Making Sense - Sam Harris - May 29, 2026


#478 — The Psychedelic Mind


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00:00:00.000 you're listening to making sense with sam harris this is the free version of the podcast so you'll
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00:00:22.960 i am here with robin carhart harris robin thanks for joining me again thanks for having me on so
00:00:29.940 remind people where you are doing your research on psychedelics.
00:00:35.140 I'm at the University of California, San Francisco. I have my lab there.
00:00:39.300 And what's the focus of your research at this point?
00:00:41.540 It's consciousness science and how it's encoded in brain activity. That's a big part of it.
00:00:46.720 How can we use psychedelics to try and tackle that question? And it translates into therapeutic
00:00:53.700 applications of psychedelics as well. I also look at harms. Yeah, so try and cover the
00:00:59.940 much of the sort of full gamut of psychedelic science and research.
00:01:04.600 Yeah, well, I want to get into all of that. I guess, big picture to start. What are your
00:01:09.040 impressions of the state of the field at this point? Where are we with research on psychedelics
00:01:15.700 and therapeutic potential and safety? And I mean, how vulnerable are we to having the rug pulled
00:01:22.400 out from under all of this by some new regime of there being a war on drugs? I mean, what's your
00:01:29.140 perception of the field, high level? Well, it's rich and complex. We rode a wave through a kind
00:01:37.280 of peak of a hype cycle, perhaps after Michael Pollan's bestseller, How to Change Your Mind,
00:01:43.160 published in 2018. And yeah, there was a period of some correction, you might say. There was a bit of
00:01:49.360 a pushback on this space for different reasons. And I think there was a market correction as well.
00:01:55.460 some of the psychedelic medicine companies had gone up to a pretty high valuation, a couple of
00:02:01.140 billion dollars, I think, one of them. And they're certainly not there now. So something's happened.
00:02:07.440 We had Lycos seemingly close to getting FDA approval for MDMA therapy for post-traumatic
00:02:15.380 stress disorder, but that was denied by the regulators, by the FDA. And so that put another
00:02:21.180 of the dent in the road. I do think that there are reasons to be optimistic, though. If you look
00:02:27.040 at the research, there's a heck of a lot of research. I mean, there's more than ever. The
00:02:31.720 publication, you know, rate and volume is higher than ever year on year. And, you know, more quality
00:02:39.480 trials, bigger trials. So I still feel that, yeah, we're knocking on the door. If FDA approval is the
00:02:47.900 prime milestone, I still think that that's achievable and probably quite close.
00:02:54.020 Yeah. So what's your sense of all of the research to date that we're relying on to
00:03:00.780 kind of organize our intuitions about the therapeutic value of psychedelics? I mean,
00:03:05.420 much of it, I think, is probably underpowered and many things probably haven't been replicated.
00:03:12.260 There's just sort of widespread in science now. There's a greater sensitivity to the possibility that results will not replicate. There's obviously a 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 or likely to hurl in the near future so as to argue for the therapeutic value and legalization?
00:03:39.140 Well, there's a lot of small studies published, you know, 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.
00:04:01.540 so not an industry-sponsored study or trial. You've got a limited budget, and you set something
00:04:09.400 up, and it's 20 patients, and you kind of sow the seed. And so that's what we did back in 2016 with
00:04:16.760 psilocybin therapy for treatment-resistant depression. So most of the trials in this
00:04:23.420 modern era have been published in the last 20 years. Really, the first clinical trial in the
00:04:29.920 clinical population was 2006. That was Francesco Moreno looking at psilocybin for obsessive
00:04:37.020 compulsive disorder. And yeah, so there are probably now, I would estimate a couple of dozen
00:04:45.200 small trials and a couple of biggies, you know. We've got the phase 2b work of Compass Pathways,
00:04:54.020 And we're also hearing the top-line findings from their phase three works.
00:04:59.360 So that takes us into the hundreds in a single trial, albeit multi-site.
00:05:05.160 Which are these for psilocybin?
