to psychotic process, people who may be at risk for developing schizophrenia, may be at increased risk for development of such disorders with a high dose of a psychedelic. And so there are reports of people, you know, particularly in their, you know, late teens or early 20s that coincide with the most probable time of onset of psychotic disorder who take a psychedelic and, disorder, who take a psychedelic and are subsequently diagnosed as schizophrenic, and they attribute the onset of that to having taken the psychedelic. And that's a lifelong nightmare from which there's no simple recovery. So that's a very important cautionary note. Do you screen out, let's say someone has a first-order

relative suffering from schizophrenia, do you screen them out of your research protocol? What's the actual criterion? Yeah, we do, and we're probably, we may be overly conservative, but I think that's the way to proceed. We'll screen out second-degree relatives. If anyone has a second-degree relative with a psychotic illness, we'll screen them out. Now, we ran a large survey study in almost 2,000 people describing their worst experience after taking psilocybin. And the results of that were interesting. So now this isn't a population estimate in so far as these are people who came upon our advertisement online, were willing to spend an hour completing a really detailed questionnaire anonymously, and they were completing it with regard to their very worst experience. But of that group, 11% reported

putting themselves or others at risk for physical harm, 3% sought medical help, and 10% reported enduring adverse psychological symptoms lasting more than a year. And about 8% of those sought out treatment. So there's a significant population of people who at least are claiming that they had this terrible experience, and a year later, they're still seeking out help for what they view as some kind of psychological problem, depression or psychotic or thinking disorders, that they're attributing to that. Now, that's not tight causality, but it fits in line with the kinds of things that we should be concerned about and makes us apprehensive about premature, and makes us apprehensive about premature, widespread use of these compounds in the general population. With respect to your point about physical toxicity, it's true, that's

incredibly limited. So it'd be very hard to overdose with these compounds. They don't produce drug-seeking behavior. They're not considered classic drugs of abuse. In fact, if one takes them repeatedly, one becomes tolerant to their effects. That is, the effects reduce. There's no withdrawal symptoms. We can't get animals to self-administer reliably psychedelics. And we have paradigms which are very predictive of abuse liability of compounds in humans. And most of those come out simply negative with psychedelics. So they're not classic drugs of abuse. Just a word to the wise, you need to remove the cocaine dispenser in the cage before you give them the psilocybin dispenser. Yeah, so the probability of getting animals to self-administer cocaine is, well, at least

in our studies in baboons, is virtually 100%. There's not, you know, under the right conditions, mammals are designed in such a way that you make cocaine available to them and they're going to take it. And that's not the case with psychedelics. As far as the pharmacology there, is it thought that these just don't drive the dopamine system. Do we think dopamine is simply not involved or it's just not involved to the degree that drugs of abuse drive it? Well, let's see. So the pharmacology of psychedelics is very different than most of those classic drugs of abuse. And most of them are thought to have their reinforcing effects mediated either immediately or downstream through some kind of dopaminergic mechanism. The psychedelics differ with respect to having

dopaminergic effects. LSD is one that is said to be very promiscuous pharmacologically, and it does have some dopaminergic effects, but certainly not to an extent that would drive self-administration of the type that we see with other drugs. That being said, I should say that MDMA, ecstasy, which is not a classic psychedelic, does serve as a reinforcer in laboratory animals, does have a dopaminergic component to it. So they're very different kinds of compounds. Well, actually, let's start with MDMA because this is the one where rumors of its toxicity have seemed most indelible. And ironically, I think these rumors originate, or at least they were amplified from your own institution, from Johns Hopkins. either political topspin or some other less than rigorous line of thinking about MDMA and its place in the culture. What's your current understanding of the physical toxicity of MDMA? So MDMA has been associated with neurotoxicity, and that's indisputable. George Ricarte has done a lot of that work was one. It was a study published in Science in

