Mind & Matter
Mind & Matter
Anesthesia, Placebo Effects, Consciousness, Subjectivity, MDMA, Ketamine, Opioids, Psychedelics | Boris Heifets | #163

Anesthesia, Placebo Effects, Consciousness, Subjectivity, MDMA, Ketamine, Opioids, Psychedelics | Boris Heifets | #163

Download, watch, read or listen to M&M episode #163

About the guest: Boris Heifets, MD, PhD is an anesthesiologist and researcher at Stanford University. His lab studies non-ordinary states of consciousness and psychoactive drugs like MDMA, ketamine, and psychedelics.

Episode summary: Nick and Dr. Heifets discuss: anesthesia and how anesthetics work; placebo effects & expectations in clinical research; ketamine as an antidepressant, anesthetic, and recreational drug; the subjective effects of psychedelics and other drugs; MDMA and Lykos Therapeutics’ attempts to gain FDA approval for MDMA-assisted psychotherapy; opioids & placebo effects; and more.

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*This content is never meant to serve as medical advice.


Full AI-generated transcript below. Beware of typos & mistranslations!

Boris Heifets 2:24

Beautiful sunny Palo Alto, California Stanford University. I'm an anesthesiologist. At least the day a week, I see patients and the rest of my time is spent doing research into non ordinary states of consciousness including anesthesia and psychedelics as a major focus of my lab we do human and animal studies trying to understand how they work.

Nick Jikomes 2:50

Okay, so you you put people under you're in the operating room putting putting them to sleep,

Boris Heifets 2:55

and then waking them up. That's the most important part actually. Yeah,

Nick Jikomes 3:00

I mean, speaking of sleep, how, how is or isn't anesthesia like sleep? Is it very similar? Or is it a distinct brain state completely? It is, if

Boris Heifets 3:09

you want to piss off a bunch of sleep specialists, you can tell them that, oh, that this anesthetic is just like chemical sleep. That's they, they don't like that. And they're right, that there, there are some similarities. And as you go through there, there's depth to anesthesia. As you might imagine, it's not a straight line necessarily. But as you get deeper as the doses of anesthetic go up, you pass through some sleep like stages on your way down, and of course on your way back up. But where we get to for surgery, as you might imagine, is state of arousal ability, where you have no memory formation, no conscious awareness that we know of immobility and hypnosis. So those are, that's a much, much deeper state of consciousness, and the EEG looks radically different from what you would see during REM sleep. I

Nick Jikomes 4:09

see. And so how does it compare just at a high level, the EEG signature, so

Boris Heifets 4:14

it's much, much simpler. So what was interesting about sleep, and there's a lot to say about this, but asleep, you know, they're asleep has an architecture is, is ancient. It's an every species that we now have, and you cycle through through different stages. And when you put someone into an SSI state, which we do regularly millions of times across the country every day, maybe not millions, but what you see is a much more organized rhythm and it's a really simple rhythm like the standard we actually have monitors that are built for monitoring depth of anesthesia using EEG and what they're targeting, you know, the like the good number is our describe a pattern that when I talk to residents and teach, basically explain like this, if a five year old kid could draw it, the patient is surgically anesthetized. And that's because it's so simple and loopy. And there isn't a whole lot of spatial complexity in the signal. And that's sort of what I, one way of thinking of what's going on in the brain is this, the soup is being kept warm by these blammo cortical rhythms, and there isn't a whole lot of information being processed, and there isn't a lot of informational content in that EG, the more you know, as you get to later stages of anesthesia, and eventually, wakefulness, all of that sensory information, the you know, chaotic noise of, of, you know, the, the smelly, tasty, you know, touching world, all of that comes in and that actually that that complexity is reflected in the complexity of the EEG rhythms and much more complicated rhythms, much finer detail. And so that's it's a, it's a simplistic way of thinking about it. But actually anesthesia and static EEG is, is simple at its base. So that's how you know that you're doing a your job and keeping the patient under.

Nick Jikomes 6:15

I see I see. So, I mean, roughly speaking, if, from a naive standpoint, we don't know anything about anesthesia, but you do know the basics of sleep architecture, you've got non REM sleep, stage, 1234, you got REM sleep, non REM sleep is when you've got these large, slow waves that you see in the EEG signature, is are you seeing large slow waves akin to that in anesthesia, even if they're not the same frequency? Or is it completely completely different?

Boris Heifets 6:42

No, you still you still have those large, slow waves, but you don't. A typical typical thing that you see during sleep, and there's another rhythm is called an alpha rhythm. And this will come up again, that is very prominent during during general anesthesia and not so much during during normal sleep. So this is something that happens when you close your eyes, you can see prominent Alpha rhythm and your occipital cortex, which is where your vision is processed. So you can make that link between the eyes closed. And suddenly there's no external sensory input. So it kind of defaults to this rhythm went in, during general anesthesia, your moat, like anywhere you look in the brain is going to have that strong Alpha rhythm. That's not something that you typically see during

Nick Jikomes 7:36

I see. And so obviously, people are unresponsive during anesthesia. And if they're in deep anesthesia, we presume that there's no conscious awareness at all. And then there's this this component of amnesia. My understanding is that when people come out of anesthesia, depending on the anesthetic, depending on the depth, there's going to be some time that they can't remember even after they start to come out of it, or when memory formation has impaired. Thinking about conscious awareness versus memory formation impairment. How do we know that mean? Is it possible that there is some level of basic awareness even in deep anesthesia? It's just that memories can't form of it, and so people don't report it?

Boris Heifets 8:19

Yeah, that's sort of a terrifying philosophical concept of like, what if you did experience everything during anesthesia, you just couldn't remember it. And you just sort of it's like, there's a black mirror aspect of that. And, you know, I think, conceptually, like, you can't, you can't know that for sure. But what you know, is the incidence of awareness under general anesthesia, which is about one in 1000. And it doesn't seem to be something that you can prevent by monitoring EEG. So to say that we know why it happens. It's actually not clear either, which is a little, you know, a little disturbing, but it is very rare. And when I say awareness, I'm talking about anything like, you know, sights, sounds that necessarily pain and like feeling like you're getting cut into, which would honestly be terrifying is extraordinarily rare, where you have like full awareness of sensory perception under anesthesia. But, yeah, so there's it like back when anesthesia was being developed. And these concepts were being worked out. People actually drew a distinction. So we stopped using the word pain. Right? So there's to talk about a patient who's anesthetized, is the patient in pain. Sounds like a reasonable question when you're getting, you know, a scalpel put to you. But technically pain is a conscious process, right? And these patients are unconscious, they have no recollection of it, they still can have a physiological response, tearing, heart rate elevation, but um If you wake them up afterwards, they'll have no recollection of obviously may still be in pain. But they won't have recall of the actual traumatic event. The other thing that sort of happened with the language is that we started using this term nociception. That's right. It's which is the idea that signals can get through, but they don't integrate, they don't integrate into conscious awareness. And you can see that actually in a number in a number of ways. So one of the things so I do anesthesia for neurological surgery, so things like aneurysm, cerebral vascular aneurysm repair, a number of other things tumors, and one of the things that we do is we monitor cortical function, we want to make sure that patients aren't having a stroke, but they're not impinging on something important. And we do something called somatosensory evoked potentials, meaning you just stimulate a nerve like your tibial nerve or radial nerve, and you can get mixed sensory motor response. And you can actually track that impulse as it goes all the way up. And you can eventually see it in your cortex. So you can see that the signal is clearly getting through there is a sensory signal that's traveling from one periphery, to the center, you can see it visual evoked potential. And if you flashlight, you'll see things going off in the accipiter cortex, even under anesthesia, brainstem, auditory evoked potentials, all these things are actually routine, things that we do to make to monitor the integrity of the nervous system to, which means that the information is getting through what's not happening is that mysterious process of integrating it into conscious awareness. And that is still very much. That's just kind of the the edge of, of science right now is understanding how that happens. And what that what that consists of.

Nick Jikomes 11:58

So it basically I think, it sounds like we understand, you know, we take in information from our sensory organs, we know that that information goes up to our sensory areas of our brain. And then it goes elsewhere in the brain, it gets combined and integrated and stuff happens to it, it's processed before it comes into our conscious awareness. And we sort of know at that level that happens, we don't actually know what that integration process looks like, exactly, we

Boris Heifets 12:24

can get some clues. And I'll point to work at the University of Michigan. But I like in particular, looking at EEG and anesthetic states, George misure is one of my my favorite researchers over there and former head of the department, but you can look at cortical organization, right? So how does inflammation move locally and globally, during anesthesia that you see a lot of change basically, in the architecture of these these cortical modules. So you can see a lot less complexity and local correlations in activity that seem to relate to depth depth of anesthesia. So again, it's this idea that you're disrupting these local and long range interactions. And that's probably related those kinds of interactions. That's probably what integration consists of. And the thing that we call consciousness is, I would say, very likely to be the result of all of those, that those inner, inner connected pieces of your cortex talking to each other in real time.

