Transcript
#625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever
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cybernetic organism, living tissue over metal and those galaxy. No Hello, boys and girls, ladies and germs, this is Tim Ferris and welcome to another episode of the Tim Ferris Show. This is an episode I've wanted to record for several years. I've been asked many times, dozens of times, possibly hundreds of times, about ketamine, and this is intended to be The most comprehensive in depth
coverage of ketamine in the podcast space. It is intended to be your one stop shopping, or at least your first stop. in all things. Ketamine. We get deep in the weeds. So if you get lost at any point or start to drift because it's technical, just wait two to five minutes and we almost always explain things. Or shift gears. And the reason also
that I wanted to do this episode is that I know friends who have averted suicide Using Supervised ketamine. And that is reason enough for me to want to put this together. My guest today is the incredible
John Crystal. Dr. John Crystal is the Robert L. McNeil Jr. Professor of Translational Research, Professor of Psychiatry, Neuroscience and Psychology, Chair of the Department of Psychiatry at Yale University, and the Chief of Psychiatry and Behavioral Health at Yale New Haven Hospital. Dr. Crystal is a leading expert in the areas of alcoholism. Post traumatic stress disorder, schizophrenia, and depression. His work links psychopharmacology, neuroimaging, Molecular genetics and computational neuroscience to study the neurobiology and treatment of these disorders. And he is very fluent, well versed in many other things, but he is best known for leading the discovery of the rapid antidepressant effects of ketamine in depressed patients. He co-directs the Yale Center for Clinical Investigation, CTSA and NIAA Center for Translational Neuroscience of Alcoholism and Clinical Neuroscience Division of the National Center for PTSD. Dr. Crystal is a member of the US National Academy of Medicine, co director of the Neuroscience Forum of the US National Academies of Sciences, Engineering and Medicine, Fellow of the Americas for the Advancement of Science.
and editor of Biological Psychiatry, one of the most selective and highly cited journals in the field of psychiatric neuroscience. He is the co founder and chief scientific officer of Freedom Biosciences, which you can find at freedombio.co, a clinical stage biotechnology platform developing next generation ketamine and psychedelic therapeutics, that just recently emerged from stealth in August of twenty. twenty two. One very important disclaimer, I'm not a doctor, nor do I play one on the internet. None of the content in this podcast constitutes medical advice or should be construed as a recommendation to use ketamine or psychedelics. There are psychological, physical, and sometimes legal risks.
With such usage. You have to be smart, you have to consult experts. Please consult your doctor before considering anything we discuss in this episode, and with all of that said. Please enjoy my very in depth, very wide ranging. Very nuanced.
I give that credit to Doctor Crystal. Conversation with Dr. John Crystal. Doctor Crystal, it is good to see you again. Thank you for making the time. For this conversation. I really appreciate it.
Well, my pleasure. And I thought we would start. with the personal. We're going to get into the scientific I've been looking forward to this conversation for a long time, as I mentioned to you before recording, because I I really think this will be an incredible resource for people, but I'd like to begin with some of your personal history. Could you please describe For people listening and for me.
Your father. And some of His bio. And history. My father was a psychiatrist and psychoanalyst named Henry Crystal.
And he passed away a number of years ago. He was born in the town of Sosnowiec in Poland. In nineteen twenty five, And at the age of Fourteen.
Was Captured by the Nazis who were rounding up the Jews in his area of Poland. And sent it. through a series of concentration camps. Importantly, you know, names people would probably recognize would be Auschwitz.
Saxonhausen Buchenwald. And he survived. The concentration camps. And he was the only member of his family. To survive. So
He was captured at the age of fourteen. And by Seventeen, eighteen when he came out of the camps was Alone in the world, essentially. Hm.
Went to school, attained some schooling in Germany. And then came to the United States. Where he had a an aunt. Who put him up and I grew up with stories of him sleeping in the cellar of her
Convenience store. Around the pickle jars that would spontaneously explode during the night because Mm-hmm. For whatever reason they were uh very Potent.
And he was able to get A Scholarship. To Wayne State University for college. And then another scholarship.
To go to medical school. And Along the way he Mastered English. And settled into the United States.
And he became Very Powerfully influenced. Bye. The chairman of the department of psychiatry at Wayne State University.
Whose name was John Dorse, who had been Analyzed by Freud. whose view of psychiatry had to do with people embracing all aspects of themselves and becoming kind of integrated human beings and
And that that was the path. Towards both a healthy life and a and a fulfilling life. Which was an idea that my father Also
not only embraced in his work, but embraced in his life. And Ironically, my name is John J O H N Which is Not commonly the
Name. Given to Jewish children. Who often Name Jonathan instead. But I'm called John because I'm named after
Doctor Dorsey who is Irish. So My dad became a psychiatrist. And In his work.
Evaluated People who survived. The Holocaust. for reparations to the German government.
And This was both an incredibly meaningful task, but also One that was extremely Challenging for many reasons. One is that
He had to relive his own traumas in the process of working with More than a thousand. People that he evaluated. For reparations from the German government. For their traumas.
And the second thing was That He was in a nearly impossible position which was That he was
Evaluating people For Psychological damages related to their Holocaust. Experience. And this was in the
Nineteen fifties, nineteen sixties. Almost twenty years before the diagnosis of post traumatic stress disorder existed. And What happened was that he and a colleague of his Bill Niederland.
From New York. They developed this idea of Survivor syndrome. The psychological consequences of trauma. That became one of the cornerstones.