00:05:06.900 This is psilocybin therapy for treatment-resistant depression.
00:05:10.340 And that's the most advanced.
00:05:12.540 That's the closest to a breakthrough, I would say, with the regulators.
00:05:17.580 Yeah, they're talking about this rolling submission where not all of the data necessarily
00:05:22.840 has to be submitted for a decision to come. On the face of it, that sounds pretty optimistic,
00:05:28.700 but then I'm hearing mixed messages as well. What were the implications and consequences of
00:05:34.780 the FDA denial of the Lycos, MAPS, MDMA petition? Yeah. I mean, it did cause this market correction,
00:05:43.520 so companies, their valuation dropped quite dramatically. And I think had that got through,
00:05:50.440 that would have caused a general uplift, you know, rising tide for everyone in this space.
00:05:56.560 Yeah, so it's...
00:05:57.700 Were the reasons for it intelligible and justifiable?
00:06:01.180 Some of them, and some of them weren't, you know. So some of the data quality in terms of
00:06:06.520 adverse events weren't fully reported, apparently. I think, you know, Lycos was the commercial face
00:06:14.420 of MAPS and MAPS Multidisciplinary Association of Psychedelic Studies headed up by Rick Doblin
00:06:22.580 and MAPS is in a sense a advocacy group for psychedelics generally like Rick brings this
00:06:30.300 incredible charisma but it's not fundamentally I think it's fair to say an academic body say
00:06:36.820 annexed to an obvious academic institution it's not really pure scientists sort of running things
00:06:44.220 and I think that makes it a very easy target for this accusation of bias I mean the bias is pretty
00:06:51.740 pretty overt really yeah and so they were very vulnerable in in that regard and so some of the
00:06:58.460 data quality issues in terms of all AEs being reported I can sort of see how that could happen
00:07:05.260 some of the some of the sites you know they weren't traditional clinical research sites
00:07:10.840 some of the dosings happening in people's homes. These are clinicians, but still it wasn't very
00:07:18.760 much wasn't the traditional model. And so I can see how it went that way. I think the FDA made
00:07:24.920 some errors in terms of their misunderstanding of psychedelic medicine and therapy. Ultimately,
00:07:32.360 they're a regulatory body that approved drugs, drugs as medicines. And so they want to be able
00:07:40.600 to look at the profile of a drug. And as this treatment was presented to them, it was a
00:07:47.600 combination treatment. Even in the framing of it, I think it was psychedelic assisted therapy or
00:07:54.160 MDMA assisted therapy for post-traumatic stress disorder. So that's leaning emphasis on the
00:08:00.460 therapy. And the FDA say, well, this isn't our remit. You know, we're not a body to approve
00:08:05.280 psychotherapy. So this is confusing to us. And I think that tripped things up quite considerably.
00:08:11.240 And I say compass pathways with psilocybin are playing it very differently. They're much more
00:08:15.640 traditional. How do you think about the promise of psychedelics? Is it inextricably bound up with
00:08:23.000 the role of a therapist or some sort of therapeutic context? Or do you think the
00:08:29.120 compounds and their utility are totally divorceable from context in that way?
00:08:34.280 Certainly not. I've written a paper called Psychedelics and the Essential Importance
00:08:40.520 of Context, so I'm very out there on this perspective that I do see it as fundamentally
00:08:46.640 a combination treatment. So, you know, MAPS, Lycos, how they presented it was right. It was
00:08:52.080 transparent and it's in my view the reality of this treatment it's the secret source of this
00:08:58.920 treatment is in that in that combination of a drug action that opens up the mind makes it more
00:09:06.200 plastic and then you you know by simple logic you have a plastic state you've got to do the
00:09:12.720 right thing with that you know it's more shapeable so shape it right and so that's where the context
00:09:20.280 really matters. And the context, we sometimes call it set and setting, set being the mindset
00:09:27.980 that you bring in, in a sense, the psychology that you bring in. Yes, expectations, but a lot
00:09:33.880 more than that. And the setting is the immediate environment for the experience. So these are just
00:09:38.820 two ways to split up, I suppose, factors that contribute to context and that context really
00:09:45.240 mattering with psychedelics on board that's a strong assumption that we hold in this space
00:09:50.880 it's actually an assumption that i'm testing right now in my lab controlling context as a variable
00:09:57.300 as a factor what are you controlling with respect to context are you talking about
00:10:02.480 therapist versus no therapist or what or variables with respect to set and setting what what are you
00:10:08.640 controlling? So it is more really what the staff do, the quality of their preparation ahead of a
00:10:16.840 dosing session, the quality of the way they hold the space and provide compassionate support if
00:10:24.560 needed during a dosing session, because the support is typically quite hands-off.
