Anesthesia, Placebo Effects, Consciousness, Subjectivity, MDMA, Ketamine, Opioids, Psychedelics | Boris Heifets | #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.Related episodes:

* How Does Ketamine Work & Is It Addictive? | Christian Lüscher | #90

* Consciousness, Anesthesia, Coma, Vegetative States, Sleep Pills (Ambien), Ketamine, AI & ChatGPT | Alex Proekt | #101

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

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* Episode transcript below.

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 som