Along with the work of many others such as Robert J Liften and others for what became the diagnosis of post traumatic stress disorder. And his work Throughout his career. About the trying to uh understand the roots of
Resilience and vulnerability. And to develop Treatments that would Help people to manage the impact of psychological traumas that was his
Life work and Profoundly inspiring for me. I've always felt. That there was no challenge that I could ever face.
No obstacle that I could ever meet that would ever match the challenges that my Fathers Father faced in his life. And
The kind of perspective that my dad brought to his own. Life challenges the way that he survived in the concentration camps. of recognizing and seizing opportunities Yeah.
Arose for him the And realizing what was happening and and seizing these kinds of opportunities. Which enabled him to survive. were also profound life lessons that
In pursuing what One. Was working on. That you had to Get outside of the constraints that the environment
Placed on you. And recognize the nascent opportunities out there. No matter how out of the box and How Unorthodox they were.
In order to have a real impact. That was A key to my father's survival. But it was also a key
For The way my father turned this process of Evaluating people for disability pensions is Turn that into the Foundation for
helping to open up the field of post traumatic stress disorder and and have a A huge positive impact. So I have no doubt that That my father's life experience and the way that he developed his career profoundly
impacted me and my thinking and the things that I I thought were important in in what I ended up pursuing in the way that I'm pursuing them. about my father was he was profoundly curious and Would read religions.
He would read history, he would read neuroscience, he would read Philosophy he would pursue Almost it. Any field that he that he thought had any relevance To what he was thinking about. And
That perspective also was normally incredibly impactful for me. And has influenced the way I approach everything that I do. Thank you. For sharing that, John.
And it's uh Part of the fabric of who you are also these stories and I had no idea. This background, of course. I mean, one of the great gifts that I get from these conversations is the excuse to do what would otherwise be very creepy in terms of due diligence on my
Friends or people that I know. And I'd love to ask you a bit more about your father. And I'm pulling from in this case A New York Times piece. Which I I believe was effectively
Upon your father's passing. And I'll just read a a short section here that will lead into the question. So he, this is your father, attributed the survival of some inmates to an almost childlike belief in their own indomitability. And then the quote is From your father. I feel that quote unquote healthy infantile omnipotence is the most important asset for dealing with life's stresses and potential trauma. Doctor Crystal wrote in a chapter he contributed to Living with Terror, Working with Trauma, a Clinician's Handbook. And uh I'll
Shorten this. to end the quote with it is an emotional mainspring of extraordinary reserves. It provides a profound, unshakeable conviction of one's In vulnerability. Is that something that he ever discussed with you? Or fostered in you, I would
I would love to To hear anything. That comes to mind. First I want to reassure you That he was like a normal person.
And so like he would never talk about the omnipotent interjected object at the dining room table. Right. You can imagine people have all kinds of ideas about what psychoanalysts talk about over dinner, and mostly it was just pretty much bread and butter things. The the second thing is that I think about is that he Believe
Yeah. The parent child interaction was Fundamental. To all human resilience. And that in that
Kind of. Nurturing Supportive interaction. Lay the root of optimism. And
That having A sense that no matter What is happening around you? That there's still the possibility The things will work out okay.
Із ге. That comes out of this kind of Nurturing. developmental experience. And so much of what he Dealt with
In treating people who had been traumatized in psychoanalysis and in psychotherapy. Was the way That Early life traumas.
Just drop that. And create a feeling. Not of optimism, but and the potential for things to work out. But the opposite.
That in the expectation That the world is a dangerous threatening place. And that failure lurks around the corner. And So
Creating the very Constraints on creativity. And motivation. Deadening. Hope.
Deadening. Creativity. Constraining opportunities. That people are putting this cage on themselves. As a consequence of
The disruption of The sense of Safety and possibility that is A natural byproduct of a
Nurturing. Childhood experience. Well let's use that as a Perfect. Leaping point.
to hop into some of the Say the salt and bread, the meat and potatoes. of some of the subjects that we'll cover. Because looking at at your bio, just as an example, Dr. Crystal's leading expert in the areas of alcoholism, post traumatic stress disorder, schizophrenia, and depression, it sounds like a roll call for one of my family reunions. And I certainly, if people are not aware, I'll just provide a little context.
Have experienced chronic or probably call it repeated, but also a very severe depression throughout my life. It appears to be hereditary and As you mentioned There are people for whom
Despair instead of hope is a default setting. Or feels like a default setting. And there can be, say, a catalyzing event where in my lived experience, there might be a situation that provokes or I should say that I allow to provoke
A feeling of despair, hopelessness. And then I'm able to observe the mindset and objectively perhaps Think. This shouldn't bother me so much. This is a failure of imagination. There are friends of mine, people I know who would deal with this with complete equanimity.
And then there's hopelessness about ever changing the mindset. And I think that is the scariest part. So perhaps we could begin with just a a brief
discussion doesn't have to be brief about depression and perhaps what people Underestimate, don't appreciate about. Depression, what you have come to realize perhaps as a clinician over many decades just to set the table, as it were, for our discussion of different treatments, comparisons, ketamine, et cetera. So I think that people
Think that Depression is like having a bad day. And Everybody's had a bad day. And everybody's had a few bad days.
And I think That Some of the confusion about depression. has to do with The way in which we use throw depression around is a term like
I spilled my coffee and I'm depressed about that. No. Yeah. That is a Disappointment, right? But it's not that kind of experience isn't what we're talking about.