00:10:30.640 It's quite indirect. It's more like a holding rather than something directive. There's often
00:10:37.940 quite little talking going on so it's not traditional psychotherapy it's not traditional
00:10:43.020 talking therapy in the session itself but it is in the prep and it is in what we call the
00:10:49.960 integration which is the therapy the psychological support that comes after the dosing session
00:10:56.440 might come the next day it might come the next week and uh you know plus maybe one or two sessions
00:11:03.440 on top of that is how we tend to do it in the field. So we do control that quality of psychological
00:11:10.020 support, both its amount and its quality. And we have a protocol to follow for that.
00:11:16.140 We control music listening as a variable. We either have it on or off. With colleagues,
00:11:24.300 we've referred to music as a hidden therapist because the sessions are so non-directive.
00:11:30.580 You ask the question, well, is there any nudging, any kind of coaxing going on here?
00:11:36.740 Yeah, no, the music can be quite an overwhelming experience, yeah.
00:11:40.720 Can't it?
00:11:41.220 And it gets enhanced in its emotionally evocative, yeah, its properties.
00:11:48.020 And we control and manipulate the quality of the aesthetics.
00:11:52.560 So in what we call this enriched condition, we have an enriched condition with all these
00:11:58.240 psychedelic therapy elements included and we have an unenriched condition with them stripped out
00:12:03.640 so there's no music the sessions are staffed but really for basic safety monitoring not for any
00:12:10.940 kind of active emotional support unless there's an emergency i mean we're guided by do no harm of
00:12:17.520 course and uh yeah we control the aesthetic so in the enriched there's lovely glowing lighting and
00:12:24.360 printed screens of beautiful nature scenes. And then in the unenriched, it's a standard
00:12:29.780 consulting room in a clinical research unit. All of this suggests that there's a fair amount
00:12:36.320 to get right or wrong with respect to how one promotes people into the role of being a therapist,
00:12:43.980 right? So I'm wondering about just kind of quality control there and screening and supervision and
00:12:49.760 training. And I'm thinking of one story I heard of someone who I think was in a group setting.
00:12:55.840 I don't even know what the compound was. It might've been psilocybin. It might've been ayahuasca.
00:13:00.080 But somebody in the setting was feeling like they were remembering childhood sexual abuse,
00:13:07.060 I think, some trauma from childhood that had not been conscious prior to taking the drug.
00:13:12.640 But they were also uncertain as to whether it was a memory or whether they were just imagining it.
00:13:16.920 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 seem to be coming at this with a very strong sense of, you know, recovered memory being, you know, very much a real thing.
00:13:41.920 And I believe they told this subject that the body never lies or the body never forgets or something like that. And this was very much the framing that got put forward and seemed to 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.
00:14:06.480 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.
00:14:35.020 what are your thoughts about quality control with respect to therapists and just how we can
00:14:40.220 build a culture that does no harm while giving people the support that they need?
00:14:46.600 Yeah, it's a biggie. It's certainly a biggie. So not knowing the specifics of that case, but
00:14:51.800 responding to how you relay it, it sounds like bad practice in terms of a therapist coming in
00:14:59.460 and transferring, in a sense, their assumptions, their beliefs, their perspective onto, you know,
00:15:05.840 the tender, opened heart of a vulnerable individual. Cases of alleged recovered memory
00:15:15.620 in this space are prevalent. It's happened in our trials. It's happened in other major sites.