Nick Jikomes 13:35

Yeah, I mean, it makes intuitive sense. Because, you know, very, very roughly speaking, right, like we, we have a sense of touch, we have, you know, we have our eyeballs, we have our ears, we have all these different streams of information. But we don't, we don't consciously perceive all these things separately, we have this one unified scene from moment to moment. So at some sense, all of these different channels have to be literally integrated together somehow so that we have that unified perception.

Boris Heifets 14:03

Yeah, that's that that is that is the mystery. There's a lot. This is actually one of the reasons why I stopped studying consciousness very early on, it's because it seemed like one of those insolvable not in solvable, but almost like philosophical questions that could come to any number of conclusions that are essentially not testable or very difficult to test. And there's been a lot of, I guess, progress in the field of consciousness studies over the last 20 years, that now we're, I think we're starting to get somewhere but very early on, I realized that the way that I like to think about these problems and kind of attack them is more of like an engineering point of view that maybe I'm not going to understand how the system works, but they at least move it predictably by doing stuff at it. So drugs, electricity, you know, non ordinary states of consciousness, how can you put these things together in a predictable way to get an outcome, whether that outcome be a particular state of consciousness, dreaming or mental health outcome or a transformational experience? And that is some of the most exciting things that I've seen going on in kind of the mental health revolution that we're, I hope, I think in the midst of right now.

Nick Jikomes 15:32

So there's probably, I would imagine a large number of anesthetics, there's certainly multiple to choose from, can you give us a sense for how as an anesthesia, anesthesiologist, you choose what anesthetic to use for a given application.

Boris Heifets 15:49

The one that I know for 100% certainly is going to get into the patient, no mistakes there. And the one that makes people not want to throw up afterwards and then actually live it's our choices to a very, my favorite anesthetic is a combination anesthetic. So it's Siva flooring, which is a gas that you breathe in. One of the honestly the coolest things about anesthesia, people are saying, we don't really know how anesthesia works. And it's like true, we don't really know anything works. But one thing we do know is that things like C before and ISO, flooring, ether, and these are all kind of related molecules work across just shockingly well across the entire animal kingdom. Now, even plants, you can mess the ties of plants, water, which is kind of messed up. And it's you know, that that raises a whole different set of philosophical issues, I guess. But the point is, it's a very old and deep process, you know, these are molecules that are related to things that aren't good bacteria will probably secreting into their environment to silence the local competition. You know, that's that they're not really complex molecules. So that's, that's my, the first. My first stop is the gas Siva Floyd. If you breathe it in, you breathe it out, I noticed getting in and it's extremely effective. And the dose is basically is very predictable from patient to patient. Now there are problems with it, and that people can sometimes wake up a little bit delirious that takes a while to wash out. And you know, one of the least fun aspects of surgery and anesthesia is the nausea afterwards, which, you know, I've experienced it, I've seen it, it's not something that I particularly look forward to. So the other drug that we add is a drug called propofol made famous, unfortunately by Michael Jackson, but it's been around for about 30 years now, it is extremely safe. And it's one of the most widely used drugs and anesthesia doesn't cause nausea. It's hypnotic, it doesn't really treat pain, you need a different group of drugs for that, but it's a hypnotic agent that causes loss of consciousness very reliably. And the thing that I like about it is it comes on and it comes off very quickly. So older anesthetics, the problems were, you know, even interfere with your heart rate, your blood pressure would cause liver kidney issues, it would take forever to wash out. This is really what modern anesthesia has done very well as turned anesthesia from something that is frankly, scary at night and the 80s. You know, there's a 2020 You remember that show? I think it's still on a show where they said something like one in one in 500 patients will wake up from anesthesia, which is like a scary, crazy thing. That honestly, I don't think the numbers are quite that high. But it was dangerous. In the intervening 34 years, a lot of changes have happened to make anesthesia, the I think the safest specialty in medicine, in that, you know, now we can monitor patients who are unconscious with great precision. There's, again, a really good safety record, the drugs have improved. Anyway, that's not that's actually what relates to something I think we're gonna talk about later, which is that the, you know, the, because of these improvements in safety, because now we operate on sicker patients, because we can now you know, anesthetize parts of your body and keep your your brain intact. That's open to a lot of doors in terms of the variety of, of anesthetic states that we see on a regular basis and it led to some very surprising observations that you know, they will talk about a bit like in particular dreaming and related related phenomenon.

Nick Jikomes 19:58

So, whether it's pro Before whether it's some of these gases that you mentioned, what are the mechanisms of action here? Do they very distinct mechanisms of action between these drugs? Or are they similar to one another?

Boris Heifets 20:09

So they're, they're different. And each there's other classes of drugs like dexmedetomidine, for example, that have very specific targets that that case an alpha to Adreno receptor, which basically suppresses all of your sympathetic outflow and really puts you that's as close as we get to like chemical sleep like I get it as dexmedetomidine. But these other drugs, protocols and flooring, they're pretty dirty. In fact, as a general theme, but my experience in psychopharmacology has been that the dirtier drugs are the more effective drugs ketamine is another example that can be used for general anesthesia is fantastically profligate in the number of receptors that it seems to hit. Yeah,

Nick Jikomes 20:59

just just for listeners. That's what you mean by dirty they interact with many different receptors. Yes,

Boris Heifets 21:03

sorry. That's it's not a quick clean drug is one that we think of as has a very simple clear mechanism of action, it binds at one receptor, Siva fluorine, for example, isoform will bind their binding sites to GABA receptors, ion channels, voltage gated calcium channels, presynaptic release machinery, like there's all kinds of ways in which it slows down neural transmission and may lead to the unconscious state. The GABA receptors, really that is the main inhibitory receptor, or the main receptor for the inhibitory neurotransmitter GABA in the brain, so what we're doing is we're basically turning off the inhibition in your brain with drugs like propofol, or see the flooring feed of barbed pentobarbital falls in that same category. Until you basically suppress all activity, and your brain goes quiet and you stop flowing memories stop perceiving any entity outside of you.

Nick Jikomes 22:06

Do so by their very nature, right? They're having a profound effect on consciousness. So there and then apparently, these are dirty drugs with so they have many parts and little widgets in the brain that they interact with. Do they have any lasting effects? Do they have any effects beyond the anesthesia itself? So for example, do people who come out of surgery ever report mood changes or improvements in symptoms for something else unrelated to the surgery, or changes in personality or anything like that? They sure

Boris Heifets 22:34

do. And it's not consistent. That's that, to me is still one of the enduring mysteries and is that people you talk to any anesthesiologist that and or even, you know, anyone really in medicine, who deals with patients who had surgery, and I guarantee you that everyone will have story about someone who woke up different bet something, you know, better or worse, and both referred both, like there's something called pump head, which is what people said Bill Clinton had after his open heart surgery, there's a pump that used to recirculate your blood while your heart stopped, that can cause some maybe some neurological issues. I'm not going to speculate, but that you know, and people attribute that alternately to the pump in cardiac surgery or the anesthesia, people will sometimes tell me like, I wasn't right for a year, like I couldn't, you know, I couldn't hold the thought together. And, you know, there's, when when you start looking at this in really big numbers, it is very hard to really pin it down to anesthesia. So and that so we're talking really about the the downsides of, of anesthesia that when you look at patients who are for example, in high risk for having cognitive decline, where you would be worried about you know, what's going to happen to my, my grandmother, you know, when she, she undergoes anesthesia, she's going to like, is it going to precipitate some sort of cognitive, further cognitive decline? And this is work from UCSF, but what is amazing to me is really, if you look at the trajectory of these patients over time, why are they having surgery now? Why did someone fall and break their hip? Right? There's overall a pattern that you know, folks are on the down downslope, yet, of course, there's the acute trauma of surgery and anesthesia. But what happens is, once they've recovered from that acute trauma, they basically rejoining a line that was on the way down, so it's very difficult to untangle what what exactly happens. So that's, that's one type of lasting effect that we hear a lot about anesthesia and you hear the same thing at the other extreme, the beige and kids is anesthesia going to cause a cognitive issue in my child, you know, right is they're developing. There's a lot Uh, you know, my brief time in pediatric anesthesia. That was a lot of what the discussions with parents were like. And again, you have to ask this question, why is the child having surgery and less than two years old, like typically there's other comorbid issues that might also affect their cognitive development. So pinning it on the anesthetic is not really that easy. And when you look again at 1000s and 1000s of patients and try and match them with, with controls, you really it is very difficult to pull out in effect of a single anesthetic, sometimes multiple anesthetics. There see, there's a little bit of a signal like the development of Attention Deficit Disorder, later in life, a couple of IQ points, you know, to be honest, if I had to choose between having a hernia repaired, and you know, a couple IQ points, I'd probably want the hernia repaired and I could play sports and whatever. So these are the, these are small, persisting effects, if they're if they're real. Now there's a flip side, which is something I'm, you know, just as if not more interested in is personality changes and transformations once we started, so a lot of the work that I do is really the intersection of mental health and anesthesia. I work closely with psychiatrists, we're looking at drugs like ketamine that are had been repurposed from anesthesia to psychiatry for depression, we're looking at other you know, anesthesia related non ordinary states of consciousness and how they might, we can leverage them for therapy. But as we started doing this work, I started getting emails from, from patients from from all over the country. And some of the stories that are just they're hard to get out of my head, but it's very hard to come up with a systematic explanation for it. This one woman told me that, again, not expecting anything, she's just coming in for carpal tunnel release. This is a minor surgery to have in a you know, on a morning, and you'd be home by for dinner, for lunch even. And she had, you know, just years and years of his voice on her shoulder, you know, this kind of compulsive, compulsive thoughts and just this, you know, this devil devil on his shoulder that made her depressed and generally miserable. Nothing she wasn't diagnosed with schizophrenia or anything, but you know, there's some mix of obsessive compulsive disorder and in depression, and anxiety, and after this carpal tunnel, release this like trivial surgery, she doesn't remember anything about in surgery. But what she remembers is the voice is gone. Like, how on earth does that, does that happen? And so when you start looking for these, like, you'll find lots of stories, but not a lot of consistency.