When we talk about depression. When we talk about Depression is more about the experience that you're talking about. The way that depression can be A pervasive mode of being.
That invades every aspect. of one's life and experience of the world. It affects the pattern of your thinking. In other words, instead of as you say seeing The world as a mixture of risk and opportunity
You see the negative in everything that you engage. It affects the way you make judgments. Instead of being able to make judgment based on reasonable risk reward kinds of Decisions.
Everything's colored by the negativity. What people often don't appreciate about depression is that It goes beyond sadness. For many people It can be a complete
Blunting of emotional experience and people describe sometimes the loss of feeling. One of the people that we treated with ketamine. Said that she was just amazed to have feelings again. After her depression began to lift. And
People often describe feeling blue. When they're depressed because The contrasts in the world, their visual experience of the world. is as if the normal contrasts are blunted and Colours seem duller and things that are exciting and rewarding seem blander, and a kind of sapping of life's
Essence. This kind of depression. is associated with A loss of energy, a loss of concentration. Difficulty sleeping, waking up early in the morning, tossing and turning, in difficulty.
relaxing and feeling comfortable. Being Overcome with pervasive. Intrusive recurring thoughts on negative things like I'm a terrible person. I let people down.
Over and over and over ruminating on these negative Horrible ideas. And I mentioned a sapping of energy. Loss of appetite, decreased interest in activities.
A kind of Withdraw This State. Was deemed by
The Greek Hippocratic doctors. as a kind of fundamental negative mode of being. That they thought was connected to black bile, which in Greek
Had the name Melon. For black. Cole for bile. And then has been known as melancholic depression. Ever since.
And There's another kind of depression that we also see. Which is people who have the capacity Two See good and bad.
But who cannot constrain the way in which they react. So Something good happens, they can react in a normal way to it, but something bad happens to them and they spiral downward in a very
Negative. Way. Beyond their control. To despair and hopelessness and extreme distress. That is not the typical profile.
Of traditional melancholic depression but as a kind of reactive depression. One of the things that we appreciate about Depression is that can be a very heterogeneous things, that there's a whole array of different kinds of depression. And we're just at the early stages of sorting that out.
But one thing that's really important. For people to understand that they often don't understand is the medical part of depression. And when I say medical part. Is that That we understand
Yes, medical depression is a state of emotional experience. And yes, it's a Altered way of brain function. But it's a brain function. Of an embodied brain.
In other words, depression is a State it affects your entire body. Medical factors Like inflammatory Processes in the body related to obesity, cardiac disease, arthritis
asthma, a variety of things that cause inflammation in the body. Increase your risk for depression. And if you have depression, it makes inflammation worse. And that means it makes All of those medical illnesses.
Where inflammation is a process worse. If you have untreated depression. On average. It shortens your life. Not by suicide.
It still shortens your life by about five years. And if you have depression in the context Of uh medical illnesses it makes The medical outcomes
Worse. Not only the psychological outcomes, but the medical outcomes worse. Depression is a disorder of the spirit, if you will, the brain. But also the whole body. And that's one of the reasons Why?
Number one. It's one of the most disabling conditions that we have in the world. And two It's From a medical
point of view it's also urgently important that people One thing you and I spoke about A little bit. before recording that I'd love for you to touch on is
Perhaps the high frequency with which you have observed partial recovery and not full recovery, or partial treatment and not full treatment. Perhaps if you could just speak to that. So psychiatry has struggled with what to do with
Partial response and non response for all psychiatric disorders. And I'm embarrassed to say that there is a strain of a history in psychiatry. When patients
Didn't get better. That they blame the patient. In other words, they would say things like, Well, that patient wasn't adequately engaged in treatment, they didn't engage in psychotherapy, they weren't a good psychotherapy candidate, they didn't blah blah blah. And Well it's true that
People engage in treatment with varying levels of motivation and understanding and things like that. We would never say For Heart attack. For heart disease.
Well, you know, the they had a heart attack, but you know, they weren't very motivated to be in treatment, so what could we do? We would never say that. We would always say Well let's look at the illness. Let's try to optimize the treatment. And if people aren't responding, let's do something about that.
That the field Of psychiatry. hasn't always taken ownership. For the fact that our treatments don't always work as effectively. as we'd like them to be.
Now there are some Underlying reasons why that tends to happen a little bit more. In psychiatry than in some other aspects of medicine.
One of them is that There's just inadequate support for psychiatry mental health treatment generally. So it's a scarce resource and people often Essentially take what they can get. And that speaks to the
inadequacy of our national approach to making sure that people have access to effective health care. A second thing is We don't measure outcomes in clinical practice in any kind of routine way.
In other words. If you have a heart attack. Then you get scans and they measure the EKG the electrical activity of the heart. Maybe you have a stress test. Maybe you have An echocardiogram to measure the ability of your heart to contract. Well, where are those tests in psychiatry?
Those tests to the extent that we have them are basically brief questionnaires that people can complete to give us Some semi quantitative idea about how people are doing. But those outcome measures
aren't routinely applied in clinical practice. And so that as a field When we look at our health care systems. There's no data on outcomes. For the clinical interventions or much less data on outcomes.
Some healthcare systems like the VA have started to embed clinical ratings into clinical care. But It's not A situation where the field has
been held accountable for the outcomes. And the field hasn't been held accountable for outcomes. The insurance companies have not been held accountable for the outcomes. The country has not been Held uh accountable for outcomes. And
That has been Particularly problematic. For depression for a number of reasons. One of the reasons is the invisibility of inadequate.