which he published a study and then subsequently found that the drug that he thought he had been giving and had published as MDMA was in fact methamphetamine. And there's no issue that methamphetamine would produce that kind of toxicity. But I think that one misstep on his part has kind of blown out of proportion a little bit. is whether the dosing parameters that produce those kinds of effects in laboratory animals are relevant to therapeutic use of MDMA. And that's a deeply contentious issue within that area. FDA has allowed therapeutic trials with MDMA to go forward, I think under the assumption that the doses given of MDMA and the number of times that it's given, that's really up to three occasions, are going to very likely be under any threshold to detect neurotoxicity. However, there are studies that have looked at people who have used MDMA extensively. These are people using high doses in rave situations where

they're using enormous doses and they're using them repeatedly. And there's some indication of memory problems and other sorts of dysfunctionality. It's not a clean slate. There is potential for toxicity. We don't know the extent of it. But what we do know is that's very different than the classic psychedelics that is psilocybin, LSD, DMT, and mescaline that are not associated with any such toxicity. And for reference here, so what is considered the appropriate human dose for MDMA? Let's see. Well, I think the clinical doses that are being used range from about 75 milligrams to 125, I think. I know clinically in Europe, they use higher doses. The protocols that are running right now,

sponsored by MAPS, the Multidisciplinary Association for Psychedelic Studies, give MDMA twice. They'll start with a dose of something like 75 and then give a booster dose an hour later. But that's around the range. So yeah, MDMA is, again, not a classic psychedelic. What's the term of jargon now that we like? Is it called an empathogen? Is that a chief currency? Yeah, that's one of the terms, the love drug. And actually, you yourself have testified to life-changing experience with MDMA.

And so that effect is remarkable for that sense of unbounded love and openheartedness that emerges under that experience. And it's being shown to be quite effective in treatment of post-traumatic stress disorder. And those are the clinical trials that are ongoing now under the sponsorship of the MAPS group. of the MAPS group and their proceeding and their effect sizes look very large and promising such that we might expect approval of MDMA as a medicine in anywhere four to six years. Yeah, so just linger on the prospect of toxicity for another second. So I guess the allegations I've heard here, one is that the studies that showed neurotoxicity in rodents

were under doses that were just, as you say, not analogous to human use. I don't know what the factor of multiplication was there, but much larger doses than would be analogous in a human body. And I guess the rave data could be confounded by what else ravers are up to, dancing for 12 hours straight and not drinking water. I mean, there's issues with overheating. What's your sense of, given the current state of things, of the risk that people run taking MDMA? Let's leave aside, again, we'll finish on some description of what would be optimal in terms of people getting access to drugs should we arrive at a future where their you know, their therapeutic use is very

well regulated. But so, you know, leaving aside the concern that, you know, someone might be taking on the street may not even be MDMA, what are your concerns about MDMA's toxicity and the normal dosage, you know, let's say in one of these therapeutic trials? I don't know. It's notable that FDA has approved this as a therapeutic agent, and so it's below their threshold of concern if given as, you know, as suggested it should be inside that protocols that have been approved. I don't know. What I suspect is there's little risk for low-dose, very intermittent exposure, but that's simply a guess. You know, our ability to tease out things like long-term neurotoxicity is given just the adaptability of the brain is crude at best. given just the adaptability of the brain is crude at best.

Yeah. Let's move on to the classic psychedelics, which, as you say, are LSD, psilocybin, mescaline, and DMT. And DMT occurs in a pure form that people have smoked or had injected, and it also is one of the active components in a traditional drug like ayahuasca. And then there's also 5-MeO-DMT, which is how anyone first discovered that this was something you could take. It has to be a pretty colorful story because this occurs in the secretions of a venomous toad that some intrepid person wound up smoking at some point in human history. How would you like to begin here? I'd like to talk about these compounds and their utility and how you view them as different or the same. Let's see. So the classic psychedelics all have a primary site of action, and that's serotonin 2A receptor. And so that kind of defines them.