Nick Jikomes 27:51

So it's not like it's not like all the patients with bipolar disorder who got propofol woke up and they felt better. There's no clear patterns like that.

Boris Heifets 27:59

You know, you got I mean, this. I don't know how many anesthesiologists are gonna listen to this show. Any of them are we have got to stop doing propofol versus see before a 4x like trying to find differences between these anesthetics for any condition is almost like other than Nausea is like, honestly, I think a fool's errand at this point. It is there seems to be very little relationship between the specific anesthetic use at this point in, you know, an anesthesia history. And any of these outcomes, even things like depression, which is something that I'm very interested in most of the data that we have hundreds, maybe 1000s of patients to this point across trials, the dominant effect is that patients are doing worse. They're not they're not improving, you know, in terms of mental health, so there's a lot of interest in repurposing anesthetics to treat mental health disorders like xenon, what's the most exciting new one? That's that has been used. I think Boris Yeltsin had a Xeon anaesthetic most expensive cardiac surgery in the in the world at that point. But the point is that the some of these drugs are being repurposed for their purported mental health benefits. But when you look in surgical patients and surgery and anesthesia, that's not what you see what you see is a big stress event. If we not specifically in terms of mental health and really general health, your body doesn't do well after severe trauma, increased risk of heart attacks, strokes, lung injury, kidney injury, liver injury, cognitive potential cognitive issues, delirium, why would we think depression or mental health would get better afternoon? So that's typically what we see when we look at large numbers of patients. Now that doesn't really address the question of, can we somehow look at anaesthetic a gyms and use them number two, your way to get a mental a better mental health outcome. But that's a different way I think we'll get there but it's a different sort of question, then I'm going to give you this drug and it's going to do this to your brain and your brain is gonna get better and you're not there for it, but you'll be cured. That is very elusive. And I don't know that we found that that bad, magical recipe yet.

Nick Jikomes 30:27

So, one drug that at least has been used for anesthesia in humans, still is in animals, I think more often is ketamine. And people have been talking about ketamine for all sorts of reasons. But let's just start with ketamine as an anesthetic, can you give us a little bit of the history there and talk about the the applications ketamine has as an aesthetic, when do you use it versus other drugs? How's it working, what doses and those things? So

Boris Heifets 30:52

ketamine, ketamine has been around for a while, but 60 years ago, I think it was. It's been in clinical use for about 50 years in the United States, and it was developed for that. It was developed as a better version of PCP things for anesthesia, the things that anesthesiologist in the 50s and 60s liked about PCP was that patients would not react to surgery, but and they would keep breathing. Right. So the the mainstay of anesthesia. And before that is drugs like ether, opioids, all of which would you know, the same time as they suppress and thorium, they also suppress your respiratory drives, and the the absence of a way to monitor your oxygenation, which we didn't have, you know, 1960 that was deadly. So there was a, it was really important to find anesthetic agents that wouldn't suppress your respiratory drive to cardiac output. So PCP actually had a lot of those features in its favor. What people didn't like it about it was the emergence, emergence, delirium. I don't know it wasn't that wasn't coined for PCP, but it was well known that people emerging from PCP anesthesia would have, you know, really delusions, delirium, a lot of agitation, it wasn't, it was kind of, you know, I would imagine, not a lot of fun to deal with. So ketamine was better. Ketamine had less of that it had all of these beneficial features. And

Nick Jikomes 32:27

it was it was engineered people synthesize this, they were trying to make a better anesthetic. Yeah,

Boris Heifets 32:32

that's exactly what happened. Edward Domino is also the University of Michigan. He just died, I think, a couple of years ago, at a ripe old age key to me, actually, that's he called the key to me, but it's a sounds great. So anyway, so, ketamine, so ketamine was initially developed as an improvement on PCP as a surgical anesthetic. You know, the story was, you know, at least from some of the pioneers at Stanford that surgeons thought they could get rid of anesthesiologist because hey, the patient's breathing, we don't need you guys anymore. And so they would do just ketamine anesthesia. And what became very obvious very quickly, is that if ketamine is the only drug you're going to use, it's not going to go that well. Patients still have a lot of these issues with wake up and there's something that I wouldn't I would not call it a joke, but it's sort of could wisdom, nurses wisdom in the recovery area after anesthesia when a patient is not, you know, they're, you know, oh, did he get ketamine? Like, that's a very, that's still the impression even though there may be no statistically visiting, increase the likelihood of delirium after surgery, there's still this general sense that patients aren't quite right for a while when you give them high doses Academy. So ketamine is kind of happily moving along in the 70s and 80s. And it's, you know, finding its place in anesthesia and typically is an adjunct meaning ease, it's ketamine and something else. Ketamine was also an analgesic, right. So it treats pain. That was something that was also recognized very early on in the late 70s. And what you know, one of the other main uses today for ketamine, outside of anesthesia is pain management. So, patients with chronic pain syndromes, they will come into ketamine clinics, for infusions, our hospital Stanford Hospital still will admit patients per five day infusions of ketamine, or refractory complex pain syndrome, since it's typically lower doses than what you would use in psychiatry. But my point is, right. So the big picture is we went from an anesthetic to an analgesic, the 80s and 90s that that was increasingly appreciated. People started realizing that if you give ketamine you need less Oh, Boyd, so called in our textbooks, it's called an opioid sparing analgesic. And that's an interesting, some so interesting further developments that maybe maybe we'll talk about later, but ketamine does interact with the opioid system, it can reverse opioid tolerance. And these things are all like great in the context of surgery and trying to treat pain in the operative theater. So this is all kind of humming along. And then in 2000, there, there was a landmark study from Yale where they were, I think, Bart looking at ketamine in a very different way. They were interested in mimicking psychotic symptoms in schizophrenia, because ketamine, again, like the weird dissociative state that it puts people into your mind it was a group led by John crystal, they they gave a low dose of ketamine slowly, I mean, they went out there from it,

Nick Jikomes 36:03

barely, so you can just keep going anyway, they will

Boris Heifets 36:07

give gave a low dose of ketamine with the idea to minimize those psychotomimetic symptoms. And so they spread it out over 40 minutes that infusion. And what they found was patients felt that their depression is a depressed patients they looked at, and after a single infusion, patient would say, I feel like I haven't felt in a very long time. I actually don't know if they said, just looking at the grasp, but I don't know if patients have said to be advocating infusions. So they will get this Rapid Relief from depressive symptoms and it would last for about a week a single infusion, even though it's cleared from your blood is still exerting effects out to weak and since that paper 24 years ago, I guess there's been a steady growth and recently an explosion in the use of ketamine for mental mental health disorders and it's gone beyond depression. It's being tested for PTSD and alcohol use disorder. Ending number of things. That's kind of a bird's eye it's more than a bird's eye view.

Nick Jikomes 37:12

Yeah. So I have a number of things to talk about. So one question I have about anesthetics generally, but but we can also use ketamine. We can also focus on ketamine because it is becoming more widely used, you know, there's plenty icy ketamine clinics all over now. So there's people going in for, you know, I guess, weekly or even more frequent infusions other than the effects on the brain? Is there any negative consequences to taking ketamine regularly? Does it does it upset your liver or your kidneys or any other organs in the body or anything like that?

