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00:00:22.960i am here with robin carhart harris robin thanks for joining me again thanks for having me on so
00:00:29.940remind people where you are doing your research on psychedelics.
00:00:35.140I'm at the University of California, San Francisco. I have my lab there.
00:00:39.300And what's the focus of your research at this point?
00:00:41.540It's consciousness science and how it's encoded in brain activity. That's a big part of it.
00:00:46.720How can we use psychedelics to try and tackle that question? And it translates into therapeutic
00:00:53.700applications of psychedelics as well. I also look at harms. Yeah, so try and cover the
00:00:59.940much of the sort of full gamut of psychedelic science and research.
00:01:04.600Yeah, well, I want to get into all of that. I guess, big picture to start. What are your
00:01:09.040impressions of the state of the field at this point? Where are we with research on psychedelics
00:01:15.700and therapeutic potential and safety? And I mean, how vulnerable are we to having the rug pulled
00:01:22.400out from under all of this by some new regime of there being a war on drugs? I mean, what's your
00:01:29.140perception of the field, high level? Well, it's rich and complex. We rode a wave through a kind
00:01:37.280of peak of a hype cycle, perhaps after Michael Pollan's bestseller, How to Change Your Mind,
00:01:43.160published in 2018. And yeah, there was a period of some correction, you might say. There was a bit of
00:01:49.360a pushback on this space for different reasons. And I think there was a market correction as well.
00:01:55.460some of the psychedelic medicine companies had gone up to a pretty high valuation, a couple of
00:02:01.140billion dollars, I think, one of them. And they're certainly not there now. So something's happened.
00:02:07.440We had Lycos seemingly close to getting FDA approval for MDMA therapy for post-traumatic
00:02:15.380stress disorder, but that was denied by the regulators, by the FDA. And so that put another
00:02:21.180of the dent in the road. I do think that there are reasons to be optimistic, though. If you look
00:02:27.040at the research, there's a heck of a lot of research. I mean, there's more than ever. The
00:02:31.720publication, you know, rate and volume is higher than ever year on year. And, you know, more quality
00:02:39.480trials, bigger trials. So I still feel that, yeah, we're knocking on the door. If FDA approval is the
00:02:47.900prime milestone, I still think that that's achievable and probably quite close.
00:02:54.020Yeah. So what's your sense of all of the research to date that we're relying on to
00:03:00.780kind of organize our intuitions about the therapeutic value of psychedelics? I mean,
00:03:05.420much of it, I think, is probably underpowered and many things probably haven't been replicated.
00:03:12.260There'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?
00:03:39.140Well, 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.
00:04:01.540so not an industry-sponsored study or trial. You've got a limited budget, and you set something
00:04:09.400up, and it's 20 patients, and you kind of sow the seed. And so that's what we did back in 2016 with
00:04:16.760psilocybin therapy for treatment-resistant depression. So most of the trials in this
00:04:23.420modern era have been published in the last 20 years. Really, the first clinical trial in the
00:04:29.920clinical population was 2006. That was Francesco Moreno looking at psilocybin for obsessive
00:04:37.020compulsive disorder. And yeah, so there are probably now, I would estimate a couple of dozen
00:04:45.200small trials and a couple of biggies, you know. We've got the phase 2b work of Compass Pathways,
00:04:54.020And we're also hearing the top-line findings from their phase three works.
00:04:59.360So that takes us into the hundreds in a single trial, albeit multi-site.
00:11:41.220And it gets enhanced in its emotionally evocative, yeah, its properties.
00:11:48.020And we control and manipulate the quality of the aesthetics.
00:11:52.560So in what we call this enriched condition, we have an enriched condition with all these
00:11:58.240psychedelic therapy elements included and we have an unenriched condition with them stripped out
00:12:03.640so there's no music the sessions are staffed but really for basic safety monitoring not for any
00:12:10.940kind of active emotional support unless there's an emergency i mean we're guided by do no harm of
00:12:17.520course and uh yeah we control the aesthetic so in the enriched there's lovely glowing lighting and
00:12:24.360printed screens of beautiful nature scenes. And then in the unenriched, it's a standard
00:12:29.780consulting room in a clinical research unit. All of this suggests that there's a fair amount
00:12:36.320to get right or wrong with respect to how one promotes people into the role of being a therapist,
00:12:43.980right? So I'm wondering about just kind of quality control there and screening and supervision and
00:12:49.760training. And I'm thinking of one story I heard of someone who I think was in a group setting.