00:15:22.780 Hopkins, I know they've had this. Let me just be clear on one thing,
00:15:26.820 lest I be misunderstood. I don't think this never happens or is never, in fact, veridical,
00:15:31.880 right? I think it's possible to remember something for the first time that you experienced in early
00:15:37.600 childhood. And I'm not fundamentally skeptical about every story, but I just know that this
00:15:43.320 mechanism or imagined mechanism has been abused by, certainly by the hypnosis community back in
00:15:49.980 the day. And I worry that psychedelics could be hypnosis on steroids. I worry too. And I
00:15:56.760 think there's an angle here from you know legal professionals seeing an opportunity and I think
00:16:04.460 that's a problem a future problem that will will clash into at some point but yes it comes up and
00:16:12.220 I treat it in that way you know we we go case by case and we've had to manage patients uncertain
00:16:21.680 about a recovered memory. I remember one in particular, he's spoken openly about it,
00:16:27.760 where he was confused about whether one of his parents had tried to smother him and kill him
00:16:34.900 with a pillow. And yeah, we had to hold that very lightly in terms of its radicality or otherwise.
00:16:42.160 And that was hard for him. He wanted some kind of closure there. He had classic ambivalence
00:16:48.240 about this parental figure projected for a while that they were all good and then had this jarring
00:16:55.700 challenge to that come up as a apparent or possible recovered memory. And so what happened
00:17:03.080 there is that there was extended therapy for that case. When you look at its data, it actually sticks
00:17:08.060 out like a sore thumb in our trial. It was our first psilocybin therapy for treatment-resistant
00:17:13.540 depression trial. And you can see there's a clinically meaningful increase in symptom
00:17:18.540 severity. He's the only one who showed that in two or three weeks after the treatment.
00:17:23.440 So we had to manage this turbulence that he was going through where he was uncertain
00:17:28.560 as to whether this happened or not. And we had to be very, very careful and professional not to
00:17:34.500 either endorse or deny, but rather just listen compassionately. And so if it's there as something
00:17:42.680 imagined, that's something to work with therapeutically. If it really happened,
00:17:47.320 that's something to work with therapeutically. But let's not make a call on its radicality.
00:17:53.860 I will add, though, that there was another case where the abuse was known ahead of time.
00:17:59.800 It had actually been a case against this, again, a parental figure of father,
00:18:05.980 and it was sexual abuse, and he was convicted. And so this was the trauma that this patient
00:18:11.120 brought in to the session, treatment-resistant depression again. And so we certainly didn't
00:18:17.880 guide him there at all. As I said, the therapy and the sessions is very hands-off. It's not
00:18:24.600 directive in terms of talking at all. But he went there and he expressed to his therapist that
00:18:32.500 i can see my father abusing me and so there the approach the response from the therapist and one
00:18:41.440 in particular was to gently suggest the going towards okay let's stay with that a while if you
00:18:48.160 can is this on psilocybin or psilocybin high dose psilocybin very very painful for for him for the
00:18:56.020 patient but he did and and the abuser was manifest as a monster with a gun you know that might be
00:19:05.860 seen as symbolic and uh and incredibly menacing terrifying and then staying with this vision 0.85
00:19:13.980 with the support it morphed and it morphed into something pathetic almost pitiful and there was
00:19:22.480 almost some forgiveness and i'm sort of echoing the patient the patient's words here um forgiveness 0.89
00:19:29.940 might be too much to say that but an understanding of sort of the pathetic you know weak nature of
00:19:38.720 of the abuser and how they could have done something like this and it was a breakthrough
00:19:45.640 at the time there was a lot of tears there were there were you know sort of wet eyes with everyone
00:19:51.380 in the room really and uh yeah it it was considered very beneficial to the patient to go through that
00:19:59.380 that experience yeah i mean so you're you're painting a picture of the obviously the other
00:20:03.880 side of this therapy question which is i mean it has to be tremendously rewarding to be a therapist
00:20:10.580 under these conditions where you're seeing people basically do you know you know decades worth of
00:20:17.600 psychological work over the course of hours. I mean, this is not the normal experience of
00:20:23.760 talk therapy where you can have a conversation with someone for 20 years and basically you're
00:20:27.600 talking to the same person 20 years later. It has to be very rewarding in success.