Boris Heifets 37:44

Well, unfortunately, yes. So ketamine has a reputation. Ketamine is on the World Health Organization list of essential medicines, that should tell you something, it's up there with like antibiotics and a couple of other things. The fact that Battlefield anesthetic it's an analgesic. And but that, that safety is really based on single dose use as in use in an operation in, you know, in in the field for dealing with acute trauma. We know a lot less about long term safety of ketamine use. What we do know already is a lot of it is actually literature from China. So China, again, there isn't a lot of public knowledge about this. They don't really publish epidemiology of their substance use disorder profile. But there is a lot of murmurs coming out of China over the last 15 years about a raging ketamine abuse epidemic. A lot of look at Yeah, actually, in 2015, China lobbied the WHO to put ketamine in schedule one the most restrictive, no medical use category, to basically halt international traffic of ketamine. Why on earth would they do that with one of the WHO essential medicines? My best guess, and I think was borne out with a lot of writing from that time was that they had a very serious problem with ketamine abuse. It's cheap, it's easy to make. And it's and what shows up in the literature. This is a little bit of a sociology of Sciences. Why is it that what papers out of China about ketamine are all about neurocognitive dysfunction after long term heavy academies? That should be a talent like, I didn't know that was an issue like where are you finding these patients who are using cyllage ketamine, so you couldn't write that paper, you know, 10 years ago in the US because it just wasn't that, you know, you could actually if you went to enough rage, but I it wasn't it wasn't like a, you know, widespread public health issue. So that said, we do know something about ketamine toxicity with prolonged heavy use neurocognitive issues. neurotoxicity. Again, we're talking really high, high dose heavy use. And oftentimes, we don't know what else these folks who are taking bladder issues are a known thing. So there's something called interstitial cystitis. And it can, it's, it typically doesn't occur with a few infusions. And it's actually pretty rare. I mean, we're under percent, but I don't have exact numbers. And it's this is a type of inflammation in your bladder, that it's not an infection. It's, it's, and it may be sort of like an autoimmune type thing. It's incredibly painful, it is very difficult to reverse. And it can lead to things like requiring a bladder replacement, which is like a major quality of life issue. So again, not common, but these are the sorts of things that you wouldn't know, unless you had done epidemiological studies of large patients over long periods of time exposed to varying doses, it doesn't seem to be associated with high doses, in particular, just repeat dosing. There's, you know, liver issues that, you know, again, rare, these things are generally rare. And when, you know, when I talk about risk, I don't want to come off as you know, alarmist or anything like, every drug has risk, this should not be a surprise, any treatment is potent, period, by definition of its potent, it also carries risks somewhere. So it's a matter of balancing, you know, the, it's, you gotta if, if you don't know about the risks, you can't mitigate them, right? So you want to balance the potential good that a drug can be against the potential harm. So these are the main, you know, it's really like bladder, like some brain stuff, and rarely, liver issues surface with heavy ketamine prolonged heavy ketamine.

Nick Jikomes 42:03

And so ketamine effects are highly dose dependent, so that high enough doses, it's anesthetic. And then based on what I know, that's out there, right, you've got the low dose application, which is all the studies being done ketamine for acute depression treatment? And then I guess you would say the medium doses are probably what you see with recreational use, is that accurate? And can you give us a sense for like how big this dose range is, and where you start to draw the line between the anesthetic effects versus the dissociative effects versus the antidepressant effects? So

Boris Heifets 42:33

there's been a lot of work trying to link this is like attention right now the ketamine field like the biomedical model where we're trying to minimize these psychiatric this acute the experience of the drug versus a school that you can call a cat ketamine assisted psychotherapy, where that altered state is actually key to the process of transformation. And I would not say at this point that there's a clear winner here. There's evidence on both sides. But so the dose is, you know, it's, it really really runs the gamut. There are patients who will say that they benefit from very low dose ketamine, most studies will show that you need some unique doses in the range that will produce effects as it like, the patient can feel it, they'll dissociate, they'll get that floaty feeling a little disoriented, maybe they'll you know, get some perspective shifts. That's that's really the you know, antidepressant dose ketamine and what you'll get in a lot of ketamine clinics in community ketamine clinics for depression, that's the starting point, the dosage just go up from there. So you can really have patients if they're not typically like giving an I mean, with extreme exception, I'm hoping most of these clinics are not getting large anesthetic dose, ketamine, what the mail order ketamine doses are like that's really and that's oral, ketamine, sublingual Academy. Those are, those are trip doses, right? So you're getting an effect this would be on par with what we would actually how we would use it with the operating room as an ad. So they're not anesthetic doses. I want to be clear that we use that typically as an adjunct to other anesthetics. But it's the same, it's the same general dose ranges and you will find patients who get tolerant to ketamine and then you have to dose escalate up to but typically the range is half a milligram per kilogram to one or one and a half milligram per kilogram for patients who are experienced in in psychiatry and psychiatric clinics.

Nick Jikomes 44:43

And so you mentioned that a lot of these anesthetics including ketamine, I think are dirty drugs in the sense that they have lots of different mechanisms in the brain that they interact with. So we know that the at least the most famous mechanism that ketamine is known for in the brain is antagonizing the nm da receptor. Two questions I want to ask here, one, to what extent do we know like that is the mechanism or a key mechanism for its therapeutic effects or its anesthetic effects? And then two would be, what are some of the other mechanisms of action that ketamine has that maybe we don't hear about as much.

Boris Heifets 45:20

So the question that NMDA receptor hypothesis has been around really since the inception of cit. It's been around since since ketamine was really appreciated as a treatment in psychiatry, is the NMDA receptor, the thing that makes ketamine antidepressant. If it is, then you would predict that other drugs that target that NMDA receptor would also be anti depressive, and there will be rapid antidepressants. What has panned out and it's been a long time since we found out about Kevin Heath is a graveyard of failed NMDA receptor antagonists. She does trial after trial, lots of different mechanism, different specificities. And you know, you can kind of quibble about details, but by and large lighten it up if that was the magic Academy and why can't we do the same trick twice? So that suggests that, you know, maybe there's something else, something else going on? So, one of the other, you know, well known for the beginning and you know, I hinted at this before ketamine is also an analgesic interacts with the opioid system that can reverse opioid tolerance. How actually does that is still a little bit controversial. But there's been this strain of thought that, you know, ketamine abuse, liability and ketamine, analgesic effects, maybe linked to the opioid receptors somehow. So I'll give Alan chafford credit for this a former chair psychiatry here at Stanford, he was under the impression that you know, people are, I'm going to paraphrase him just getting high. That's really what's going on with ketamine. And it's not an all that's happening is that this is a euphoria. And, and it's, you know, that it's an opioid like effect, and I don't agree with him on that. I didn't to begin with and I don't in the interpretation, but one thing he was right about, which is he predicted that if ketamine works through opioid receptors, you should be able to give someone an opioid receptor blocker and then block the antidepressant effect that ketamine actually, that was totally not going to work in 2016 when we started talking about it, but we did the trial, again, this is empirically testable. This is I think, was a great example. And there were very are still very, very few examples where you do that kind of testing in in mental health testing mechanism. So what do we do so this is a study it was led by Nolan Williams and myself and supervised by by Alan, we got patients with treatment resistant depression. And we had them it was a crossover trial, meaning they would come in they would get their first ketamine infusion, you know, with now trek zone, the opioid blocker or not, and then once they recovered back to baseline, which typically took about a week or two, because ketamine doesn't last forever, they would come back and they would be crossed over to the other trigger. So if you were patient in the study the first time you might get ketamine and do great and then you would come back for the next one. And we would generally expect that ketamine works once it'll work again. The next time though, you get naltrexone before you get ketamine, and what we found on average was that naltrexone completely blocked the antidepressant effects of ketamine. Well, so that

Nick Jikomes 49:01

would mean that so ketamine has this acute antidepressant effect in people with depression. If you give this opioid receptor blocker and then give the ketamine presumably the NMDA receptor is still being antagonized. But something is now different in terms of what is going on through the opioid system, you're blocking some opioid receptors, then you're saying that gets rid of the antidepressant effect.

Boris Heifets 49:25

That's what we saw. It was a small study to be fair, 12 patients. So I think I look forward I am confidence that there is a replication study in the works from the UK. So I, I think it will actually hold up. But yeah, that's basically what we found. Does that mean it the NMDA receptor isn't involved? It does not mean that it just means that well, there's also another system involved, not a surprise and then again, when we you know, there are a lot of interpretations right. This doesn't mean that ketamine acts directly to opioid receptors. There is some evidence, it could mean that ketamine releases, endogenous opioids like Pfenning Kathlyn. That's something that ketamine can do. It's also possible and this is something we didn't really take that seriously the time but I've come to think, is, what if naltrexone, what if opioids are involved in a totally other process that you need to or another part of your physiology that just needs to be in place in order to get a Kettering effect, but what I'm getting at is placebo. One of the things that Naltrexone is known for Naloxone related drug is that you can block with SIBO effects, you can block the effect of expectancy with opioid antagonists in

Nick Jikomes 50:54

which seven which opioid receptor are these blocking. They, they

Boris Heifets 50:58

are, they're not selective for mu or kappa. But all of the imaging evidence and the evidence to date indicates that it's the mu opioid receptor that it's working through, but there is a placebo. This is very well understood for placebo analgesia and a little bit less well understood for placebo antidepressant responses, but they work through the new opioid receptor and they are very likely generated by the release of endogenous opioids. Thank you.

Nick Jikomes 51:32

Yeah, so ketamine is potentially interacting with opioid based mechanisms in the brain that may underlie placebo effects themselves. And then, of course, we've got this issue that we can also talk about, which is how you do placebo controlled studies for psychoactive like this. And so it sounds like it's gonna get pretty complicated here. It gets

Boris Heifets 51:51

pretty complicated. One way of looking at this data is that ketamine is all placebo that people are walking in with an explicit expectation that like, Hey, I'm gonna, I'm in this cool trial, and I'm gonna get better. And we do this horrible thing by blocking the expectation benefit with naltrexone and then surprise, there's no effective ketamine. So one way to look at that is like, you know, honestly, outcomes razor is that well, there is no, ketamine is specific effect that it's, it's placebo. Yeah,

Nick Jikomes 52:23

I guess the first thing that comes to my mind there is just animal studies.

