#478 — The Psychedelic Mind

Sam Harris speaks with Robin Carhart-Harris about psychedelic research and its therapeutic potential. They discuss the current state of the field, the FDA denial of MDMA-assisted therapy for PTSD, the critical role of set and setting, risks for vulnerable populations, the REBUS model of how psychedelics work on the brain, the default mode network and ego dissolution, microdosing, the neuroscience of consciousness, DMT entities, and other topics. 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 http://samharris.org/subscribe.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:02Speaker 00

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• 0:24Sam Harris?

  I am here with Robin Carhart-Harris. Robin, thanks for joining me again.

• 0:28Speaker 02

  Thanks for having me on.

• 0:29Sam Harris?

  So remind people where you are doing your research on psychedelics.

• 0:35Speaker 02

  I'm at the University of California, Sam Francisco. I have my lab there.

• 0:39Sam Harris?

  And what's the focus of your research at this point?

• 0:41Speaker 02

  It's consciousness science and how it's encoded in brain activity. That's a big part of it. How can we use psychedelics to try and tackle that question? And it translates into therapeutic applications of psychedelics as well. I also look at harms. Yeah, so try and cover the much of the sort of full gamut of psychedelic science and research.

• 1:04Sam Harris?

  Yeah, well, I want to get into all of that. I guess, big picture to start. What are your impressions of the state of the field at this point? Where are we with research on psychedelics and therapeutic potential and safety? And I mean, how vulnerable are we to having the rug pulled out from under all of this by some new regime of there being a war on drugs? I mean, what's your perception of the field at a high level?

• 1:30Speaker 02

  Well, it's rich and complex. We rode a wave through a kind of peak of a hype cycle, perhaps after Michael Pollan's bestseller, How to Change Your Mind, published in 2018. And yeah, there was a period of some correction, you might say. There was a bit of a pushback on this space for different reasons. And I think there was a market correction as well. Some of the psychedelic medicine companies had gone up to a pretty high valuation, a couple of billion dollars, I think, one of them. And they're certainly not there now. So something's happened. Uh. We had Lycos close to seemingly close to getting FDA approval for MDMA therapy

• 2:14Speaker 02

  for post-traumatic stress disorder, but that was denied by the regulators, by the FDA. And so that put it another dent in the road.

• 2:22Sam Harris?

  Mm hmm.

• 2:22Speaker 02

  I do think that there are reasons to be optimistic, though. If you look at the research, there's a heck of a lot of research. I mean, there's more than ever. Uh, the publication, you know, rate and volume is is higher than ever year on year. And, you know, more quality trials, bigger trials. So I I still feel that, yeah, we're knocking on the door. If FDA approval is the prime milestone, I still think that that's achievable and probably quite close.

• 2:54Sam Harris?

  Mm hmm. Yeah. So what's your sense of all of the research to date that we're relying on to kind of organize our intuitions about the therapeutic value of psychedelics? I mean, much of it, I think, is probably underpowered and many things probably haven't been replicated. There's just sort of, you know, widespread in science now, there's a a greater sensitivity to the possibility that results will not replicate. There's obviously a replication crisis, uh, so branded in, uh, the social sciences and psychology. What's your sense of the quality of the the evidence that we're hurling at the FDA or likely to hurl in the near future so as to argue for the therapeutic value and, you know, legalization?

• 3:39Speaker 02

  Well, there's a lot of small studies published, you know, a few of them have come from, uh, myself and my colleagues. And what's happened historically is that, you know, this space has been up against it. So we've done everything that we can to raise money, and much of that's come from philanthropy. And typically, running an investigator-led study, so not a, uh, industry-sponsored study or trial, you've got a limited budget and you set something up and it's 20 patients and you kind of sow the seed. And so that's what we did back in 2016 with. Psilocybin therapy for treatment resistant depression.

• 4:20Speaker 02

  So most of the trials have in this modern era have been published in the last twenty years. Really, the first clinical trial in a clinical population was two thousand and six. That was Francesco Moreno looking at psilocybin for obsessive compulsive disorder.