Responses. So what can happen? is that people will Start treatment. Maybe they start treatment with psychotherapy and maybe the treatment is
Somewhelmful for them, but it hasn't worked entirely. And then Maybe they Then add a medication to the psychotherapy. And
Maybe that medication is somewhat helpful. But not entirely. But The person has gone from an eight Out of ten.
to uh five out of ten. So they're substantially better than they started off. But they're substantially symptomatic. And in ways that
take a toll on them, their social relationships, their work productivity. So Why is it invisible? It's invisible because Both the doctor and the patient. Have worked really hard over a long period of time.
To get to the point. Where they're only a five. And there is justifiably A sense of Accomplishment.
an investment in that new status quo. But What there is, though. Is a failure to say. Have I exhausted all possible outcomes?
To go from a five. out of ten. To a two out of ten. And the answer. Is
In most cases The Possible outcomes have not been explored. And this is really important. We have to keep pressing.
Because not only is there a possibility of adding another kind of treatment that would be making the patient better. But there's also the possibility that we might need to remove a medication that's interfering with resilience and recovery. The other thing is that We are in a country Which
Has restricted the availability of certain what are so called gold standard or definitive treatments and and one of those would be electric convulsive therapy. Now electric convulsive therapy we know is somewhat controversial in in areas. It's obviously a treatment that has both medical
And in some cases cognitive risks for patients. On the other hand. What's often appreciated and one of the reasons I mentioned the medical risks of depression. Is that depression?
When untreated. Has medical. and cognitive risks at all that have to be balanced against the risks of the and benefits of these treatments. But the number of sites that administer Electriconvulsive therapy has been progressively decreasing in this country.
Which means that access to this treatment Has become Progressively Limited even though for people who fail to respond to multiple different kinds of medications.
Electricovulsive therapy is sometimes the only treatment that will work. So let's if you're open to it, John, give people also A preview of maybe Some light at the end of the tunnel. We're going to talk more about
Some of the biological bases or Perhaps mistaken. hypotheses about biological bases of Depression, but could you give us just a a preview of As it stands today, what excites you about some of the findings?
Related to ketamine. as compared to other treatment modalities, and then I'm gonna come back to And perhaps this will be part of your answer, but limitations of the serotonin hypothesis, which has been pervasive. Certainly it is become on some levels a hypothesis that even lay people will throw around very casually. But I would love to know what excites you.
About Cademy and and Sort of variance. Thereof. If you don't mind, I might
Track the historical story. Because it it really takes us from The serotonin hypothesis to What's really Exciting. And
I told you this before and I really believe it that this is the most exciting scientific time in the entire history of the field of psychiatry, you know, that that we have been operating in some ways in the dark with not a very good understanding of what's happening in the brain for the last sixty years in the sunlight is really Just beginning to
penetrate into our understanding of the brain in in ways that are relevant to thinking about the biology and treatment of depression and and other kinds of issues. So the serotonin story. The serotonin hypothesis. Really. Emerge from
the appreciation of the effectiveness of antidepressant medication treatments. The first antidepressant that we had Which was discovered in nineteen fifty seven, which makes it one year older than I am. Yeah. was a drug called monoamine oxidase inhibitor. A drug
That prevented the breakdown of the of norepinephrine and serotonin to chemicals have that have been implicated in in depression. And it's a great story because the first monoamine inhibitor given to depressed patients was givenally Because it was a treatment for tuberculosis.
And they discovered that the tuberculosis patients Their tuberculosis was getting better, but so was their depression. And so that that's how they discovered That first antidepressant. Then they discovered
Through a similar a little bit accidental. Pass. The Tricyclic antidepressants. Then much later.
In the nineteen eighties the SSRIs, which are like the tricyclic antidepressants, but act in a more narrow and specific way in the brain to block serotonin. We have taken. John, before we move on, and I don't want to throw us off track, so So we're we're at tricyclic and then we're gonna
move forward in the chronology, but I'm so curious Could you just briefly explain The mechanism by which MAO inhibitors. Improve.
Or I should say reduce symptoms of depression. What is actually happening there? So the way that monoamine oxidase inhibitors work is by inhibiting an enzyme called monoamine oxidase. which is involved in the breakdown The metabolism of the chemicals norepinephrine and serotonin.
Yeah. And so when you give a monoamine oxidase inhibitor You Raise. The level of serotoninphrine in
The synapse. The space between nerve cells. and you increase the stimulation of the receptors for those chemicals. And in that way They're a little bit like
The SSRIs which Instead of preventing the breakdown. They prevent Sells from
Taking up. Out of the synaptic space. These same chemicals. The monoamine oxidase inhibitors also Release
A bit. Norepinephrine and serotonin. So that they release a little bit. And they prevent the uptake.
Antidepressant. They have some side effects that uh and risks that have limited their use in modern clinical practice, but in the era in which I Trained were very commonly prescribed. What are the main risks and side effects? And this is tying into something that's been recently on my mind, which I'll I'll bring up in a second, and then we'll hop back into the chronology. I won't lose track. But what were the side effects and uh what are some of the risks of of those monomine oxidase inhibitors?