00:12:55.840I don't even know what the compound was. It might've been psilocybin. It might've been ayahuasca.
00:13:00.080But somebody in the setting was feeling like they were remembering childhood sexual abuse,
00:13:07.060I think, some trauma from childhood that had not been conscious prior to taking the drug.
00:13:12.640But they were also uncertain as to whether it was a memory or whether they were just imagining it.
00:13:16.920And 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.
00:13:41.920And 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.
00:14:06.480I 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.
00:14:35.020what are your thoughts about quality control with respect to therapists and just how we can
00:14:40.220build a culture that does no harm while giving people the support that they need?
00:14:46.600Yeah, it's a biggie. It's certainly a biggie. So not knowing the specifics of that case, but
00:14:51.800responding to how you relay it, it sounds like bad practice in terms of a therapist coming in
00:14:59.460and transferring, in a sense, their assumptions, their beliefs, their perspective onto, you know,
00:15:05.840the tender, opened heart of a vulnerable individual. Cases of alleged recovered memory
00:15:15.620in this space are prevalent. It's happened in our trials. It's happened in other major sites.
00:15:22.780Hopkins, I know they've had this. Let me just be clear on one thing,
00:15:26.820lest I be misunderstood. I don't think this never happens or is never, in fact, veridical,
00:15:31.880right? I think it's possible to remember something for the first time that you experienced in early
00:15:37.600childhood. And I'm not fundamentally skeptical about every story, but I just know that this
00:15:43.320mechanism or imagined mechanism has been abused by, certainly by the hypnosis community back in
00:15:49.980the day. And I worry that psychedelics could be hypnosis on steroids. I worry too. And I
00:15:56.760think there's an angle here from you know legal professionals seeing an opportunity and I think
00:16:04.460that's a problem a future problem that will will clash into at some point but yes it comes up and
00:16:12.220I treat it in that way you know we we go case by case and we've had to manage patients uncertain
00:16:21.680about a recovered memory. I remember one in particular, he's spoken openly about it,
00:16:27.760where he was confused about whether one of his parents had tried to smother him and kill him
00:16:34.900with a pillow. And yeah, we had to hold that very lightly in terms of its radicality or otherwise.
00:16:42.160And that was hard for him. He wanted some kind of closure there. He had classic ambivalence
00:16:48.240about this parental figure projected for a while that they were all good and then had this jarring
00:16:55.700challenge to that come up as a apparent or possible recovered memory. And so what happened
00:17:03.080there is that there was extended therapy for that case. When you look at its data, it actually sticks
00:17:08.060out like a sore thumb in our trial. It was our first psilocybin therapy for treatment-resistant
00:17:13.540depression trial. And you can see there's a clinically meaningful increase in symptom
00:17:18.540severity. He's the only one who showed that in two or three weeks after the treatment.
00:17:23.440So we had to manage this turbulence that he was going through where he was uncertain
00:17:28.560as to whether this happened or not. And we had to be very, very careful and professional not to
00:17:34.500either endorse or deny, but rather just listen compassionately. And so if it's there as something
00:17:42.680imagined, that's something to work with therapeutically. If it really happened,
00:17:47.320that's something to work with therapeutically. But let's not make a call on its radicality.
00:17:53.860I will add, though, that there was another case where the abuse was known ahead of time.