• 4:38Sam Harris?

  Mm hmm.

• 4:38Speaker 02

  And, uh, yeah, so there are probably now, I would estimate a couple of dozen small trials and a couple of biggies, you know. We've got, uh, the phase two B work of compass pathways. And we're also hearing the top line findings from their phase three work. So that takes us into the hundreds in a, a single trial, albeit multi-site.

• 5:05Sam Harris?

  What, which are these for psilocybin or?

• 5:07Speaker 02

  This is psilocybin therapy for treatment resistant depression.

• 5:10Sam Harris?

  Uh huh.

• 5:10Speaker 02

  And that's the most advanced. That's the closest to a breakthrough, I would say, with the regulators. Yeah, they're talking about this rolling submission where not all of the data necessarily has to be submitted for a decision to come. On the face of it, that sounds pretty optimistic, but then I'm hearing mixed messages as well.

• 5:31Sam Harris?

  What were the implications and consequences of the FDA denial of the Lycos Maps MDMA petition?

• 5:40Speaker 02

  Yeah, I mean, it did cause this market correction. So, you know, companies were, were their valuation dropped quite dramatically. And I think, you know, had that got through, that would have caused a, a general uplift, you know, rising tide for everyone in this space. Yeah, so it's.

• 5:57Sam Harris?

  Were, were the reasons for it intelligible and justifiable or?

• 6:01Speaker 02

  Some of them, and some of them weren't, you know, so some of the data quality in terms of adverse events weren't fully reported, apparently. I think, you know, Lycos was the commercial face of maps.

• 6:16Speaker 02

  And MAPS, Multidisciplinary Association of Psychedelic Studies headed up by Rick Doblin. And MAPS is, in a sense, a advocacy group for psychedelics generally. Like, Rick brings this incredible charisma, but it's not fundamentally, I think it's fair to say, an academic body, say, annexed to an obvious academic institution. It's not really pure scientists sort of running things. And I, I think that makes it a very easy target for this accusation of bias. I mean, the bias is pretty, pretty overt, really. Yeah. And so they were very vulnerable in, in that regard.

• 6:57Speaker 02

  And so some of the data quality issues in terms of all AEs being reported, I can sort of see how that could happen, some of the, some of the sites. You know, they weren't traditional clinical research sites. Some of the dosings happening in people's, you know, homes. These are clinicians, but still it wasn't, very much wasn't the traditional model. And so I can see how it went that way. I think the FDA made some errors in terms of their misunderstanding of psychedelic medicine and, and therapy. Ultimately, they're a regulatory body that approves drugs, drugs as medicines.

• 7:37Speaker 02

  And so they want to be able to look at the profile of a drug. And as this treatment was presented to them, it was a combination treatment. You know, even in the framing of it, I think it was psychedelic assisted therapy or MDMA assisted therapy for post-traumatic stress disorder. So that's leaning emphasis on the therapy. And the FDA say, well, this isn't our remit. You know, we're not a body to approve psychotherapy. So this is confusing to us. And I think that tripped things up quite considerably. And I say, compass pathways with psilocybin are playing it very differently. They're much more traditional.

• 8:16Sam Harris?

  How do you think about the promise of psychedelics? Is it inextricably bound up with the role of a therapist? Or a therapist, some sort of therapeutic context? Or do you think the compounds and their utility are totally divorceable from context in that way?

• 8:34Speaker 02

  Certainly not. Yeah, I've written a paper called psychedelics and the essential importance of context. So, you know, I'm very out there on this perspective that I do see it as fundamentally a combination treatment. So, you know, maps like us, how they presented it was right. It was transparent. And it, in my view, the reality of this treatment, it's the secret source of this treatment is in that, in that combination of a drug action that opens up the mind, makes it more plastic. And then you, you know, by simple logic, you have a plastic state, you've got to do the right thing with that, you know? It's more shapeable, so shape it right.