As you recall. These Manu Minastase neighbors cause A form of release of neuropinephrine and seroton and prevent their breakdown. So anything independent of the m drug increased
the release of Norepinefin and serotonin. had the potential to produce massive increases in norepinephrine and serotonin the body. And so the the problem you get in if you have a massive increase
in neuropinephrine is you can get big increases in blood pressure that can can be life threatening. And if you get a big increase in serotonin you can develop something called a serotonin syndrome, which can also be very serious medically. It raises body temperature and creates a stress on the system. And the thing was that the kinds of things that most commonly were a problem is that there's a compound in aged cheese And wines.
in lots of really things that people really enjoy eating. These kinds of foods have a lot of tyranine. And so people would like be on a monoamine oxidase inhibitor and have several glasses of Chianti with uh cheese pizza with lots of cheese on it, aged cheese, and then their blood pressure would go through the roof. And some people would even have a a negative r a really bad complication like a stroke or something like that. That happened
vanishingly, extraordinarily uh rarely. And plus they can these medications can interact with certain medications, a particular worrisome interaction was They're involved with the metabolism of meperidine or demerol. And so there was a famous case in New York.
of someone who was on a a monoamine oxidase inhibitor who was then given demerol in the emergency room and then died from the interaction. So They're really great drugs, but but they do you do have to have to be a little careful with Just a quick thanks to one of our sponsors and we'll be right back to the show.
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So the reason I'm Doing Some digging on this is There are several reasons. The first is that
There's a collection of presentations from a symposium called ESPD fifty, which Investigated. Specifically. A
Monoamine oxidase inhibitor. Called Harmion. And the reason they were looking at Harmine is because Harmine Harmeline And uh believe there's at least one other
Monoxidase that we've identified exist in the Benisteriopsis copy vine, which is one of the two typical ingredients in ayahuasca. And The reason that I bring it up is that for a long time For simplicity, I'll just say Western scientists.
Largely dismissed. The vine. And ascribed to it one purpose, and that was to render the N DMT found in Chakruna.
They're the leaves of this shrub. orally available so that people could have these visionary experiences. Lo and behold A number of things are true, or appear to be true. One is that The vine itself and these monoaminoxase inhibitors, which should not be a surprise to you at all, it wouldn't be, have in and of themselves therapeutic effects, including increasing
brain drive neurotrophic factor of BDNF. And That's part one. Part two is and I did not realize this, but you were just discussing H cheese, wine, and the
Well Some Again, for simplicity, Western scientists have also dismissed what are sometimes referred to as dietas or preparatory diets related to ayahuasca consumption. And for hundreds and thousands of years. at least w so we believe, given some of the carbon dating that has been done in places like Chile, although with different compounds, but Outcome related.
There are restrictions. There are food restrictions that include Cheese. and fermented products. I don't know the term and content of fermented foods. But certainly alcohol alcohol prohibitions. And these have been And still are by many people dismissed as pure superstition. Well, it turns out that
jungle biochemists who have had the opportunity to run trial and error for f at least a few hundred years may have figured out a few things. Which is not to say they're aren't tremendous amounts of superstition In many of these traditions there are But I do find The
Duplication on these two lists to be notable. That's why I bring it up. So to come back to the the chronology. You went from MAO inhibitors to Tricyclic. antidepressants and then we're we were moving Closer to present day, if if you if you wouldn't mind continuing.
My colleagues The people that I trained with and and have had my Career with. In particular my mentor, a Dennis Charney, with whom We did the first ketamine study.
You know, they spent their careers trying to figure out What was the role of These chemicals, serotonin andphrine. in depression and anti depressant treatment. And
This was an era of really Clever. Creative psychopharmacology research. It's before Cat scans.
Before M R I For Femerite. For PET scans for any of that. And they had to use pharmacology And look measuring neuroendocin responses and behavior as a way to try to
Figure out what was going on in the brain. So just to pause for a second. So for people who may not know the acronyms, we're talking about basically a lack of imaging. So you have an inability to look Inside the brand. So you're trying to If I'm hearing you correctly. You're trying to infer what is happening inside by observing what is happening outside. Is that
That's right. So the brain is Perhaps the most complex structure in the entire universe. And you're trying to draw inferences about what's happening in certain connections.
By whether When you give a drug, does the cortisol level go up? Does the prolactin level go down? Does it like so it's really Rough and ready. Neuroscience. And
It's a little bit like Ptolemaic astronomy. In the sense that You have no understanding about really how the universe is constructed. And yet
Remarkably. The Ptolemaic astronomers could build elaborate explanatory systems to explain how the planets were moving in relation to each other. And that's really Where psychiatry was. in the eighties. And this was the
bleeding edge. of mechanistic research. In other words the first in some ways Kinds of mechanistic research going on in psychiatry and What they figured out.
Building on the work of an alumni. A graduate of our our department who who moved to McGill Claude de Montigny. They developed a strategy For depleting the body of
Sotonic. It builds on the idea that Tryptophan, which is the precursor for serotonin, is an essential amino acid. So if you deplete the body of tree tryptophan, then the body All over the body you can't make any more serotonin, and you can drop the level of serotonin in the blood and in the body and in the brain. And we could use that technique. Pedro Delgado really led the
clinical projects in those days. We could use that technique to ask First the question. Which Is such a fundamental question, but had not yet been answered. Is serotonin necessary for the antidepressant effects of prosec?
Couldn't be a more Basic question. But we didn't know. So what Pedro did was to deplete the body of serotonin using the this tryptophan depletion technique, which involved giving all the other amino acids
tryptophan restricting and then giving all the other amino acids to drive protein synthesis. And use up all the free tryptophan so it couldn't be used to make serotonin. dropping the serotonin levels and producing a brief relapse of depression. And so you could show that the antidepressant effects of drugs Like
Prosic Dependent on The ability of the brain to in on an ongoing way to have a big supply of serotonin. And that was really important. And it really supported
mechanistic ideas that had already been underway In a series of pioneering laboratories around the country, including the Laboratory of Georgia Aganian at Yale, that at neuroadaptations Associated with serotonin synapses really Underlay the
Antidepressant. effects as an initial and uh in some ways ongoing. mechanism of action for the SSRI antidepressants like prosec. But When you depleted serotonin.