The ones that have been used most frequently, as you say, are DMT and mesclin, which is active in the peyote cactus used by Native American, and psilocybin, which has certainly been widely used, particularly in Mexico and other parts of the world, as the 2A. And there's every reason to believe that most of the interesting effects that they produce are mediated through that receptor signaling pathway. And that's been shown through a series of animal studies, antagonist studies, studies using knockout mice where they knock out serotonin 2A, and then human studies where they can give selective antagonists at that receptor site and block the effects of these drugs. That being said, they're certainly not identical. They're more similar than different, but they have different onsets, they have different

duration of actions, and in some cases hit, well, in all cases, they also hit different sets of receptors. And the most complex of those being LSD that hits a variety of different receptor targets. a variety of different receptor targets. So frustrating to me and those of us interested in this area is that good double-blinded studies have not been conducted that actually compare these drugs. So there's a lot of anecdotal reports about differences among these compounds, but we won't know for sure about those differences until we can give them under adequately blinded conditions to people under uniform conditions of controlling for expectancy. But again, they're more similar than different. But again, they're more similar than different. They all produce the set of experiences, as I described with our initial study with methylphenidate.

They're going to produce visual illusions and emotionality and cognitive changes. But I think that far and away the most interesting area with these drugs is that they produce at least two kinds of very memorable effects. One is that they're quite apt to produce under supported conditions, under optimized conditions. They're likely to produce a constellation of phenomenological effects that really map onto classical mystical type experiences. So, you know, the description of those and actually psychologists in the psychology of religion who have paid a lot of attention to that and developed questionnaires that probe those kinds of effects and have factor analyzed the components of those effects would suggest that those effects can be described as six kinds of categorical features. One being this sense of unity, this sense of the interconnectedness of all people and things.

of all people and things. Another is a sense of the preciousness of these experiences. Some people might use the term sacredness or reverence, but there's something compellingly, impressively deserving of respect for these experiences. There's a sense that's described by William James as the noetic sense, the sense that there's something more real and more true about these experiences than everyday waking consciousness. And then there are positive mood, very often sense of open-heartedness, sense of open-heartedness, transcendence, joy, transcendence of time and space where the past and the future collapse into the present moment. So it's all about right now. Space becomes either vast or endless or totally empty. And then this sense of ineffability, one of the first things that people say after having such an experience is that I can't put it into words. on our part to develop a scale with that name because it's an empirically derived scale. It doesn't assume any non-material kind of spiritual realities. It's just hardcore science, and

we've done the appropriate psychometrics to evaluate that scale. There is a justification for it in the sense that these kinds of experiences are the classical, contemplative, religious, mystical experiences, which are, again, the experiences of a human brain under some parameters. And it's just a fact that these drugs are not producing experiences that the brain isn't capable of having. I mean, you would expect somebody somewhere to have experiences precisely of this kind without having ingested one of these compounds, because these compounds are just mimicking neurotransmitters or changing their level of action, you know, at the synapse. And LSD, psilocybin, mescaline, DMT, I mean,

in the case of DMT, DMT is already an endogenous neurotransmitter itself whose action I'm not sure we yet understand. In either case, whether you're Meister Eckhart espousing your heretical unity with God or you're somebody who has taken a psychedelic, the resulting experience is something the brain is doing. Absolutely. And I mean, for me, Sam, that's exactly what makes this so exciting. These experiences map on to these naturally occurring mystical type experiences. And so the puzzle up until now has been, what are these experiences? Are they believable? And they haven't been amenable to prospective scientific study because they occur unpredictably and erratically. I mean, it's more probable if someone engages in spiritual austerities or goes on long-term meditation retreats or does prayer practice,

but by no means are they probable. And there's some people who are given to interpreting them as a gift of divine grace. So, of course, you can't manipulate them. And what I see that we have with psilocybin, because we can occasion these experiences in a very high proportion of people that we prepare and run through our protocol, like 80%. prepare and run through our protocol, like 80%. So that to me speaks to the fact that these are biologically normal effects. We're wired for them, if you will. And it raises a whole bunch of interesting questions about what kind of evolutionary selectivity has gone on there, if that's the mechanism, presumably, that makes these experiences probable. And then what in the