• 9:17Speaker 02

  And so that's where the context really, really matters. And the context, we sometimes call it set and setting. Set being the mindset that you bring in, in a sense, the psychology that you bring in. Yes, expectations, but a lot more than that. And the setting is the immediate environment for the experience. So these are just two ways to split up, I suppose, factors that contribute to context. And that context really mattering with psychedelics on board. That's a strong assumption that we hold in this space. It's actually an assumption that I'm testing right now in my lab, controlling context as a variable, as a factor.

• 9:59Sam Harris?

  What are you controlling with respect to context? Are you talking about therapist versus no therapist? Or what, or variables with respect to set and setting? What, what are you controlling?

• 10:09Speaker 02

  So it is more really this what the staff do, the quality of their preparation ahead of a dosing session, the quality of the way they hold the space and provide compassionate support if needed during a dosing session, because the support is typically quite hands off.

• 10:30Sam Harris?

  Right.

• 10:31Speaker 02

  It's quite indirect. It's more like a holding rather than something directive. There's often quite little talking going on. So it's not traditional psychotherapy. It's not traditional talking therapy in the session itself. But it is in the prep and it is in what we call the integration, which is the therapy, the psychological support that comes after the dosing session. It might come the next day, it might come the next week. And, uh, you know, plus maybe one or two sessions on top of that is how we tend to do it in the field. So we, we do control that quality of psychological support, both its amount and its quality, and we have a protocol to follow for that.

• 11:16Speaker 02

  We control music listening as a variable. We either have it on or off. With colleagues, we've referred to music as a hidden therapist.

• 11:27Sam Harris?

  Mm hmm.

• 11:27Speaker 02

  Because the sessions are so non-directive. You ask the question, well, is there any nudging, any kind of coaxing going on here?

• 11:36Sam Harris?

  Yeah, no, and music, the music can be quite an overwhelming experience. Yeah.

• 11:40Speaker 02

  Can it? And, and it gets enhanced in its emotionally evocative, yes, properties. And we control and manipulate the quality of the aesthetics. So in what we call this enriched condition, we have an enriched condition with all these psychedelic therapy elements included. And we have an unenriched condition with them stripped out.

• 12:03Sam Harris?

  Hmm.

• 12:04Speaker 02

  So there's no music, the sessions are staffed, but really for basic safety monitoring, not for any kind of active emotional support unless there's an emergency. I mean, we're guided by do no harm, of course. And yeah, we control the aesthetics. So in the enriched, there's lovely glowing lighting and printed screens of beautiful nature scenes. And then in the unenriched, it's a standard consulting room in a clinical research unit.

• 12:32Sam Harris?

  Mm hmm. All of this suggests that there's a fair amount to get right or wrong with respect to how one promotes people into the role of being a therapist, right? So I'm wondering about just kind of quality control there and screening and supervision and training. And I'm thinking of one story I heard of a, um, someone who I think was in a group setting. I don't even know what the compound was. Maybe it might have been psilocybin, it might have been ayahuasca, but somebody in the setting was feeling like they were remembering, you know, childhood sexual abuse, I think, some trauma from childhood that had not been conscious prior to taking the drug. But they were also uncertain as to whether it was

• 13:14Sam Harris?

  a memory or whether they were just imagining it. And the therapist, you know, to my ear, who was, um, in charge at that point, came in, uh, uh, it was, it was a heavily enriched context, but you might think it was enriched by this, this therapist's, you know, dogmatism or delusion, because they seemed to be coming at this with a, a very strong sense of, uh, you know, recovered memory being a, you know, very much a real thing. And I believe they told this, uh, subject that, you know, the body never lies, or the body never forgets, or something like that. So, and this was very much the framing that got put forward and I, and, and it seemed to decisively shape this person's experience. This person came

• 13:57Sam Harris?

  away thinking, okay, they have recovered memories of childhood sexual abuse, uh, with the aid of this compound. But their initial experience was much more equivocal than that. I mean, they were uncertain as to whether this was a memory or they were imagining it. And they were then in the presence of a therapist who had very strong ideas about what was likely or almost certain to be true. All of that worries me, given what I believe about, you know, what we know about the, certainly the, the recovered memory under hypnosis legacy. I mean, I, you know, I, I'm fairly aware of that phenomenon and of how, um, so many, uh, witnesses were led to believe things that in many cases, almost certainly didn't happen. What are your thoughts about quality control with respect to therapists?

