Making Sense with Sam Harris - #478 — The Psychedelic Mind

Episode Date: May 29, 2026

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.  

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and find it valuable, please consider subscribing today. I am here with Robin Carhart Harris. Robin, thanks for joining me again. Thanks for having me on. So remind people where you are, doing your research on psychedelics. I'm at the University of California, San Francisco.

I have my lab there. And what's the focus of your research at this point? 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 much of the full gamut.

of psychedelic science and research. 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? 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, high level?

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. We had Lycos seemingly close to getting FDA approval for MDMA therapy for post-traumatic stress disorder. But that was denied by the regulators by the FDA. And so that put another dent in the road. 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. The publication, you know, rate and volume is higher than ever year on year. And, you know, more quality trials, bigger trials. So 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. 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 greater

sensitivity to the possibility that results will not replicate. There's obviously replication crisis so branded in the social sciences and psychology. What's your sense of the quality of the evidence that we're hurling at the FDA are likely to hurl in the near future so as to argue for therapeutic value and legalization. Well, there's a lot of small studies published. A few of them have come from 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 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. So most of the trials, in this modern era, have been published in the last 20 years. Really the first clinical trial in the clinical population was 2006. That was Francesco Moreno looking at celestimine for obsessive-compulsive disorder. And 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 the Phase 2B work of Compass Pathways, and we're also hearing the top line findings.

from their phase three works. So that takes us into the hundreds in a single trial, albeit multi-site. Which are these for psilocybin? This is psilocybin therapy for treatment-resistant depression. 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. What were the implications and consequences of the FDA denial of the Lycos MAPS, MDMA petition? Yeah. I mean, it did cause this market correction. So companies were their valuation dropped

quite dramatically. And I think, you know, had that got through, that would have caused a general uplift to it, you know, rising tide for everyone in this space. Yeah, so it's... Were the reasons for it intelligible and justifiable? 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.

And maps, multidisciplinary association of psychedelic studies headed up by Rick Doblin. And MAPS is, in a sense, a advocacy group for psychedelics generally. Rick brings this incredible charisma, but it's not fundamentally, I think it's fair to say, an academic body,

say annex to an obvious academic institution. It's not really pure scientists, sort of running things. And I think that makes it a very easy target for this accusation of bias. I mean, the bias is pretty, pretty overt, really. And so they were very vulnerable in that regard. 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 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 therapy. Ultimately, they're a regulatory body that approved drugs, drugs as medicines. 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 solosybin are playing it very differently. They're much more traditional. How do you think about the promise of psychedelics? Is it inextricably bound up with the role of a therapist or a therapy, some sort of therapeutic context? Or do you think the compounds and their utility are totally divorceable from context in that way? 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 in my view, the reality of this treatment, it's the secret source of this treatment is 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. 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. What are you controlling with respect to context? Are you talking about therapists versus no therapist or variables with respect to set and setting? What are you controlling? So it is more really 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.

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 plus maybe one or two sessions on top of that is how we tend to do it in the field. So we do control that quality of psychological support, both its amount and its quality, and we have a protocol to follow for that. 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 because the sessions are so non-directive. You ask the question, well, is there any nudging, any kind of coaxing going on here?

The music can be quite an overwhelming experience. Can it. 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. 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 aesthetic. 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. 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 someone who I think was in a group setting. I don't even know what the compound was. 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 a memory or whether they were just imagining it.

And the therapist, you know, to my ear, who was in charge at that point, came in, it was a heavily enriched context, but you might think it was enriched by this therapist's, you know, dogmatism or delusion because they seemed to be coming at this with a very strong sense of, you know, recovered memory being, you know, very much a real thing. And I believe they told this 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 seemed to it decisively shape this person's experience. This person came away thinking,

okay, they have recovered memories of childhood sexual abuse 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 recovered memory under hypnosis, legacy. I mean, I'm fairly aware of that phenomenon and of how so many 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 and just how we can build a culture that does no harm while giving people the support that they need? Yeah, it's a biggie. It's certainly a Biggie. So not knowing the specifics of that case, 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, recovered memory in this space are prevalent. It's a happened in our trials. It's happened in other major sites, Hopkins. I know they've had this. Let me just be clear on one thing, lest I'd be misunderstood. I don't think this never happens or is never, in fact, veretical, right? I think it's possible to remember something for the first time that you experienced 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. I worry too. And I think there's an angle here from, you know, legal professionals seeing an opportunity. And I think that's a problem, future problem, that will clash into at some point. But yes, it comes up and I treat it in that way.