00:17:59.800It had actually been a case against this, again, a parental figure of father,
00:18:05.980and it was sexual abuse, and he was convicted. And so this was the trauma that this patient
00:18:11.120brought in to the session, treatment-resistant depression again. And so we certainly didn't
00:18:17.880guide him there at all. As I said, the therapy and the sessions is very hands-off. It's not
00:18:24.600directive in terms of talking at all. But he went there and he expressed to his therapist that
00:18:32.500i can see my father abusing me and so there the approach the response from the therapist and one
00:18:41.440in particular was to gently suggest the going towards okay let's stay with that a while if you
00:18:48.160can is this on psilocybin or psilocybin high dose psilocybin very very painful for for him for the
00:18:56.020patient but he did and and the abuser was manifest as a monster with a gun you know that might be
00:19:05.860seen as symbolic and uh and incredibly menacing terrifying and then staying with this vision0.85
00:19:13.980with the support it morphed and it morphed into something pathetic almost pitiful and there was
00:19:22.480almost some forgiveness and i'm sort of echoing the patient the patient's words here um forgiveness0.89
00:19:29.940might be too much to say that but an understanding of sort of the pathetic you know weak nature of
00:19:38.720of the abuser and how they could have done something like this and it was a breakthrough
00:19:45.640at the time there was a lot of tears there were there were you know sort of wet eyes with everyone
00:19:51.380in the room really and uh yeah it it was considered very beneficial to the patient to go through that
00:19:59.380that experience yeah i mean so you're you're painting a picture of the obviously the other
00:20:03.880side of this therapy question which is i mean it has to be tremendously rewarding to be a therapist
00:20:10.580under these conditions where you're seeing people basically do you know you know decades worth of
00:20:17.600psychological work over the course of hours. I mean, this is not the normal experience of
00:20:23.760talk therapy where you can have a conversation with someone for 20 years and basically you're
00:20:27.600talking to the same person 20 years later. It has to be very rewarding in success.
00:20:33.200What do we know about people for whom psychedelics hold obvious therapeutic promise and people who
00:20:42.340should stay away? I mean, what are the exclusion criteria and contraindications you're working
00:20:46.560with in research, and what do you think is just a ground truth insofar as we understand it for
00:20:51.580people out there in the public who probably shouldn't take any of these drugs? You might
00:20:57.400want to differentiate the various classes of drugs or specific compounds with respect to risk, but
00:21:02.880what's your view of who benefits and who is courting obvious harm? Sure, yeah, well, I can
00:21:10.260respond to that empirically. While it's true that most of the studies that have been done are small,
00:21:16.560There 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.
00:21:45.520so for me that's quite telling very telling so very consistent positive results just to explain
00:21:51.180why you would expect that i mean an mr scanner in terms of setting is aesthetically pretty awful
00:21:58.040setting i mean it's if you're claustrophobic at all you're going to freak out and it's also loud
00:22:03.020and yeah you can't move in fact because you can't get data on someone who's moving so it's just
00:22:08.080it's i mean there are a lot of people who are not on drugs who can't get scanned in uh an mri
00:22:14.480machine and many people who can only, if they take, you know, benzodiazepam to lower their
00:22:21.240anxiety, you know. And then that's a big confound, of course, isn't it? Yeah. So, yeah, it's not the
00:22:26.900best set and setting. It can be tolerated. I've done a lot of work putting people in scanners and
00:22:31.760giving them high doses of psychedelics, but there's a way to do it. And, you know, it's not
00:22:36.780an optimal set and setting. It's not an optimal context. It's not obviously therapeutically
00:22:41.020supportive there's no music listening that i'm aware of that they experience so yeah it's very
00:22:47.480very noisy claustrophobic and all the things you say so you know looking at the results at that
00:22:52.880high level all of these depression trials now there's a couple of eating disorder trials we've
00:22:58.320got one coming out very soon looking at psilocybin therapy for anorexia that reports positive
00:23:04.260results, obsessive compulsive disorder. If we're including MDMA, the PTSD results are very
00:23:10.900promising, very large positive effect sizes there. There are anxiety disorders. There's a phase three
00:23:18.600trial LSD therapy for general anxiety disorder. There are addiction disorders, alcohol use
00:23:26.000disorder, opiate use disorder, cocaine out of Alabama. There's a lot, and I'll be missing
00:23:34.820things. And there's also the weight of evidence in favor of betterment of well people or the
00:23:41.780worried well, if you want. So improvements in well-being, life satisfaction, sense of meaning
00:23:47.440in life, flourishing, these positive psychology domains, that's very reliable as well. And also
00:23:55.420So in a mixed methods approach, and what do I mean by that?