• 14:38Sam Harris?

  And just how we can build a culture that does no harm while giving people the support that they need?

• 14:46Speaker 02

  Hmm. Yeah, it's a biggie. It's certainly a biggie. So not knowing the specifics of that case, but but responding to how you relay it, it sounds like bad practice in terms of a therapist coming in and transferring, in a sense, their assumptions, their beliefs, their perspective onto, you know, the tender, opened heart of a vulnerable individual. Cases of alleged uh recovered memory in this space are prevalent. It's happened in our trials. It's happened in other major sites, Hopkins, I know they've had this.

• 15:25Sam Harris?

  But let me just be clear on one thing, lest I be misunderstood. I don't think this never happens or is never, in fact, veridical, right? I think it's possible to remember something for the first time that you experienced in in, you know, early childhood. And I'm not fundamentally skeptical about every story, but I just know that this mechanism or imagined mechanism has been abused by certainly by the hypnosis community back in the day. And I worry that psychedelics could be hypnosis on steroids.

• 15:54Speaker 02

  I worry too. And I think there's an angle here from, uh, you know, legal professionals seeing an opportunity. And I think that's a problem, a future problem that will will clash into at some point. But yes, it comes up and I I treat it in that way. You know, we we go case by case. And we've had to manage patients uncertain about a recovered memory. I remember one in particular, he's spoken openly about it, where he was confused about whether his, one of his parents had had tried to smother him and kill him with a pillow.

• 16:36Speaker 02

  And yeah, we had to hold that very lightly in terms of its veridicality or otherwise. And that was hard for him. You know, he wanted some kind of closure there. He had classic ambivalence about this parental figure, projected for a while that they were all good, and then had this jarring. Challenge to that come up as a apparent or possible recovered memory. And so what happened there is that there was extended therapy for that case. When you look at its data, it actually sticks out like a sore thumb in our trial. It was our first psilocybin therapy for treatment resistant depression trial. And you can see there's a clinically meaningful increase in symptom severity.

• 17:19Speaker 02

  He's the only one who showed that in two or three weeks after the treatment. So he had to manage this turbulence that he was going through, where he was uncertain as to whether this happened or not. And we had to be very, very careful and professional not to either endorse or deny, but rather just listen compassionately. And so if it's there as something imagined, that's something to work with therapeutically. If it really happened, that's something to work with therapeutically, but let's not make a call on its veridicality. I will add though, that there was another case where the abuse was known ahead of time.

• 17:59Speaker 02

  It had actually been a case against this, again, a parental figure, a father. And it was sexual abuse and he was convicted. And so this was the trauma that this patient brought in to the session, treatment resistant depression again. And so we certainly didn't guide him there at all. As I said, the therapy and the sessions is very hands off. It's not directive in terms of talking at all. But he went there and he expressed to his therapist that I can see my father abusing me. And so there, the approach, the response from the therapist and one in particular

• 18:42Speaker 02

  was to gently suggest that going towards, okay, let's stay with that a while if you can.

• 18:48Sam Harris?

  Is this on psilocybin or?

• 18:50Speaker 02

  This is psilocybin, high dose psilocybin. Very, very painful for him, for the patient, but he did. And the abuser was manifest as a monster with a gun, you know, that might be seen.

• 19:06Speaker 02

  A symbolic and incredibly menacing, terrifying. And then staying with this vision with the support, it morphed. And it morphed into something pathetic, almost pitiful. And there was almost some forgiveness, and I'm sort of echoing the patient's words here. Forgiveness might be too much to say that, but an understanding of sort of the pathetic, yeah, weak nature of the abuser and how they could have done something like this. And it was a breakthrough at the time. There was a lot of tears.