Boris Heifets 52:27

Well, animal studies, I mean, show me a depressed mouse. Yeah. Okay. Okay. So I, again, I do this work. So I'm very, you know, I'm sensitive to the criticism, but that's one of the issues that is honestly when you look at, but I digress a little bit, but like, Why have pharma drugs, left CNS their, like central nervous system, mental health therapeutics over the last 1520 years? It's because like, there's really nothing comes out of these animal studies for what like, when I was an undergraduate, every week, I would see like, we cure depression, again, in a mouse, substance P or MNDA, or whatever. And these drugs would fail. And if they would fail using these very specific, you know, specific behavioral tests, and in mice and rats, yeah.

Nick Jikomes 53:14

I mean, I eventually wanted to talk with someone about this on the podcast, it didn't occur to me that it might come up with you today. But I mean, what's your general view on our ability to model things like depression and anxiety in rodents, and how much stock we should put in to that work? When we're thinking about clinical applications in humans? Yeah.

Boris Heifets 53:31

So I said, Well, that's a philosopher then empiricist, that, if the models worked, we'd have found some new drugs by Yeah, all right, eighth generation SSRIs. So some things do seem to work, some models do seem to work better than others. So abuse, drug abuse, like that's like, something that's consistent across, you know, across species, even fruit flies, and we've worked out, you know, the dopamine system, like, it seems like that is pretty consistent. And you can model a lot of that self administration behavior. And in animals, like mice and rats, depression is difficult. And again, you have to, you know, that it ties into things that are honestly objectively hard to, to measure. So with substance use disorder, you can look at objective outcomes, like, are you compulsively seeking and using a substance? Have you sold all of your possessions is your life you know, are you basically ignoring your friends and family? Are you using escalating doses? Are you tolerant? Like, those are things that are like are they are actually objectively measurable? Depression is a little bit, you know, trickier. And I'm not a psychiatrist. So I'm not going to I want to leave it to your next guest to handle that. Like, how do we diagnose depression? Is it one disease, and I'll just point folks to Leanne Williams also Stanford had a wonderful study this this last week, where they go subtype depression based on imaging markers, you know, to six different categories. So, you know, each which may be sensitive to different drugs. And the point is we don't do nearly as good a job as that. In, in, in depression, in with with mice working subtyping being able to predict drug effects. And right you know, there's been a big push to change how we approach modeling period. So starting about 15 years ago, there's a big push at the National Institute of Mental Health, to stop using these like learned helplessness models, we put a mouse into, you know, a cup of water and see how long you struggle is. And that's like, hopelessness, we're like, yeah, you have upside down and see how long he the tail suspension test, I hate that thing. So and it's moved more to looking at dimensions of, of disease. So for example, depression, it's not, you know, depression has a lot of symptoms, one of the depression of one of the symptoms is off change sensitivity to reward anhedonia, where, right? Well, words just aren't as rewarding you sleep, that's another domain that you could model. It's the effect of stress on all of these things. So so we're getting better at not trying to anthropomorphize mice quite so much. And

Nick Jikomes 56:29

just do better, more granular phenotyping of these very broad terms that we apply. Yeah.

Boris Heifets 56:34

And, to me, the big challenge, and, you know, what lies ahead is building bridges now that we're starting to understand the physiology and like the biomarkers that underlie these component processes, then trying to find, you know, how does that show up in the human? Right, it's not necessarily the same going to be the same way. And we see that again, and again, where things that should look like they should work. Based on you know, what are the stress human look like? Like, in this mouse looks like it's stressful? You know, why does it respond to psychedelics? The way I think it should? You know, that's that, that basically speaks to the difficulty in understanding like, what, how do behaviors actually translate? And whether they translate at all, you know, does the physiology can you find the same types of physiology, physiological processes happening in mice, rats, non human primates and humans? And there's a lot of there's a lot of guests there, and a lot of I don't know.

Nick Jikomes 57:41

So, with regard to ketamine, addiction liability, where do How does that look? Because on the one hand, you know, there's animal research, I've talked to Christian Lucia, for example, in the podcast, and you know, he's done head to head comparisons of cocaine and ketamine in rodents, and shown pretty clearly that it's certainly much less addictive than cocaine, when you do the head to head comparison, but on the other hand, clearly, there is some abuse liability, because, you know, you mentioned the China thing earlier. And you know, there are clearly I've seen people who have a problem with ketamine. So it's clearly addictive to some degree. how addictive is it? And do we really have a handle on that even? So,

Boris Heifets 58:22

it's, it's, it's not as addictive as cocaine or alcohol or opioids, I think it would be a mistake to say that it's also, you know, probably on par with, you know, how addictive is MDMA, it's not as addictive as methamphetamine. But it's certainly people will abuse it. And, and the issue is, you take something that has, you know, mild to moderate abuse liability, and just talk to people or wander on Reddit, you will get all the evidence you need, that, you know, people can very quickly move from taking it in a therapeutic setting to just using it on their own and developing a problem. The issue is, you know, alright, not it's not it's not everyone, it's going to be a segment, maybe 10%, maybe less, but the more you expose people to it, right, with limited regulation, where now, you know, 1% of a million is actually quite a lot of people. Right? That's, that's, you know, 10,000 people. Now, if you how many people have depression in the United States? I don't know estimates are up to 50 million is that is that you're, you know, if they're all eligible to receive a mail order, ketamine, you can do the math, that's like a lot of people with a new substance use disorder that they didn't necessarily have before. And again, these numbers are, what is the actual percent of patients who go on? I don't think we have good information out there yet, because we're just at the beginning of mass exposure to cadmium in the United States, really spurred on by what I think is irresponsible more Marketing, to telehealth providers

Nick Jikomes 1:00:05

for ketamine, for psychedelics for all the drugs that you know everyone's really excited about right now that are psychedelics are related psychoactive compounds. There's this question of to what extent are the subjective effects that people consciously experience actually necessary or important for their therapeutic effects? So as we mentioned, as I've covered on the podcast before ketamine is being studied pretty intensively right now because it has these acute antidepressant effects. I know that you've done at least one study where you masked you basically combined ketamine with anesthesia so that people obviously weren't aware of the effects when they took the ketamine Can you set up that study for us? And just describe what the motivation was? What the basic results were?

Boris Heifets 1:00:46

Sure. So the drug versus the trip? That's that is one of the most interesting and compelling and impactful questions because it really dictates where do we go when we try and develop this, I mean, scale it out. And, you know, just point to folks like David Olson, Brian Roth, who and developing non hallucinogenic, psychedelic analogues, which is a great empirical test of this question, drugs that have very similar biochemical effect the classical psychedelics, but don't trigger that, that the experience that will those studies are underway, they have not been, they've not been tested in a formal clinical trial for a mental health condition in humans. As far as I know, we don't know the answer to whether taking the the trip out of the drug works. So being an anesthesiologist, you know, I saw a very clear solution. Another alternative solution to answering the same question is, we have patients with depression all the time coming in for major surgery, hips, these hernias, things like that. And we could set up a test we could basically eliminate the, the, the conscious awareness associated with and really the dissociated effect the trip by giving ketamine the same psychiatric dose, it's used in countless studies. While they're under general anesthesia and be clear, they're getting a different general anesthetic. It's not a ketamine anesthetic. It's where we started protocol. See before aim is most of the patients in our study. So we tried to set it up as close as we could to a a psychiatric ketamine study, we worked with Laura hack, and now Jasprit. Again, who are both actual psychiatrists to help us get it right. So what we did is we reached out to patients early on, these details are gonna be important later on. Patients don't usually hear from surgeons and anesthesiologist about their mental health. So some of these folks are a little surprised. They're like, why are you asking? You know, a lot of folks didn't want to talk about it at all. But we reached out early, we told them that we're interested in studying mental health. And we asked them if they want to be a study of a potential therapeutic option that night treat depression during surgery. That was the setup. We took folks who were had moderate to severe depression, on average, they had been for years. These look a lot like patients who are in other academies settings that came before. And we track their symptoms using standard scales. And when they show up on the morning of surgery, we meet them who have gone for surgery to go off to sleep. And we basically waited until they reached a certain depth of anesthesia. So all of our patients were basically at a equivalent depth that's associated with general anesthesia and no recall. Right? This is where we where we started our conversation. And when they're in that state, we gave them ketamine. We were blind, we were just putting a syringe we didn't know what it was. The patients were obviously unaware of what we were doing because they are under general anesthesia having surgery. And the anesthesiologist when they were lost, I didn't know what what were they going to know. So it was a standard dose, again, a single dose this was really aimed at, if you take away the conscious experience, and you just have the drug in your system, you still get some sort of antidepressant effect. And we were looking at short outcomes, meaning the one to three days after the infusion this is when a lot of the earlier single dose studies Academy, how they're set up is there, the peak effects where it goes one to three days. And so what did we find? The ketamine group that folks that got ketamine, they, they got better, they got a lot better 50% response 30% of remission meaning half for them cut their symptoms in half or more, and a bunch of them no longer met criteria for major depressive disorder for at least a few days. This is looks a lot like what ketamine does in, in other studies. Now, the placebo group also had about 50% response and 30% remission, we could not tell the difference between the groups, both of them had this enormous, enormous treatment effect. And there were patients were, you know, I swear to God, like I talked to I taught there two in particular, where I saw them after surgery. And one of them was telling me like, I could dance like I this was like her fifth surgery for cancer, like, not someone who is like, you know, prone to, you know, exuberant outbursts like, she was like, like, just legitimately, like, just happy, like it was infectious. There's something that, you know, people we know about, you know, in healthcare generally, like, sometimes, like, when you find yourself, you know, the patient's attitude rubbing off on you. That's, that should tell you something like, that's how bright this, this woman was, I was thinking, Oh, my God, like, this is working. Like we took the trip out of the dragon. Like, it's got to be in the ketamine group, placebo, of course, another patient where, you know, she actually had a pretty rocky postoperative course. But she was, you know, she told us like, she's so happy to be in this trial. And she's able to deal with stress in a way that she wasn't before she's taking exams from her hospital bed. Anyway, these are, these are the stories that I was accumulating as we're doing the study. So what I what I want, why I'm telling you that is, these were real trends, like transformative experience, and those are the patient, those are words that patients use. I didn't, I didn't suggest that. And it was shocking to me to find out that, like, we're getting these effects in the placebo group. And that, I think, made a lot of people uncomfortable. We got we got a little bit of hate mail for, say, I wouldn't say hate mail. But it's one way to look at this study is that, well, this shows the academy doesn't really work because it's no better than placebo. That is not how I look at the study. And to be honest, you can't really interpret it in that way, because there was no third and you know, where they were awake, for example, and got ketamine right. So