In healthy people. You did not make them depressed. So There had been an idea Floating around.
Yeah. Depression. was a manifest Of a pure deficit. In
Serotonin. Lower serotonin. You get depressed. Take a Prozac. You get underpressed. We knew that
I idea was wrong right from the start. Because you take a tablet of Prozac You do not Yeah. Underpressed.
From a single tablet or proz. It can happen. It's extraordinarily rare, and it usually doesn't last when that occurs. But the world is really complicated and uh maybe we'll come back to it. And what's complicated is That serotonin does have a lot of acute effects in the brain.
and a single dose of Prozac does change some things. So for example, Caser and Harmer at the University of Oxford in the United Kingdom. Has Done a large number of studies to show That some of the negative biases that people have
When they're depressed. Go away. At least transiently. With a single dose of Prosac. So it's not that there aren't some acute effects.
And that those effects aren't related to depression. It's just that The simple minded idea that Low serotonin equals depression. Normal serotonin equals
Healthy life. That idea is We knew that Pretty much from the start couldn't Possibly
Be true as it was initially suggested. The other thing I'll say just before moving on. Because there's a tendency to want to make the world simple. Either it's all serotonin?
Or it's no serotonin. But As I said. Would the Most complex structure in the universe really work in such a simple minded way that it had to be everything or nothing.
Probably not. And there are brain scan studies in depression involving Positron. emission tomography the work of people like Ramin Parsi and and others. That do find some
Changes in the regulation of certain Serotonin receptors. That may be intrinsic. to the biology of depression. So I'm not in any way Arguing for a really simple minded uh idea of depression. But I do want to highlight
That these Mano amine depletion studies were A Conceptual crisis like the Philosopher.
Thomas Kuhn. would say. You come to a point Where you have a body of theory. And then you have a single experiment.
Which in a fundamental way Challenges the idea that this idea that's Depression is simply a disorder of the very primitive And very few number of serotonin cells.
That live in a very primitive part of the brain, the midbrain and little bit of the brain stem. That these primitive cells could be the cause of This pervasive syndrome of cognitive behavioral et cetera, et cetera, impairment. Probably was
Just that idea itself was probably Flawed from the start. But Like all conceptual crises. It was incredibly stimulating in terms of creative thought about what the alternative ideas about depression.
And so In those days when these experiments were going on. Dennis Charney, who is the Now my boss as well as my collaborator. His office was upstairs. On the ninth floor, he had a really good view of Long Island Sound and I had a l little office on the eighth floor.
You know, I would go up at the end of the day and we would talk about science and all the things that are going on. And we wrestled with this. This is one of the things That we wrestled with a lot. If it wasn't serotonin. Simply.
What could it be? And The answer was That we came to us Let's turn it on. Let's turn the brain on.
On its head? Gosh, that's a really Weird turn of phrase, but yeah, let's turn this problem upside down. If Depression isn't a disorder of these really simple And few
Serotonin cells in the brain. Then maybe it's a disorder. That has a major part of its biology. In the parts of the brain. That are responsible
For regulating emotion. For processing reward. for making plans for interpreting the world In other words.
The higher cognitive centers like the cortex. Cerebral cortex. and the higher emotional centers in the limbic system. And there was a profound consequence of that small conceptual shift.
Because The cortex in the limbic system are predominantly driven by different chemical messengers. than serotonin and arbinephrine. Serotonin and Norepinephrine.
Tune and modulate the activities of the higher brain centers, but it pulled us To think about. the intrinsic circuit mechanisms of the cortex and limbic system and to try to Approach those circuits.
Directly. with pharmacology. These higher brain centers predominantly use Two neurotransmitters. Glutamate.
Which accounts for something like ninety percent. Of the synapses of the brain. The main information highway of the brain, ninety percent of the synapses. The main excitatory driver for brain activity. And Gabot.
Which is the main inhibitory transmitter of the cortex. The function of the cerebral cortex and limbic system is essentially a dynamic tension. Like yin and yang. Between
Factors driving excitation. the magnitude of excitation and the timing of excitation and the spatial Dispersion of activity in the brain. And Gabba.
Balancing and inhibition. And we thought, well Gee. How can we Tap into
Signaling. True. The main Information highway to bring. And it's really remarkable, isn't it? Serotonin is maybe
A couple of percentages of the synapses in the brain. Glutamate is ninety percent. Psychiatry have been studying. Depression for fifty years by that point. Put all of its chips on serotonin and rubber nephrin to two percent.
And completely ignoring Yeah. Ninety eight percent of the other mechanisms in the brain. So we thought well let's
Try that. So by that time I had been studying for At least five years I had been studying ketamine to try to understand its role in Snapdic signalling. In disorders, problems, cognitive processes, behavior, other things related to schizophrenia.
We thought well We can use ketamine to probe the integrity of glutamate synaptic signaling, that's been what I've been working on for the last five years. Let's bring that. into testing depression.
And we designed a study. And we gave ketamine. To depressed patients. And ketamine did Transiently.
Produce some Cognitive impairment and um Changes and things like that. An hour or so. And then those effects went away.