• 19:47Speaker 02

  There were, you know, sort of wet eyes with everyone in the room, really. And yeah, it was considered very beneficial to the patient to go through that, that experience.

• 20:00Sam Harris?

  Yeah, I mean, so you're painting a picture of the, obviously, the other side of this therapy question, which is, I mean, it has to be tremendously rewarding to be a therapist under these conditions where you're seeing people basically do, you know, decades worth of psychological work and over the course of hours. I mean, it's just, this is not the normal experience of talk therapy, where you can have a conversation with someone for 20 years and basically you're talking to the same person 20 years later. It has to be very rewarding in success. What do we know about people for whom psychedelics hold obvious therapeutic promise

• 20:41Sam Harris?

  and people who should stay away? I mean, what are the exclusion criteria and contraindications you're working with in research? And what do you think is just a ground truth insofar as we understand it for people out there in the public who probably shouldn't take any of these drugs? You might want to differentiate the various classes of drugs or specific compounds with respect to risk, but what's your view of who benefits and who is causing obvious harm?

• 21:08Speaker 02

  Sure, yeah, well, I can respond to that empirically. While it's true that most of the studies that have been done are small. There are a lot of studies now, and I I didn't speak to the reliability in terms of the clinical benefits. Because the results are very reliable, they've been very well replicated. Positive results, almost without exception. I think there was one. Uh, negative result trial. Uh, and you know, again, this would be in a couple dozen or close to that now. And they dosed the individual in a, in a M R scanner. And there was no psychological support. So for me, that's quite telling, very telling. So very consistent, positive results.

• 21:50Sam Harris?

  Just to explain why you would expect that, I mean, an M R scanner in terms of setting. Is aesthetically pretty awful setting. I mean, it's. If you're claustrophobic at all, you're going to freak out and it's also loud and.

• 22:03Speaker 02

  Yeah.

• 22:03Sam Harris?

  Uh, you can't move, in fact, because you can't get data on someone who's moving. So it's just, it's. There are a lot of people who are not on drugs. You can't get scanned i- in uh, an M R I machine and. And many people who can only if they take, uh, you know, benzodiazepines to. Lower their anxiety, you know.

• 22:22Speaker 02

  Um, and then that's a big confound, of course, isn't it? Yeah. So, uh, yeah, it's not the best set and setting. It can be tolerated. I've done a lot of work putting people in scanners and. Giving them high doses of psychedelics. But there's a way to do it and, you know, it's not an optimal set and setting. It's not an optimal context. It's not obviously therapeutically supportive. There's no. Music listening that I'm aware of that they experience. So, yeah, it's very, very noisy, claustrophobic and all the things you say. So, you know, looking at, at the results at that high level, all of these depression trials, now there's a couple of. Eating disorder trials, we've got one coming out very soon. Looking at psilocybin therapy for anorexia that reports positive results. Uh, obsessive compulsive disorder.

• 23:07Speaker 02

  If we're including M D M A, the P T S D results are very promising.

• 23:11Sam Harris?

  Hmm.

• 23:12Speaker 02

  Very large positive effect sizes there. There are anxiety disorders, there's a phase. Retrial LSD therapy for general anxiety disorder. Uh, there are addiction disorders, alcohol use disorder, opiate use disorder, cocaine, um, out of Alabama. There's, there's a lot and I'll be missing things. And there's also the, the weight of evidence in favor of betterment of, you know, well, people or the worried well, if you want. So improvements in, in well-being, life satisfaction, sense of meaning in life, flourishing, uh, these positive psychology domains.

• 23:52Speaker 02

  That's very reliable as well. A- and also in a mixed methods approach. And what do I mean by that? So surveying people taking psychedelics in the wild, as we say, meaning in every kind of context, they could be at Burning Man, they could be in their bedroom. They could have gone off to Oregon to have legal adult supervised psilocybin experiences. We've looked at that too, but, you know, across those different contexts, when we pull the data, very positive results there as well. So, yeah, so most people is, is the short answer, seem to benefit, but not everyone.