world are their function, both culturally, you know, and for the survival of our species. And this kind of leans into your interest in the well-being of conscious creatures. I think there's something uniquely interesting about the resulting impact of these experiences, because one thing I really haven't talked about is what the long-term consequences of having these kinds of experiences are. on a lifetime scale from, you know, like a daily experience to once a week, once a month, once a year, once every five years, you know, 10 most, five most, single most important or meaningful experience of your life. We have about 80%, 90% of people saying it's in the top five most meaningful, spiritually significant experiences of their entire lifetime, comparing it to the birth of a firstborn child or the death of a parent. And that is simply astounding to me. So as a clinical pharmacologist who's worked with dozens of psychoactive drugs

and given them at high doses to people, and I'm accustomed to querying people about their effects. That observation literally blew me away because there's something about these experiences that people interpret as having enduring meaning going forward. I mean, so if you give a high dose of an opiate or a sedative or cocaine and ask someone a month later, tell me about that experience, they'll remember it. Oh, yeah, you know, it's like I got drunk, you know, we had, we were laughing, we had fun, whatever. But it's just, it's a memory. The people who have these kinds of experiences really talk about the enduring salience of that experience. It's not uncommon for people to say, you know, I continue to think about that experience

every day, or it's just inform my life going forward. And that's the curiosity about these effects. The other component about it that I think is so interesting is that it has this strong positive valence to it, very often in a strong pro-social direction. So there's something about these experiences. I think it's particularly the unity, the sense that everything is connected and the profound sense that we're all in this together. There's something incredibly humbling about these experiences. And if that's coupled with the reverence for it and the truth value of it, that this is real, more real and more true than everyday waking consciousness, that becomes reorganizational in a way that I think has

profound ethical and moral implications. Yeah, yeah. I guess I'm just tempted to echo some of that. And I guess I would put MDMA into this class as well, just for the purposes of this distinction. But the point you make in your inventory around the noetic quality of the experience, the fact that something, when it goes well, and again, we should always remind people that it's possible to have a bad trip that has a very different character here where, and again, I'd leave MDMA out of this, but with classic psychedelics, you can have an experience that is very much like psychosis. And when you come down, you're having the experience of your sanity being restored to you.

But when you have a good experience on, let's say, LSD, and here I would also include MDMA, it is the experience of something that certainly seems more true, more real. And when you come down from that place, the phenomenon is one of having your usual habits of mind, your usual preoccupations, the ways in which you tend to use your attention, begin to obscure this deeper truth that was laid bare during the peak of the experience. that was laid bare during the peak of the experience. And that's what's so, it's among the things that makes these experiences so durably transformative. Because what you can no longer deny, you know, after having seen this, is that it's possible or should be possible to live from a much deeper place, to be engaged with the present moment in a way that conduces to awe and reverence and a recognition of beauty that by tendency you are disposed to overlook,

right? And it's just you're viewing your life through this kind of scrim of discursive thinking and judgment and reactivity and self-talk, and for reasons which you're beginning to understand pharmacologically, that gets held in abeyance for a time, and you have this full-on collision with the intrinsic beauty of consciousness in the present. It can't just become a memory because it becomes a reference point. Hence the very common experience of seeking out meditation and other techniques of changing one's engagement with the present moment because they're both legal and they have fewer risks when used ad libitum. The transformative power of even one experience is not really mysterious once you've had it.

Yeah, but let me just comment that it's relatively rare. I mean, when we consider the millions of young people who got exposed to psychedelics back in the 60s, it was only a very tiny fraction that were drawn into meditation and going off on a path of seeking. For most people under these kinds of conditions, the experience is, if not uncomfortable, even if it's transcendent, if not uncomfortable, even if it's transcendent, there's no conceptual frame, there's no way to understand it. And so it's very often just put in a box and forgotten about. And that's where that's my enthusiasm. So we have actually studied now psychedelics in beginning meditators and in long-term meditators, because I think there's a convergence of those practices. I think that both are complementary approaches to exploration of the nature of mind.