00:20:33.200 What do we know about people for whom psychedelics hold obvious therapeutic promise and people who
00:20:42.340 should stay away? I mean, what are the exclusion criteria and contraindications you're working
00:20:46.560 with in research, and what do you think is just a ground truth insofar as we understand it for
00:20:51.580 people out there in the public who probably shouldn't take any of these drugs? You might
00:20:57.400 want to differentiate the various classes of drugs or specific compounds with respect to risk, but
00:21:02.880 what's your view of who benefits and who is courting obvious harm? Sure, yeah, well, I can
00:21:10.260 respond to that empirically. While it's true that most of the studies that have been done are small,
00:21:16.560 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 dosed the individual in an MR scanner, and there was no psychological support.
00:21:45.520 so for me that's quite telling very telling so very consistent positive results just to explain
00:21:51.180 why you would expect that i mean an mr scanner in terms of setting is aesthetically pretty awful
00:21:58.040 setting i mean it's if you're claustrophobic at all you're going to freak out and it's also loud
00:22:03.020 and yeah you can't move in fact because you can't get data on someone who's moving so it's just
00:22:08.080 it's i mean there are a lot of people who are not on drugs who can't get scanned in uh an mri
00:22:14.480 machine and many people who can only, if they take, you know, benzodiazepam to lower their
00:22:21.240 anxiety, you know. And then that's a big confound, of course, isn't it? Yeah. So, yeah, it's not the
00:22:26.900 best set and setting. It can be tolerated. I've done a lot of work putting people in scanners and
00:22:31.760 giving them high doses of psychedelics, but there's a way to do it. And, you know, it's not
00:22:36.780 an optimal set and setting. It's not an optimal context. It's not obviously therapeutically
00:22:41.020 supportive there's no music listening that i'm aware of that they experience so yeah it's very
00:22:47.480 very noisy claustrophobic and all the things you say so you know looking at the results at that
00:22:52.880 high level all of these depression trials now there's a couple of eating disorder trials we've
00:22:58.320 got one coming out very soon looking at psilocybin therapy for anorexia that reports positive
00:23:04.260 results, obsessive compulsive disorder. If we're including MDMA, the PTSD results are very
00:23:10.900 promising, very large positive effect sizes there. There are anxiety disorders. There's a phase three
00:23:18.600 trial LSD therapy for general anxiety disorder. There are addiction disorders, alcohol use
00:23:26.000 disorder, opiate use disorder, cocaine out of Alabama. There's a lot, and I'll be missing
00:23:34.820 things. And there's also the weight of evidence in favor of betterment of well people or the
00:23:41.780 worried well, if you want. So improvements in well-being, life satisfaction, sense of meaning
00:23:47.440 in life, flourishing, these positive psychology domains, that's very reliable as well. And also
00:23:55.420 So in a mixed methods approach, and what do I mean by that?
00:23:59.060 So surveying people taking psychedelics in the wild, as we say, meaning in every kind
00:24:04.700 of context, they could be a burning man, they could be in their bedroom, they could have
00:24:09.260 gone off to Oregon to have legal adult supervised psilocybin experiences, we've looked at that
00:24:16.240 too.