And you know, we saw Nothing special. Cetamine has the same kind of effects. In depression as it does in healthy subjects. And then the day test day went on.
And within a couple of hours people said, You know? I'm feeling a little better. We thought Right. You're feeling a little better.
Great. Fantastic. And then we sent them home. And then we called them the next day. Did you have any bad effects from your ketamine exposure? Do you have any hangover? Do you have any Lasting effects Did you sleep okay last the night before and they said
You know what? My depression's all better. And we we said What? And
Okay. We know that These kinds of things. happen, you know, you give somebody A glass of tea and the next morning
A cup of coffee. A uh really good quest song. And the next day they really feel better. Fantastic. But that we know we don't really we didn't really think You know, with the first can't rely on the croissant effects. Exactly. But it happened over and over and over in this
Pilot study. And We didn't really No. Exactly what to make of it.
And we started Sharing the findings with people. And You know, science is just Wonderful because
The dominant mode of Interaction in science is skepticism. So We would present these data and we'd say, No, people got a dose of ketamine and the next day they were uh several of them were better. And they'd say, Right. You know, skepticism.
Overall. And It took a long time. For other groups to Even try
To replicate. that ketamine finding. First. results for the first time in nineteen ninety seven. And the first paper.
of a study that tried to replicate ketamine effects came out in two thousand and six. And that was because Dennis Charney had moved to NIMH, he had built a program, he and Husseini Manji and Carla Sarati Designed and executed a study. To replicate the initial findings.
And you know what? Basically exactly what we found. And then More and more groups started to replicate that work. And
Find the same thing over and over again. And People started to believe it. And You know, something really remarkable. happened, which is
Yeah. I started to give talks and I would describe how We gave ketamine this this research procedure. And it produced these antidepressant effects and now what we need are definitive trials. 'Cause we really have preliminary evidence, but we really need definitive trials.
And then psychiatrists would tell me from the audience What are you talking about? I've already started using ketamine in my clinical practice and I'm having great results. And I would like Go pale.
And I would freeze And I would say Well It's still an experimental procedure. It's not we don't have enough evidence to really adopt it yet in clinical practice, but that's really what happened.
Which is somewhere in between ninety seven and I guess the first presentation And the early two thousands that that I started to hear about It's Use.
already in clinical practice. Which doctors can do because it's an FDA approved drug. And the other key turning point. I think for the feel came in two thousand ten. with the work of my late colleague Ron Duman. And Ron was
Just an incredible trailblazing scientist, remarkably brilliant in talented neuroscientist and a wonderful Person and colleague and friend. And he did this study. In collaboration with
George Aganian. No. For those In the psychedelic world you may be familiar with it, name. But George Aganian.
And Danny Friedman, who was his mentor around Nineteen sixty, nineteen fifty eight, nineteen fifty nine, nineteen sixty, the early Nineteen sixties. Did some of the first studies to implicate serotonin signaling in the a mechanism of action of psychedelic drugs. And George was the first
person, the first physiologist to record The activity of serotonin nerve cells in the brain. And showing that psychedelic drugs changed the activity rate of these serotonin neurons, giving one of the first neural signatures of psychedelic drugs in the brain. As well. So it's really kind of
Life goes full circle in a way. That George Agajanian and Ron Duman together Showed That If you give a dose of ketamine to stressed animals.
that it produced rapid and profound biochemical Electrophysiological And structural change in the brain. Within twenty four hours. And this builds on an idea.
that really came first from the Pioneering scientist Bruce McEwen. Who is just a w another wonderful person and and scientist who is based at the Rockefeller University.
That If you stress animals Severe stress over a period of time long period of time. that not only do they have behavioral changes, but that those behavioral changes R
Associated with the loss of the synaptic connections in the brain. that the circuits involved in the regulation of cognition and mood Lose A small percentage of the synapses.
But enough. They have profound Functional and behavioral consequences. Stress related behaviors. Impairments in cognition.
Difficult solving problems. Difficulty regulating emotions. Excera. All of these behavioral changes that we associated With
stress related changes in animals and depressions in people, that loss of connections between Neurosells in the brain are part of that. series of events. And that within twenty four hours of a single dose These brain connections could go back.
What a profound new way of thinking about what we're doing in the brain. And One of the things that's Maybe a subtle point. But to me profound Is
I view depression treatment as about thinking about how we restore Behavioral and emotional resilience. And how we can tap into the brain's intrinsic capacity For resilience to promote behavioral resilience. So what we've done.
By giving a single dose academy. Is We're not Making random new connections in the brain. That would be a bad thing.
The brain is not Chaotic. Structure. And we don't want to make random connections because that would make Things worse in theory. I mean that's what you get with epilepsy.
a growth of inappropriate connections and parts of the brain. What we do. Is overcome whatever intrinsic Resistance there is To recovery.
In the brain. Two Give a brief pulse of Academy. And enable A restoration of the brain's intrinsic.
capacity to develop and maintain structural connectivity. And we think that is a part of the story. of how ketamine works in the brain. That insight happened around two thousand and ten and that was really Fundamentally important.
In terms of driving The whole Field forward and helping to reduce A lot of the scepticism about ketamine. As a treatment.
So looking at the timeline. I just want to recap a little bit and I have several questions because I love the history of science and I feel like One of the best ways to try to hone
One self, not speaking for myself because I'm just a tourist, but to prepare the mind for future discoveries to examine past. Discoveries. So let me just lay out a few things for folks. Number one. Is
Timelines. So animal studies in the early nineteen nineties suggest there might be antidepressant effects. I'm gonna come back to that. Nineteen ninety seven, your first presentation of results. Two thousand first paper is published, two thousand six publication of the first replication. Big deal. That was in treatment resistant depression. And then we may come back to this, but two thousand nineteen FDA approval of As a ketamine.