00:23:59.060So surveying people taking psychedelics in the wild, as we say, meaning in every kind
00:24:04.700of context, they could be a burning man, they could be in their bedroom, they could have
00:24:09.260gone off to Oregon to have legal adult supervised psilocybin experiences, we've looked at that
00:24:16.520But, you know, across those different contexts, when we pull the data, very positive results
00:24:23.140there as well so yeah so most people is is the short answer seem to benefit but not everyone
00:24:32.560so then the critical question is where is this bottom margin you know who falls into that
00:24:38.960who's at special risk who's a risk of being a you know in that outlier bracket where they
00:24:46.120don't improve and if if anything they get worse where could this be iatrogenic you know as as
00:24:52.420they say, meaning it actually worsens your health. And there we have found empirically that people
00:25:00.540with a history of a diagnosis, I'm being very concrete here, but history of a diagnosis of a
00:25:06.980personality disorder. And what is that? Well, it's an emotional volatility can come in different
00:25:14.800forms, but it can be a sort of histrionic character presentation, very volatile, very
00:25:21.560splitty, as we would say in psychology, meaning jumping from positive projection, everything is
00:25:27.940good, or this person is all good, entirely flawless, to this one is all bad and entirely
00:25:33.620malevolent, you know, quite irrational. But people do that, they make the world black and white.
00:25:39.620And that kind of psychological volatility is a risk factor. We actually found that people with
00:25:46.980that history were four times more likely to fall into a bottom margin in our grouped data so they
00:25:55.520were the worst cases and another bit of detail that that group actually did okay numerically
00:26:03.020a very slight improvement in well-being in in the short period after the experience but then they
00:26:10.440fell off a cliff so to speak then they further out they they showed a clinically meaningful
00:26:16.740worsening in their mental health. And these were individuals taking psychedelics in the wild. So
00:26:23.560this wasn't in a controlled trial. This is sampling people taking psychedelics in any kind
00:26:28.940of context. In the controlled trials, we actually screen those individuals out. So this field could
00:26:35.620be accused, I think, fairly for cherry picking more resilient populations. So we screen out
00:26:46.100people with a history of psychotic illness. In that same study, people with a history of say
00:26:50.900schizophrenia, they were twice as likely to fall into that bottom margin than everyone else. So
00:26:57.120personality disorder, which is quite close to psychosis, is sometimes called borderline
00:27:02.980personality disorder. And that borderline means sort of borderline psychotic, some divorcement
00:27:09.580from reality close to, to being, you know, diagnosed psychotic. So that's, that's the
00:27:16.380vulnerability space. And that's where we have to be especially careful. And we are in the trials,
00:27:21.260but by doing that, we've arguably, and I think fairly cherry picked this sample and, um, of
00:27:29.960the more resilient types. It's funny. It's not funny, but it's sort of ironic to say that about
00:27:35.740something like depression, but it's a certain kind of depression that doesn't have, say,
00:27:40.320psychotic features or features of personality disorder, this special volatility.
00:27:46.420Would you say that the same contraindications apply for MDMA, or is that not an issue with
00:27:54.840a propensity toward psychosis or something like borderline or any of the other clinical
00:28:02.960conditions or risks you're talking about having a first order relative with with one of these
00:28:07.880conditions do you think mdma poses similar or or any uh risk i think it poses some risk everything
00:28:15.800does but maybe it's more resilient to context mdma somewhat is less of a heaven and hell that
00:28:25.340you get with the classic psychedelics lsd psilocybin ayahuasca dmt you know you can take
00:28:31.920mdma at a rave and have a very good time quite reliably you take lsd and it's much more
00:28:38.240unpredictable it doesn't seem to be a distortion of cognition and perception in the same way with
00:28:44.960no it's it's subtle yeah subtle shift in perception maybe a softening maybe a softening of ego you
00:28:54.360might say whereas the classic psychedelics are called ego dissolvers or disintegrators
00:28:59.480Yeah, 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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00:29:31.900Improvements in well-being, life satisfaction, sense of meaning in life.
00:29:37.000I'm worthless. Life is pointless. It's all pointless.
00:29:41.240I'm more valuable in the world if I'm skinny.
00:29:44.100And psychedelics seem to be like a heat-seeking missile for that kind of self-generated BS, as I call it.