00:24:16.520 But, you know, across those different contexts, when we pull the data, very positive results
00:24:23.140 there as well so yeah so most people is is the short answer seem to benefit but not everyone
00:24:32.560 so then the critical question is where is this bottom margin you know who falls into that
00:24:38.960 who's at special risk who's a risk of being a you know in that outlier bracket where they
00:24:46.120 don't improve and if if anything they get worse where could this be iatrogenic you know as as
00:24:52.420 they say, meaning it actually worsens your health. And there we have found empirically that people
00:25:00.540 with a history of a diagnosis, I'm being very concrete here, but history of a diagnosis of a
00:25:06.980 personality disorder. And what is that? Well, it's an emotional volatility can come in different
00:25:14.800 forms, but it can be a sort of histrionic character presentation, very volatile, very
00:25:21.560 splitty, as we would say in psychology, meaning jumping from positive projection, everything is
00:25:27.940 good, or this person is all good, entirely flawless, to this one is all bad and entirely
00:25:33.620 malevolent, you know, quite irrational. But people do that, they make the world black and white.
00:25:39.620 And that kind of psychological volatility is a risk factor. We actually found that people with
00:25:46.980 that history were four times more likely to fall into a bottom margin in our grouped data so they
00:25:55.520 were the worst cases and another bit of detail that that group actually did okay numerically
00:26:03.020 a very slight improvement in well-being in in the short period after the experience but then they
00:26:10.440 fell off a cliff so to speak then they further out they they showed a clinically meaningful
00:26:16.740 worsening in their mental health. And these were individuals taking psychedelics in the wild. So
00:26:23.560 this wasn't in a controlled trial. This is sampling people taking psychedelics in any kind
00:26:28.940 of context. In the controlled trials, we actually screen those individuals out. So this field could
00:26:35.620 be accused, I think, fairly for cherry picking more resilient populations. So we screen out
00:26:46.100 people with a history of psychotic illness. In that same study, people with a history of say
00:26:50.900 schizophrenia, they were twice as likely to fall into that bottom margin than everyone else. So
00:26:57.120 personality disorder, which is quite close to psychosis, is sometimes called borderline
00:27:02.980 personality disorder. And that borderline means sort of borderline psychotic, some divorcement
00:27:09.580 from reality close to, to being, you know, diagnosed psychotic. So that's, that's the
00:27:16.380 vulnerability space. And that's where we have to be especially careful. And we are in the trials,
00:27:21.260 but by doing that, we've arguably, and I think fairly cherry picked this sample and, um, of
00:27:29.960 the more resilient types. It's funny. It's not funny, but it's sort of ironic to say that about
00:27:35.740 something like depression, but it's a certain kind of depression that doesn't have, say,
00:27:40.320 psychotic features or features of personality disorder, this special volatility.
00:27:46.420 Would you say that the same contraindications apply for MDMA, or is that not an issue with
00:27:54.840 a propensity toward psychosis or something like borderline or any of the other clinical
00:28:02.960 conditions or risks you're talking about having a first order relative with with one of these
00:28:07.880 conditions do you think mdma poses similar or or any uh risk i think it poses some risk everything
00:28:15.800 does but maybe it's more resilient to context mdma somewhat is less of a heaven and hell that
00:28:25.340 you get with the classic psychedelics lsd psilocybin ayahuasca dmt you know you can take
00:28:31.920 mdma at a rave and have a very good time quite reliably you take lsd and it's much more
00:28:38.240 unpredictable it doesn't seem to be a distortion of cognition and perception in the same way with
00:28:44.960 no it's it's subtle yeah subtle shift in perception maybe a softening maybe a softening of ego you
00:28:54.360 might say whereas the classic psychedelics are called ego dissolvers or disintegrators
00:28:59.480 Yeah, people like to say that MDMA is a heart opener rather than a head opener. So it promotes relational exchange, 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.
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00:29:31.900 Improvements in well-being, life satisfaction, sense of meaning in life.
00:29:37.000 I'm worthless. Life is pointless. It's all pointless.
00:29:41.240 I'm more valuable in the world if I'm skinny.
00:29:44.100 And psychedelics seem to be like a heat-seeking missile for that kind of self-generated BS, as I call it.
00:29:52.860 Thank you.