And meditation, it seems to me, is the tried and true course, but it's very difficult indeed to course, but it's very difficult indeed to reach some of those states and sustain them. I think of psychedelics as the crash course, and I think optimally some wise conjoint use of them may be the best approach to producing sustained senses of well-being and appreciation. Hmm. Is there any reason to prefer naturally occurring compounds like the psilocybin in magic mushrooms or the mescaline in peyote over LSD or MDMA, or is the distinction between what is synthesized and what is naturally occurring spurious? And if so, what do you see the prospects of our devising new compounds that are even more interesting in terms of their effects? Well, let's see. So with respect to synthesized, let's just take psilocybin. Is there a difference between synthesized psilocybin and psilocybin delivered in the

form of mushrooms? You know, we don't know. They've never been compared head to head. People have strong opinions that surely there are differences. As a pharmacologist, I doubt that there are meaningful differences. There's theoretically a possibility something like psilocybin also has other potentially psychoactive tryptamines in it. So there could be some qualitative differences. You mean the mushroom may have things in addition to psilocybin?

Yes. Yeah. We know it does. And some of those are psychoactive, but how those interact with psilocybin and whether they're at doses sufficient to alter the nature of the effects is unknown. Yeah. Actually, you're answering a slightly different question, which I should have asked, but yeah, I was taking it sort of as a given that synthesizing psilocybin is getting you the real molecule, and it would be the same as what's in the mushroom. But I guess some people might have a bias, or at least imagine that there's good reason to prefer a chemistry that we've evolved around, right? So these are compounds that have been in plants and even in ourselves for millions of years. And then there are molecules that people just invent, right? And have whatever effects they have. And you have someone like Sasha Shulgin, who

whatever effects they have. And you have someone like Sasha Shulgin, who was holed up in his lab in Berkeley, just cranking out new psychedelics, many of which I think he's the only person on earth who ever took. So what do you think about that? I mean, in terms of just pure innovation in this space, pharmacologically? Let's see. So as a psychopharmacologist, I think the prospects are just remarkable. I mean, there are probably thousands of variants of these that can be synthesized and examined, and there are going to be differences among them. I don't have any strong a priori reason to think that the naturally occurring substances are going to be better than synthesized compounds. But I suppose that may be the case.

But I just see this area as just ripe for an explosion of investigation of the nature of these effects, the nature of mind, if you will, the nature of consciousness. You know, I sometimes feel, because we were able to reinitiate these studies in naive people after this, you know, decades-long hiatus, you know, I feel kind of like Rip Van Winkle, you know, waking up with the tools of science today and everything that could have been done and that wasn't done for several decades. And what I see is the prospects for this just to continue to unfold unless somehow this project goes off the somehow this project goes off the rails prematurely and we get a societal clamp down on these compounds, which I think would be tragic as far as I'm concerned.

There's so much to learn about the nature of human experience, the nature of consciousness, but in particular, the implications for ethical and moral behavior, I think, is preeminent for me. I think it is for you, I'm sure, because of your interest in moral landscape and meditation. experiences that shine a bright light on the nature of consciousness, although we don't understand it, and something to do with the deepest roots of the moral and ethical behavior that comes out of this understanding that comes so clearly through these experiences that we're all in this together. One of the things that just strikes me about these experiences is that one is confronted with the unlikely fact that here we find ourselves as these highly evolved creatures over millions of years who can navigate the world. We have vision. We can manipulate things.