you know, 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 one of his parents had tried to smother him and kill him with a pillow. And yeah, we had to hold that very lightly in terms of it's of ridicality 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 an 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 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 symptoms of severity. He's the only one who showed that in two or three weeks after the treatment. So we 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 radicality. I will add, though, that there was another case where the abuse was known ahead of time had actually been a case against this, again, a parental figure of 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 was to gently suggest the going towards, okay, let's stay with that a while if you can. Is this on psilocybin or Mdum? This is psilocybin, high dose solosybin. 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 as 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. you know, 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.

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 experience. 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. You did 20 years later. It has to be very rewarding in success.

what do we know about people for whom psychedelics hold obvious therapeutic promise and people who should stay away? I mean, what are the exclusion criteria and contradictions 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 courting obvious harm? 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 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 negative result trial. And, you know, again, this would be in a couple dozen or close to that now. And they dose the individual in an MR scanner. And there was no psychological support. So for me, that's quite telling. Very telling.

So very consistent, positive results. Just to explain why you would expect that. I mean, an MR scanner in terms of setting is aesthetically pretty awful setting. I mean, if you're claustrophobic at all, you're going to freak out. and it's also loud and you can't move, in fact, because you can't get data on someone who's moving. So it's just, it's, I mean, there are a lot of people who are not on drugs who can't get scanned in an MRI machine and in many people who can only if they take,

you know, benzodiazepam to lower their anxiety, you know. And then that's a bit confound, of course, isn't it? Yeah. So, 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 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, obsessive-compulsive disorder, if we're including MDMA, the PTSD results are very promising, very large positive effect sizes there. There are anxiety disorders. There's a phase three trial LSD therapy for general anxiety disorder. There are addiction disorders, alcohol use disorder, opiate use disorder, cocaine, out of of Alabama. There's a lot, and I'll be missing things. And there's also the weight of evidence in favor of betterment of, you know, well people or the worried well, if you want. So improvements in well-being, life satisfaction, sense of meaning in life, flourishing, these positive psychology domains. That's very reliable as well. 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 a burning man, they could be in their bedroom. They could have gone off to Oregon to have legal adult supervised salicybin 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 the short answer seem to benefit, but not everyone. 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, you know, in that outlier bracket where they don't improve and if anything, they get worse.

Where could this be itrogenic, you know, as they say, meaning it actually worsens your health. And there we have found empirically that people with a history of a diagnosis, I'm being very concrete here, but history of a diagnosis of a personality disorder. And what is that? Well, it's an emotional volatility can come in different forms, but it can be a sort of histrionic character presentation, 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. 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. And another bit of detail that that group actually did okay numerically, a very slight improvement in well-being in the short period after the experience. But then they fell off a cliff, so to speak. Then they further out, they showed a clinically meaningful worsening in the way. their mental health. And these were individuals taking psychedelics in the wild. So this wasn't in a control trial.

This is sampling people taking psychedelics in any kind of context. In the control trials, we actually screen those individuals out. So this field could be accused, I think, fairly for cherry-picking, you know, a more resilient populations. So we screen out people with a history of psychotic illness. In that same study, people with a history of, say, schizophrenia, it 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 divorcement from reality close to being, you know, diagnosed psychotic. So 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, and I think fairly, cherry-picked this sample and 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 personality disorder, this special volatility. Would you say that the same contraindications apply to, for MDMA?

Or is that not an issue with, like, a propensity toward, you know, psychosis or, you know, something like borderline or any of the other clinical conditions or risks you're talking about having a first order relative with one of these conditions? Do you think MDMA poses similar or any risk? I think it poses some risk. everything does. But maybe it's more resilient to context, MDMA somewhat is 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. It doesn't seem to be a distortion of cognition and perception in the same way. with no it's subtle yeah subtle shifting 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. Members can hear the full conversation by subscribing at samharis.org.

Subscribers get a private RSS feed you can use with your favorite podcast player. Improvements 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.