Nick Jikomes 1:07:35

yeah, so how do you interpret it? And then I have a basically a question about the study design. Sure.

Boris Heifets 1:07:41

So the way I interpreted it, we considered a few different possibilities. One that anesthesia blocked the effects of ketamine with which we think is unlikely because the size of the ketamine effect was so similar to every study before. The other possibility, we consider it as maybe it's a common factor, maybe anesthesia itself is an antidepressant. And we talked about that a little bit before and going back over hundreds and hundreds of patients, where mental health is monitored, surgery and anesthesia make depression worse in almost every study. So it's, that seems very unlikely to explain this. So what we settled on is that it's maybe its expectation, maybe I hinted at this before, this process of reaching out to patients, patients feel seen, they feel heard in a way that they usually don't in the run up to serve us, they're patients who have issues, major life issues that are dragging them down, and on top of it, they have surgery coming up. And that, you know, that sets in motion a series of expectations, and that made me really think a lot about psychedelic trials, and just how heavily selected patients are there, how excited they are to be in such an interesting study being an elite group of patients like I am, you know, it's, it's, it's, it's, it's being part of something,

Nick Jikomes 1:09:08

right? I mean, I can, you know, I can remember when, like, when I went to grad school, like when you're applying to grad school, and they invite you to the interviews, you just, you feel so good. You're like, I get to go and I get to be part of the group.

Boris Heifets 1:09:19

Like I'm on the team. Like, it's that that's real, and we didn't, you know, we we I was excited to get every single one of these patients because, you know, it's not easy to get folks who are willing to do a study this surgery.

Nick Jikomes 1:09:32

Does this. Do you think this sort of fits with the other results we talked about earlier with the opioid blocker? Well,

Boris Heifets 1:09:39

that is the question because it really like the simplest explanation for all of these data, which is again there are other interpretations. The simplest one is that either ketamine is working through the placebo system, or maybe is all very much expectation based. If these patients didn't know, they were getting ketamine and didn't know they were in a study, they might not have had an antidepressant response. If so, there's I don't think that's actually right. I think it is, we have some data to suggest that it's more complicated than that. But what it does suggest that that there certainly is a similarity between the mechanisms that our brain engages during a strong placebo. And I'm not talking about like, a two and column in the morning like a real placebo, that's called Hope. Right? What do you really engender hope in another person? Yeah, technically, that's placebo effect. But it's not a trivial thing to do, which you probably know from trying to talk to people who are in a difficult spot, it's easy to break through to them. So it to that extent, you know, that process that you know, a hope inducing hope, maybe ketamine is acting through whatever that process is. Maybe psychedelics are acting through that. That process, maybe they're enhancing it. One of the most intriguing findings and re analyzing this data is that we looked at patients who were on chronic opioids, right? These are patients who come in for surgery, sometimes you're on opioids for pain. And one of the predictions we would have is that we know that the placebo system is involved with opiate opioid receptors are involved in when you're on opioids, sometimes you develop, oftentimes you develop a tolerance to opioid medication that could manifest also as an impaired placebo response. Right. And when we looked at the data, again, this is very exploratory. But what we saw is that patients in the placebo, the ones who were on opioids before they got surgery, like usually for a couple of months, they actually had like, no placebo effect, very little placebo effect, whereas the ones who were not on opioids, they had a big placebo effect. And

Nick Jikomes 1:12:01

that would imply that, you know, if you're on opioids, you've got tolerance, the receptors have been internalized, there's fewer of them. And if the placebo effect is acting through those receptors, then that's exactly what you'd expect to see. So

Boris Heifets 1:12:13

it didn't treat there's something in it all, you know, it's like it's been in front of us this whole time about ketamine. What is ketamine do long before we started getting excited about ketamine for depression, we, you know, we were using it as an opioid sparing analgesic. We're using it to reset opiate, opioid receptor sensitivity. And once again, very exploratory analysis, not a lot of patients. But I think it's pretty interesting. When we look at the patients who got ketamine, those who were not on opioids had a nice big effect. In our study. Those who were on opioids also had a nice big effect. It's almost as if ketamine reset that, that, that opioid desensitization, that happens but ongoing opioid therapy and basically reset the placebo response system. It's an I'd say animal, it kind of points to something anyway, okay.

Nick Jikomes 1:13:15

So this is why earlier in the discussion, you said something like ketamine can reverse opioid tolerance. This is what you were talking about.

Boris Heifets 1:13:21

This is it reverses opioid receptor tolerance, very well known for analgesic like opioid like, right, like when you get patients out of opioids over the course of a long surgery, eventually, the opioids don't work as well. And that's an acute tolerance process. And you can reverse or unwind that process by giving ketamine a single dose of ketamine and oftentimes, will after surgery, you know, getting washed out, patients will now be sensitive to opioids, they'll be able to be treated with opioids. So it's, you know, these pieces without it's not it's not dead, certainly not not established.

Nick Jikomes 1:14:01

It's not fully formed. But yeah, this is this is about it know about all this, yeah,

Boris Heifets 1:14:05

this, this is where we're where we're going at least, and really, you know, the mechanism of placebo, it I think is going to be central to understanding how ketamine and even psychedelics might work and it really speaks to the importance of experience in a way. Yeah.

Nick Jikomes 1:14:23

So before we get into some some other stuff, I have to ask this question because you just triggered me. So ketamine is becoming more popular as a street drug it has for a number of years now. So it's, it's out in the world, people get up. We're also obviously in the middle of an opioid epidemic. So given what you've taught, told us about how ketamine can reverse opioid tolerance. Is there any danger that if people are out in the world mixing, even if not at the same time? If you're on opioids or abusing opioids, and then you take ketamine, then then you take the same dose of opioids you were taking? Yes Today, are there any risks here? So

Boris Heifets 1:15:03

it's a really good question. I'll be honest, I don't know the answer to it, it has come up a number of times. And when I've looked, I have not found anything very compelling this kind of prediction would make that if you have someone who's now starting to use ketamine, and they're they were opioid tolerant, are they now going to be opioid sensitive and, you know, sensitive to all of the effects in the respiratory packs? I don't know the answer to that.

Nick Jikomes 1:15:26

But in theory, that's what you'd expect, right? That someone

Boris Heifets 1:15:31

like would have a higher opioid effects work the same way necessarily, like the analgesic effects are different from the respiratory depressant effects, like where the opioid receptors are in your brain and brainstem. So, you know, it's not a foregone conclusion that it would work, but it is something that I'm very curious about and could become an issue.

Nick Jikomes 1:15:55

So I'm going back to just this general question surrounding psychedelics and related psychoactive, you know, are the subjective effects necessary or important components of the therapeutic benefits? So, a dual question here, one, do you have a strong intuition on what you think is likely going to be the outcome there? And two, what is conclusive evidence going to look like and how soon will we see that? Do you think?