• 24:32Speaker 02

  So then the critical question is where is this bottom margin? You know, who falls into that? Who's at special risk? Who's a risk of being a, you know, i- in that outlier bracket where they don't improve. And if, if anything, they get worse. Where could this be iatrogenic, you know, as, as they say, meaning it actually worsens. Hmm. Your health. And there we have found empirically that people with a history of a diagnosis, I'm being very con- concrete here, but history of a diagnosis of a personality disorder. And, and what is that? Well, it's a in emotional volatility can come in different forms, but it can be a sort of

• 25:16Speaker 02

  histrionic character presentation, uh, very volatile, very splitty, as we would say in psychology, meaning jumping from positive projection, everything is good or this. Person is all good, entirely flawless, to this one is all bad and entirely malevolent. You know, quite irrational, but people do that. They make the world black and white. Uh, and that kind of psychological volatility is a risk factor. We actually found that people with that history were four times more likely to fall into a bottom margin in our grouped data. So they were the worst cases.

• 25:57Speaker 02

  And uh, another bit of detail that that group actually did okay numerically. Uh, a very slight improvement in wellbeing in in the short period after the experience. But then they fell off a cliff, so to speak. Then they further out, they they showed a clinically meaningful worsening in their in their mental health. Uh, and these were individuals taking psychedelics in the wild. So this wasn't in a control trial.

• 26:25Sam Harris?

  Right.

• 26:25Speaker 02

  This is sampling people taking, yeah, psychedelics in any kind of context. In the control trials, we actually screened those individuals out. So this field could be accused, I think, fairly for cherry picking, you know, a more more resilient populations.

• 26:43Sam Harris?

  Mm hmm.

• 26:44Speaker 02

  So we we screen out people with a history of psychotic illness. I- in that same study, people with a history of, say, schizophrenia, they were twice as likely to fall into that bottom margin than everyone else. So personality disorder, which is quite close to psychosis, it's sometimes called borderline personality disorder. And that borderline means sort of borderline psychotic, some some divorcement from reality, close to to being, you know, diagnosed psychotic. So that's that's the vulnerability space. And that's where we have to be especially careful. And we are in the trials, but by doing that, we've arguably,

• 27:24Speaker 02

  and I think fairly, cherry picked this sample and um of the more resilient types. It's funny, it's not funny, but it's sort of ironic to say that about something like depression. But it's a certain kind of depression that doesn't have, say, psychotic features or features of of personality disorder, this special volatility.

• 27:46Sam Harris?

  Would you say that the same contraindications apply to for MDMA? Or is that not a an issue with even like a propensity toward psychosis? Or something like borderline or any of the other clinical conditions or risks you're talking about having a first order relative with with one of these conditions? Do you think MDMA poses similar or any risk?

• 28:13Speaker 02

  I think it poses some risk. Everything does, but maybe it's more resilient to context MDMA somewhat. It's less of a heaven and hell that you get with the classic psychedelics. LSD, psilocybin, ayahuasca, DMT. You know, you can take MDMA at a rave and have a very good time quite reliably. You take LSD and it's much more unpredictable.

• 28:39Sam Harris?

  It doesn't seem to be a distortion of cognition and perception in the same way with MDMA.

• 28:46Speaker 02

  It's subtle, yeah, subtle shift in perception, maybe a softening, maybe a softening of ego, you might say, whereas the classic psychedelics are called ego dissolvers or disintegrators. Yeah, people like to say that MDMA is a heart opener rather than a head opener. So it promotes relational exchange, you know, social exchange. It's easier to open up with people. You can talk more easily on MDMA versus a classic psychedelic like LSD. So you can do some somewhat conventional talk therapy.

• 29:23Speaker 00

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• 29:31Speaker 02

  Improvements in in well being, life satisfaction, sense of meaning in life. I'm worthless. Life is pointless. It's all pointless. I'm more valuable in the world if I'm skinny. And psychedelics seem to be like a heat seeking missile for that kind of self generated BS, as I call it.