We've developed mathematics and language and ways of thinking. We've developed science. But the most amazing piece of this is that we are aware that we're aware, and we don't have a reason, an answer for that as you and your wife has wonderfully written in her book, Consciousness. The hard problem of consciousness is not solved, but what is apparent when one is deeply contemplating that is the mystery of that and the sense of the enormity of that mystery, the gratitude for me, at least, that arises from being gifted this opportunity to exist in this playground of consciousness, the wonder of what in the world does that mean and kind of the humility of that. And then recognizing that

all conscious beings share that. We're all kind of entrapped. This is what we know. This is the only thing that we know is that we're conscious, right? It's the only thing we're really certain of. And once you recognize that of yourself, it's humbling. And then you recognize it in other people. And there's this sense that, geez, we are in this together. We need to take care of ourselves and one another if we're going to survive as a species. And there's something just so uplifting about that. I'm guessing that's what guides you and your interest in developing the waking up app and teaching people the prospect of investigating the nature of consciousness and the nature of self.

And I think these are super powerful tools that go right along that same line. Yeah, well, so one of the features of the psychedelic experience that people find so transformative, and it's the one that's directly targeted by meditation, is this suppression or cutting through of the sense of self. Again, we have to issue the obvious caveats. There are ways in which a sense of self can be eroded or destabilized, which are so notable that you just experience. I mean, it is the thing that allows for the unity experiences of the kind you described. There's no longer a boundary between the knower and the known. You're no longer standing on the side of the world looking in.

You are for a moment or for an inherent turning point in time. You'll need to subscribe at SamHarris.org. You'll get access to all full-length episodes of the Making Sense podcast and to other subscriber-only content, including bonus episodes, and AAs, and the conversations

I've been having on the Waking Up app. The Making Sense podcast seems to be that we have these structures in the brain that have been linked together in a having on the waking up app one the making sense podcast seems to be that and relies entirely on listeners structures in the brain that has been described now linked together in a construct called the default mode network which is a series of midline areas in the brain which come online preferentially when people are whether when their minds are wandering when they're just thinking quietly to themselves and not really on a task. And these regions are further invoked when you give someone a task that is explicitly self-referential, when they have to think about whether adjectives apply to themselves or

have to think about some kind of narrative reconstruction of something that refers to them. kind of narrative reconstruction of something that refers to them. And so this is, it seems to be, again, in the studies that have been done, that meditation diminishes activity in this network, and psilocybin does as well. I guess I'm asking you, has the research been done on LSD and mescaline and DMT? Do we know what they do to the default mode network? LSD also decreases functioning in the default mode network. I believe DMT does as ayahuasca, but I'm uncertain. But it does seem to be a relatively robust finding across a number of different investigations. And it makes wonderful sense because it really is connected with a sense of self-referential processing, and that's decreased in long-term meditators.

It's decreased under psilocybin. Interestingly, activity in the default mode network has increased in depression, and psilocybin is being evaluated for treatment of depression. So it makes this wonderful story, but I guess I would also underscore, you know, what a primitive understanding we have of the nature of self and consciousness. And it's surely going to be way more complex than that. But that's a level of analysis and consistency of finding that's really captured the imagination and is explicable. It's a great start, but we have a long ways to go before we understand it. Right. Yeah. I mean, the other confound here I would introduce is that from my point of view,

from the point of view of meditation and the loss of self that is experienced there, it need not be associated with anything changing at the level of the contents of consciousness, really. I mean, you can have a very ordinary, entirely sober, non-psychedelic awareness of your visual scene, say, and if you know how to be mindful of the intrinsic selflessness of consciousness, well then it's just obvious that there's no subject in the head being aware of the visual scene. There's simply the visual scene. And that experience can be had, you know, the sense of self can really be dissected out of conscious experience in a way that doesn't entail many of the other effects that are classically associated with psychedelics. I mean, there's a lot more you get on psychedelics in addition to a loss of self,

if indeed you get that at all, depending on your experience. Yeah, let's see, I absolutely agree. I agree. I think one really interesting area of future investigation is to look at low-dose psychedelics under conditions of meditation. Yeah, actually, I meant to ask you that because obviously microdosing is very much in vogue. What's your understanding of that and attitude toward it. I don't think we really understand anything about microdosing. There's no science behind it, but it is in vogue. I don't doubt that there are effects there. It's a difficult kind of project to undertake scientifically because in order to do it, you need permission to give people psychedelics and let them out in the wild.

