#478 — The Psychedelic Mind

[MUSIC] You're listening to Making Sense with Sam Harris. This is the free version of the podcast, so you'll only hear the first part of today's conversation. If you want the full episode and every episode, you can subscribe at samherris.org. There are no ads on this show. It runs entirely on subscriber support. If you enjoy what we're doing here and find it valuable, please consider subscribing today. I am here with Robin Carrhard 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. What's the focus of your research at this point? It's conscious in the 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. 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? 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 peak of a hype cycle, perhaps after Michael Pollan's best seller, 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. 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 like us, 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 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 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 your sort of 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 or likely to hurl in the near future? So as to argue for the therapeutic value and legalization? Well, there's a lot of small studies published. You know, a few of them have come from myself and my colleagues. 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 an 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 Salasibin therapy for treatment-resistant depression. So most of the trials have 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 Salasibin for obsessive-compulsive disorder. And yeah, so they're 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 3 works. So that takes us into the hundreds in a single trial or be it multi-side. Which are these for Salasibin or- This is Salasibin 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 they're 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 of it, you know, rising tide for everyone in this space. Yeah, so it's- were the reasons for it intelligible and justifiable or- 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, multi-disciplinary association of psychedelic studies headed up by Rick Doblin. And maps is, in a sense, a advocacy group for psychedelics generally. Now, 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 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, there are a regulatory body that approved drugs, drugs as medicines. And so they want to be able to look at the profile of the 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 Solace Ivan 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 therapist 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 in the essential importance of context. So, you know, I'm very out there on this perspective. 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. 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 of 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 set in what what are you controlling? So it is more really this what the staff do the quality of their preparation ahead of the 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 psychotherapies, 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 might come the next day, it might come the next week. And you know, 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 asked the question, well, is there any nudging any kind of coaxing going on here? The music can be quite an overwhelming experience. And it gets enhanced in its emotionally evocative properties. And we control and manipulate the quality of the aesthetics. And we have a very important thing 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. And we control the aesthetics of enriched as 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. And I'm wondering about just the quality control there and screening and supervision and training. And I'm thinking of one story I heard of a someone who I think was in a group setting. I don't even know what the compound was. It might have been psilocybin and it might have been ayahuasca. But somebody in the setting was feeling like they were remembering childhood sexual abuse, I think, some trauma from childhood that had not been conscious prior to taking the drug. They were also uncertain as to whether it was a memory or whether they were just imagining it. And the therapist, you know, Tamayir, 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 dogmatism or delusion, because they seem to be coming at this with a very strong sense of recovered memory being 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 shaped 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 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, you know, I am 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. On to, you know, the tender, opened heart of a vulnerable individual cases of alleged recovered memory in this space are prevalent. It's happened in our trials. It's happened in other major sites, hotkins. I know they've had this. Let me just be clear on one thing that lest I be misunderstood. I don't think this never happens or is never in fact, veritical, 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 imagine mechanism has been abused by, certainly by the hypnosis community back in the day. Yeah, 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 problems that will, will clash into at some point. But yes, it comes up and I treated 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 his, 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 its of veriticality 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 parent 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 cell of cyber therapy for treatment resistant depression trial. And you can see as a clinically meaningful increase in symptoms of verity. He's the only one who showed that in two or three weeks after the treatment. 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. So if it's there is something imagined that something to work with therapeutically, if it really happened that something to work with therapeutically, but let's not make a call on its veriticality. I will add though that there was another case where the abuse was known ahead of time that actually being 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 didn't 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 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 amnibis? Yes, 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 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 there. And 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, to 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 and 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 contraindications you're working with in research? And what do you think is just a ground truth and so far 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 were 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 again, this would be in a couple dozen or close to that now and they dose the individual in a MR scanner and there was no psychological support. For me, that's quite telling, very telling. So very consistent, positive results. Just to explain why you would expect that. 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 there are a lot of people who are not on drugs who can't get scanned in an MRI machine and many people who can only if they take benzodiazepam to lower their anxiety. And then that's a big confound of course, isn't it? So yeah, it's not the best setting 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 it's not an optimal 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 yeah, 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 cellosybin therapy for anorexia that reports positive results. Oh, obsessive compulsive disorder. People are including MDMA, the PTSD results are very promising, very large positive effect sizes there. There are anxiety disorders. There's a face retrial LSD therapy for general anxiety disorder. There are addiction disorders, alcohol use disorder, opiate use disorder, cocaine out of Alabama. 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, 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 cellosybin 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 at risk of being at, you know, in that outlier bracket where they don't improve and if anything, they get worse. Where could this be? Iatrogenic, 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 and been 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, a very volatile, very splity 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 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 would 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. We are in the trials, but by doing that, we've arguably, 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. What would you say that the same contraindications apply to Fremdia, or is that not an issue with it, like the 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 you pose as some risk. Everything does. But maybe it's more resilient to context than the may somewhat is less of a heaven and hell that you get with a 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 MDMA. 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, social exchange. It's easier to open up with people. You can talk more easily on MDMA versus a classic psychedelic like LSD. You can do some more conventional talk therapy. Members can hear the full conversation by subscribing at samherst.org. Subscribers get a private RSS feed. You can use it with your favorite podcast player.