Boris Heifets 1:16:27

To be clear, the study, the last study we did does not say anything about whether there's subjective effects to this. That's another another conversation, we ended up really showing more than what non drug factors like try it, like the just the structure of the clinical trial does. But our My intuition is that the experience is kosher is central to the therapeutic effect that we're seeing. I think that it's you know, we'll see what happens with these non hallucinogenic analogues. But it's, it's going to be difficult to, to prove something like that. And in the problem basically goes like this is that if what are you going to compare it to? What are you going to compare a drug that induces both biochemical effects and experiential changes? What are you going to compare it to? When we're not really sure which one? Or whether they act together, whether it's, you know, basically an uninterruptible? Whole? So, you know, do you compare it to something that also produces a similar experience? Well, the, you know, the closest, how are you going to recreate the experience of a psychedelic? So we actually have a, an approach to this. And it's not, you know, it doesn't rule out a special role for psychedelics or a special mechanism. But it gets at this question, what if you were to break this apart? Right? What if you could reproduce an experience, like psychedelics without the use of a psychedelic, right? And here, what I'm kind of coyly hinting at is that something, you know, a powerful internally generated experience, you know, you that's something that we see when patients emerge from anesthesia so that if we really, we can focus on that and extend that period prolong that period, patients wake up and say some truth like we've we talked about this before, but we're starting to see more regularly. This is something that we're doing on purpose, that really unearth a lot of emotions, and a lot of just really dreamlike experiences that really, it's hard to ignore the comparison with psychedelics, but let's back up for a minute, what is what is proof going to go into look? So, there are a couple of ways to get it this one is, can you is it can you separate out the the hose and genic experience from the receptor. So there are some theories out there specifically for psilocybin, that the therapeutic effect is mediated through a different receptor than the hallucinogenic terror serotonin to a receptor is responsible for the hallucinogenic effect and people will reasonably sure about that, but the therapeutic effect might be mediated through a different receptor. For example, the serotonin one a receptor, and so you do a study where you block the one a receptor, blocking the therapeutic effect, still get the experience, patients have every reason to believe they're gonna get better, but you can you can judge that outcome. So that is, you know, if, if that's true, it's not

Nick Jikomes 1:19:52

true. Instead of instead of trying to engineer out the hallucinations, you block the therapeutic mechanism that is in the tentative foods nations, well, we still have them.

Boris Heifets 1:20:01

And we actually did that with our academy naltrexone study and that patients all dissociated, just fine moving now tracks. We didn't ask what they thought they got, which is our oversight, you know, 2018. But that's a study you can do. There are other, you know, other I think really interesting study designs where he basically test the, you know, the, the prediction that these biochemical effects spot dendritic spine with neuroplasticity, these are processes that you can actually interrupt, probably without interrupting the psychoactive effects of of a psychedelic, those are, you know, those trials a little further down the line. But that's one way that you could get it this is basically retaining the psychedelic effect, but removing what we think is the biochemical effect. Now my prediction is that, you know, those two things are never really going to be far apart from each other, that if you think about this in another context, right, these are transformational experiences. Yes, I can think in my own life of transformational experiences. And, you know, having Bar Mitzvah, having a child, you know, sometimes you hear about, you know, old angry asshole, you know, guys having heart attacks, near death experiences, and then changing their personality, realizing they don't, you know, need to be so hard charging, maybe they should be vegan, maybe they should talk to their children similar, right? Like, those are transformational experiences. Am I really even make sense to say like, what receptor does the transformational experience operate? Right? It's complicated. It's just like one.

Nick Jikomes 1:21:42

Yeah, when I have these discussions, what I always like to bring up as well, okay, let's think about why people get major depression do like, people don't walk down the sidewalk, and you know, one NMDA receptor comes loose in the right synapse, they have a set of experiences over a period of time, and that induces the state we want to treat.

Boris Heifets 1:22:00

I think without getting too philosophical, a little bit philosophical, I feel like this is a vestige of success, you know, so many other areas of biomedicine, where, you know, the shining single molecule single receptor, like, Well, look, we have, like, cured some forms of cancer. It's, I mean, that is a revolution. Truly, and it is a result of this kind of, you know, targeted engineering and focus on kind of single molecules and, and highly engineered drugs, I don't think it's going to work that way for for mental health. And as you said, it's, you know, how do you if we think about depression really is like a, maybe a normal response to extreme stress? First of all, is that a disease? And second, how are you going to unwind that without, right, like, the most complicated drug I can imagine, is, you know, the sound of my voice, the touch of my hand, and, you know, the relationship that we build over time, right, like, that's what drugs and assets are like, approximating and pieces of that have pieces of experience. So why not use the whole thing? Why not? You know, why try and put it in a box? This way with, you know, just really, you know, there's over compartmentalization. So I think experience has a central role in this. And Trump, the, the big picture really, is that coming up with evidence for that is not straightforward. I can think of some ways to do it. But that redirects, the, you know, the the pharmaceutical industrial complex a little bit, right, if we had clear evidence that there's nothing intrinsically special about the serotonin to a receptor, that it's a means to an end. And that end is a is a transformative experience. Well, if we knew if we had convincing evidence that if that were true, then wouldn't we redirect resources away from developing targeted to a ligands particular receptor and just the right way, and maybe move them towards how do you contain it A, the or how do you? How do you manage a transformative experience? How do you induce it in a reproducible, somewhat safe way? I mean, this sounds crazy in you know, with medicine the way it is, you know, that we're going to try and engender a transformative chaotic experience, which is, you know, what trips often are made of, and that's going to be the unit of therapy, but, you know, talk to psychotherapist, that's a lot of times what they're, you know, trying to dredge up in the process of psychotherapy, Max, Max Wolf, because a lot of interesting things to say, if you ever get a chance to talk to him. I think you'd be you'd be fine. But that's, that's so so, you know, I don't even know what question I'm answering this way. But I think it's appearance matters. But what is going to matter in order to get the kind of development we need and to get this incorporated into medicine is to find a way you can't give everyone a near death experience. You can't administer one bar mitzvah as needed. I guess but what you can do I mean, you can give people a psychedelic, right? But it's, the focus now becomes different. It becomes like, not so much like the drug itself, but in how do you, you know, who's who's appropriate? What kind of patients are appropriately? This is the realm of psychology is not not mastered, but and then how do you make that experience special, meaningful and impacted?

Nick Jikomes 1:25:42

Yeah. In the time we have left, I want to talk about MDMA. Getting a lot of attention right now, given the the recommendations that were just released to the FDA ahead of the FDA actually making some big decisions coming up here. I don't know. I'm assuming you filed this at least somewhat. Can you just tell everyone what's going on right now with Lycos therapeutics and MDMA assisted psychotherapy in terms of whether or not it's going to be FDA approved?

Boris Heifets 1:26:11

Sure. I have been following it very closely. And you know, I, I was a early, honestly, early adopter, this wrong word. But I was very excited about maps, which is since split into like us, from a pretty early age. That was like college, I came out to California, after college to work on the only nbma study in the US that was ongoing at the time. I you know, got 500 bucks from Rick Doblin the MAXVALUE dime for, you know, reviewing ancient papers giving MDMA to pigeons and rats, you know, as part of the you know, Ind filing that was supervised by an actual scientist, Matt Matt Baggett at the time. But anyway, so I've been, you know, fascinated by this thing that caught my attention very early on, through personal experience, to be honest, is that transformation, like the life changing experience? How could this not be Bennett good for something, right, and when you know, you when I occurred for the first time, and, you know, the mid 2000s, that they want to explore this for PTSD, like, it makes sense, like you can get you these memories that are so painful, awkward, humiliating, you know, et cetera, like, you can deal with them, you can process them, you can move on. That's, that, to me was what was so so compelling about this, though, what's happened in the interim? Is, but you know, what does it take to get nbma? A drawing has been illegal since the mid 80s. And schedule one, how do you make that into medicine, it takes some evangelism. And that, you know, maps and Rick Doblin, you know, who I know and love, but it is an evangelist, that is at the heart of it, and he believes in this stuff. And it's not the kind of attitude that really lends itself to carefully controlled agnostic, you know, equipoise in a clinical trial, which is what you need to get this over the hump into a medicine into something that insurers are going to pay for a doctor can say, this is going to help you here the studies to back it up, you know, regardless of whatever societal hype there is around. So this, to me was the basic challenge that they're, you know, that they have. It's not a pharmaceutical company in the conventional sense. And they didn't present the FDA with, you know, clinical trials that look like other phase three clinical trials, the maps, MDMA assisted psychotherapy for PTSD application, to my knowledge includes two clinical trials, they're pretty small, by most standards, about 80 patients each. For reference, the compass, psilocybin trial, phase two to be, like 250 patients, and then like that's typically drugs are approved for 1000s of patients and trials. So there's not a big trial. And they did you know, they got breakthrough status in 2017, or 2018, meaning that the FDA would work with maps on designing the trials and getting them right so that they wouldn't be approvable by any of the results once they came for the FDA. So what happened in the last couple of months, is that some independent independent bodies and the FDA advisory committee started reviewing the data. And what came out of this hearing, which happened earlier this month, which was this very widely publicized. 11 to one, you know, no confidence vote in MDMA. was basically the revelation of just a number, like a dozen, maybe more issues with the way the trials were done with the measures they use with the design with deviations from what, you know, the FDA had recommended, which, you know, I don't fully understand why some of those choices were made, you know, if the FDA is giving you a checklist of things to do to get your drug approved, like, I would do every single one of them to the absolute best of my ability. I did anyway, so somebody was mystified. But so what happened, the long story short is that MDMA to two very successful clinical trials were published very high profile papers, where folks just got folks who had not gotten better from anything with severe PTSD, were getting, you know, in remission, lots of patients cover of The New York Times, right, like really big news that this could work. And, you know, I'll be honest, like it played into my own biases that, yeah, like, of course, it was like that, that's what I thought would happen. But you know, you need to give these trials, you need to have some anchor points, you need to not already assume the results before you can get it in hand. So that, despite all of that, you know, excitement about the clinical trial result, when the details, and more importantly, some of the allegations about misconduct in the trials, that really, I think sunk the application, what were the allegations? So one of them is not just an allegation, but just the finding of fact that there is a sexual assault in one of the phase two trials in Canada by an unlicensed therapist, that happens. And that, you know, could have been handled more transparently, I think, by by maps, but it doesn't really inspire confidence, you know, in the process. Again, this is assault, I guess you can't blame assault on MDMA. It's like, there's like people who do the assault, like that's who you should be blaming, primarily, but it raises questions that, you know, why are these our patients can be, you know, hyper suggestible to this kind of things. And I don't think we have an answer to that. So that's I'm not really saying one way or another, but we just certainly it raises a question that we don't yet really fully understand, you know, what, what is the risk? Is that something, you know, can we disclose that to patients, you know, before given nbma like that, it raises questions like that. There are other you know, unsubstantiated allegations and Assam substantiated to my view that, you know, their patients were very much pressured to give certain answers when they will be excommunicated from, you know, very much an in group community if they said anything other than, you know, MDMA saved my life. I don't know if that's, again, this