And I think most review committees are going to be reluctant to do that, allow that. But I think that needs to be done. I don't know if you saw the recent study of, we've done a study in long-term meditators, we haven't published it yet, but there was a recent study of psilocybin given to people on a Buddhist retreat. It was, I think it was a six-day retreat, and half the group got psilocybin on day five. They got a moderate dose of psilocybin, but not a microdose. The other half didn't. And they produced all the kinds of effects that we would expect and the kinds of effects that we've seen in long-term meditators that actually people find that it deepens their practice, they're more engaged with it.

In the case of the retreat, the deeper the experience on psilocybin, the more positive enduring effects they had at four months. And that's what we found, that in spite of the fact that people may have tens of thousands of hours of experience with meditation, that nonetheless, they find these experiences to be informative and interesting in ways that they find useful for their, most people, useful for their contemplative practice. They're less likely, however, to find them discontinuous with anything that they might have expected out of their contemplative experience because they're accustomed to understanding the nature of mind, the nature of appearances of objects in mind, and de-identifying with those.

I think of long-term meditators, if they come out of certain contemplative conditions, are advantaged in terms of being able to learn from these experiences uniquely. And what I'm intrigued with is what could be made of low-dose, repeated low-dose experiences under conditions where people were really taking them into contemplative practice and trying to learn further about the nature of mind. What do you make of the fact that DMT is endogenous to the brain? And also the pharmacology of it seems unique in that I now speak as one who's never taken DMT. I've never taken ayahuasca and I've never smoked DMT, but apparently smoking DMT

gives you not only what is reputed to be the most intense psychedelic experience, but the time course is incredibly short. I mean, it's like a 10-minute experience as opposed to 10 hours with something like LSD. And again, this is a compound that already exists in the body. How do you think about that phenomenon? I don't know. There's a lot of speculation that maybe that accounts for near-death experiences or prophetic experiences, but it's arguable whether DMT occurs in concentrations sufficient to produce effects. But I can tell you, it's really an interesting compound. We just have completed, actually, I'm writing up right now, a pretty large survey study in which we were asking people who had experience with DMT and reported this phenomena that seems most probable with DMT,

although it occurs with other psychedelics, of encountering a seemingly autonomous entity. And so Terence McKenna spoke a lot about the machine elves. And so I was just deeply curious about that because we had actually also earlier had conducted this survey of experiences that people interpreted were going to be bizarre, dysphoric kinds of experiences, often unpleasant. Rick Straussman talks about people feeling like they're being experimented on, or there could be insectoid kind of bizarre creatures. If I recall correctly from his book, his book is titled DMT, The Spirit Molecule, at least one person felt that they were being raped by a crocodile, which doesn't immediately recommend itself. No, but this really kind of was fascinating to me. So number one, so this was like over 2000 people, you know, when we posted this thing, people were just dying to, you know, give an hour to tell, tell us about this experience. So there's this group of people who've had experiences that are, you know, dying to try

to explain them. And, and so one thing that comes out is that there was no modal description of the nature of that entity. It was most often described as a being or a guide or a spirit. Most people felt like they communicated with that entity. They described the predominant emotions that they and the entity experienced as love, kindness, and joy. That was a surprise. But they felt this much like our God Encounter survey. When we asked them, what attributes did this entity have? And let me just say, they're saying that this entity was more real than everyday waking consciousness. They believe that this entity existed. It continued to exist after the experience profoundly changed their basic conception of reality. We ask them what attributes do they attribute to this being?

And the top ones were intelligence, consciousness, and benevolence. So very much like the God encounter survey, and a great factoid for you, Sam, is that among those who identified as atheists before, that significantly dropped to about a third. So people who considered themselves to be atheists were less likely to identify as such atheists. If you'd like to continue listening to this podcast, you'll need to subscribe at SamHarris.org. You'll get access to all full-length episodes of the Making Sense podcast and to other subscriber-only content, including bonus episodes and AMAs and the conversations I've been having on the Waking Up app.

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