Nick Jikomes 1:33:13

is like allegations, allegations, doesn't inspire confidence. as a, as a scientist, when you look at those phase three trial results, those studies, do you think the results are compelling? Even if, you know, traditionally, you'd want those trials to have more patients? Do you think there's any serious pitfalls in how the trials were conducted?

Boris Heifets 1:33:35

Can you repeat that question? I went out for a sec. Oh, how

Nick Jikomes 1:33:38

compelling do you find those studies? The phase three clinical trial studies?

Boris Heifets 1:33:43

I mean, I thought they were pretty compelling, to be honest, you know, assuming that there is assuming the patients were free to answer as they as as they wanted it, you know, there are, of course, their issues. And, of course, it's not, you know, a blinded study, which you can't do really for this kind of drug. And honestly, you know, you look back at all of the drugs that have been approved for mental health indications, you know, we have no, the assumption actually shouldn't be that none of them. So, I don't think that's as big an issue, as has been made out. I think what would have been nice, this is what they could have done better. And, of course, this is Monday morning quarterbacking there to two big ways to address the placebo. Right? It's like so right. But like the default criticism is, well, it's all placebo effect, which, you know, even though you don't really see that degree of placebo effect in patients with severe PTSD, okay. That one thing to do is a dose dose ranging study, right, you just if there is a dose dependent effect, you should see, right if it depends on the drug, you should see an escalating effect with increasing drug dose. Also not totally blind, but it addresses some of because that would have been a nice thing to do. The other thing that I think they really whiffed on, is the long term follow up, right? I don't know, a placebo effect that lasts a year. Right? Yeah. So, you know, whatever, you know, there's the hype, you know, of the study, and like, there's an experience associated with it, a lot of that stuff, you know, you'd expect to wear off and people go back to their normal lives and eventually be settled back to where they were. Right now, if you really had you dealt with some trauma in a very real and lasting way, you could follow those patients out and still see improvements. And that would speak volumes, I think, to the fact that this is a drug or a treatment specific effect, not just placebo. They, you know, unfortunately, the data that they that they collected on that was not really interpretable. And their patients knew what group they were in, or they were told, you know, there's some placebo patients who thought they got MDMA, you know, so it there could have been with enough numbers and enough follow up. And of course, they had lost a lot of patients to follow up. So you know, what happened to the ones they didn't follow up with all of these questions like it? It really, it's, it wasn't a really high quality, long term follow up setting. So those were, you know, the big issues.

Nick Jikomes 1:36:24

So do you think oh, I mean, I guess my my, my intuition here would be the FDA probably says, We want to see more data.

Boris Heifets 1:36:34

Yeah, so, you know, whatever. The sins of Lycos were our I don't know, we still have an intractable public health issue, for which there are very few effective treatments. And, you know, the FDA is, you know, they're judging safety and efficacy. But one of the, you know, there's one of the safety and one of the risks that you I think is a real risk is that by saying no to this, you are also stifling developments of other drugs. And that is, you know, I'm I'm purely speculating here. But I think that may have been involved, for example, you know, why did the FDA include an Alzheimer's drug and its subsidiary bullets for lack of efficacy and safety is because nothing had been approved for Alzheimer's in decades. And you know, at some point, you're gonna stop, stop taking shots at that. S ketamine, the, you know, the trial data for s ketamine not that impressive, but the FDA approved it, and again, to me, it was a strong signal to the industry, guys, like, please like, this isn't working on approach. Keep working on it. Yeah. You know, so that's, that's, that's sociology, not science. And, you know, it's, I think, thankful, I don't have to make that decision on the FDA. But so I think there's a possibility that they will still approve it on that basis, they, you know, there, they'll have a really restrictive rams, which is the risk evaluation mitigation strategy that will, you know, really kind of tie up halfway, who could get MDMA, how many times they can get it, who gives it to them, you know, really make it difficult, make it expensive, which none of that is great for patient access. But it will allow, you know, leave the door open to give more data to, you know, read and maybe change the label. And it gives the signal to other startups, of which there are many that, hey, there's there's at least a possibility here that we're not closed off to the possibility that you can have a drug that really primarily works in the context of psychotherapy, it's approvable. It's not the kind of thing they're used to approving. But there's press, there's precedent for drugs that have abuse liability. In the mid in the height of the opioid epidemic, the FDA approved, you know, a new formulation of an incredibly potent opioid that's, you know, 10 times more potent than fed milks. So there's precedent for that there's precedent for the FDA approving drugs that require some sort of psychological support. Buprenorphine for opioid use disorder, Bupropion or MS Chantix, for for smoking cessation. These, you know, these are approved with the proviso that you're in some sort of ongoing support. So there is there's these are MDMA is I think approvable given the right, you know, they're given the right shape and, you know, quantity of clinical data is I don't know if I don't know if that's enough to make the FDA overrule it. 11 to one.

Nick Jikomes 1:39:50

Yeah, we'll see. Towards the end of the day on a Friday, I don't want to take too much more of your time, Boris. I know that you're busy. Is there anything that you want to reiterate about what we discussed today are any final thoughts you want to leave people with these general subjects psychedelics, anesthesia, consciousness, the role of subjectivity, any of that stuff?

Boris Heifets 1:40:10

Yeah, I think I just I really want to reiterate that point about, you know, experience and not falling for a trap that, you know, I feel like I've fallen into many times, which is this like, reductionist, mechanistic, you know, illusion, that we can boil things down to something as simple as a shiny pill, you know, this is going to hit this receptor, like turn on the lights. It's so you know, that that can happen. But I don't think that's how this stuff is working. And I think chasing that as a, as a strategy is, is really not going in the right direction, I think, experience, transformative experience, ritual expectation, but build up the, you know, all of these things like that seems to be the common through line through all of these drugs, that there's something important about generating those types of experience. And they're done. You know, just look at the pharmacology of ketamine, MDMA, psilocybin, not really that similar, but they all seem to have this guess they're psychoactive. They have durable effects. And, you know, these are, these are potent, potent therapeutics, that's it to me, it really seems to center around around transformative experiences. Yeah,

Nick Jikomes 1:41:39

and I guess, like, one final thing I want to say, you know, as I'm hearing you say, all these things, and when we had our discussion about some of this stuff, when you think about all of you think about this historically, and anthropologically, all of the things that are the most transformative for people in society centered around rituals, where everyone where you feel special, think about a marriage ritual, or a rite of passage, you know, becoming a man or a woman, all of the the ceremonies that cultures all over the world have always used involve all all the ingredients, minus the drugs that we seem to be talking about. But the drugs but sometimes with the drugs, too.

Boris Heifets 1:42:18

Yeah, that's, you know, I think there's a, we can go too far in that direction of it, you know, Dwejra is medicine really the the home for transformative experience? It's maybe not. But you know, it's taken over so much of our lives. And it's, it would be, it's an important lesson that I think is what we should be taking away from these trials. And this means that, and it's not the lesson that everyone is, is taking away. I think the less you know that there's a lot of excitement about derivatives and analogues and reengineering of compounds, and maybe less exciting because it's hard to generate intellectual property around and experience but to me that's that's the frontier is really trying to engineer experiences and in a thoughtful and somewhat predictable way to affect change.

Nick Jikomes 1:43:11

All right, Dr. Boris Heifetz, thank you for your time.

Boris Heifets 1:43:14

Thank you Nick

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