So my question to begin is related to Ron Duman and the animal research with ketamine. So for people who really have no history on ketamine
And I want you to fact check this and and correct me if I get anything wrong, but ketamine is a dissociative anesthetic. It is widely used, very inexpensive. it is partially so widely used because it does not at least normally suppress respiration. So you find it being used in military capacities in the field in veterinary medicine, but it's not a horse tranquilizer per se, which is I think what some people
believe, but it is used in medicine and it is one of the world health organization's most essential medicines. I mean this is a pervasive An aesthetic. How did Ron or others involved with the annual research even choose that. As in
intervention to begin with. So first I have to tell you a about a cartoon that I saw about ketamine related to its use as a horse tranquilizer. Which is it's uh The cartoon says And it's r I think related to the abuse of ketamine. It says ketamine and it's got a picture of a horse.
Just say nay. N E I T H That's good. At the time that I was Studying ketamine.
I was interacting regularly with this broader group of people. Ron Duma was at Yale, George Aganian at Yale. Eric Nestler Dennis Charney, obviously my collaborator and mentor. And many other people.
So One of the things that was really striking Was When we had made this finding with ketamine and and shared the results with Ron.
I had the feeling that Ron Thought that it was more important Then we did. So You know, he would say
This is like the most important finding in fifty years. And we would say, What? And so he was really highly motivated to try to understand how ketamine worked and his own research. was in the area of the basic neuroscience of stress and antidepressant. He was the first to show that antidepressants
stimulate something called neurogenesis, which is the birth of new nerve cells in the hippocampus In animals and And there's been some work to show that that might happen in in human brain as well. And he was one of the pioneers of studying the role of
Neurotrophic signalling. in depression and its treatment. So his laboratory Had all the pieces of the story. About how
Nerve. Growth. might be involved in antidepressant treatment. And so he was in some ways Uniquely
situated to discover this Profound structural change. And what was really important about the work is not only that they describe the profound structural change, but they Map the molecular signaling mechanisms. that you alluded to about nerve growth factors engaging
A fundamental mechanism for resilience in the brain, these growth factors as a consequence of chemical communication in the brain. So Although ketamine is a glutamate. Receptor Blocker. One of the things that it does is
is block the excitation of inhibition inhibitory cells. That's a really complicated It's like If you had a break. And then you had another brake that you stepped on to relieve the brake instead of stepping on the gas pedal.
That's what ketamine is like in the brain. So ketamine Allows more glutamate release. To happen in certain circuits of the brain. You get a pulse. if you will, of glutamate, which is good for the brain.
As opposed to sustained high levels. of glutamate, which is toxic for the brain. The brain is really sensitive to temporal dynamics. So a pulsive glutamate is good. That stimulates A type of glutamate receptor.
That Triggers the elevation of BD and F levels. It causes a local seepage of PD and F the ner nerve growth factor out of the nerve cells. And activates. Signaling.
And then Aqu Way station. And I'm gonna get a little technical. Because we're I know we're probably gonna come back to this point later.
A key way station in the signaling of the nerve growth factor. Is a protein in nerve cells. That's got the Name MTOR or MTORK. An MTOR.
is the mechanist is called is an abbreviation for something really complicated, the mechanistic target of Rapamice. And It turns out that if you activate the MTOR Then you
activate all of the downstream mechanisms that lead to the regrowth. Of these. And stabilization of these New synaptic connections. This might be a good time.
to come back and think about a little bit about the complexity of the neurobiology of glutamate abnormalities and depression. Is this a good time do you think this would be a good time to do it or do you think we should do that, but I want to Just follow up on what you said to ask. How was the hypothesis formed? At all.
That Ketamine. Instead of A million other interventions or pharmacological tools.
might be useful for Preparing. The Structural damage of stress. Or alleviating.
Depression. Was it something that was observed in the field? For instance, one of the rumors that I've heard is that veterans who are administered This anesthetic seemed to experience less PTSD that was somehow recorded in the field, and that led to hypothesis generation and and use of ketamine That
Seems pretty tenuous. I don't know if that's true, but how did it go from An aesthetic to Of all the things we could choose. We're in a Mess around with ketamine.
First off, I love hearing stories about how I and uh Dennis came up with Cademy for depression. I just would my like people. I know it's like Oh?
It's a great idea. To be clear, this isn't specific to you. It's just I'm so fascinated by the the genesis. stories of these things. I think they're important. So I'd love to hear the
The real story as opposed to the Santa Claus version. So the real story Is not related to depression at all. It's related to schizophrenia. So it so happens In the
Great cosmic Universe of coincidence. The A friend Of my dad's
In Detroit. And his family was a friend of our family and we went on vacation together. I remember intertubing down a river in northern Michigan. I grew up in Michigan inter tubing down a river
With his daughter we were maybe ten or nine or ten at the time. His daughter is now is named Joan Luby. She's now an endowed professor in an expert in child psychiatry at at Washington University in Saint Louis. Anyway, this fellow's name was Elliot Louby
And in nineteen fifty nine. He published a paper. That was the first time Fencyclade. or Cernal was given to a human being. This happened at the Lafayette Clinic in Detroit, uh an entity, a building which no longer exists, and un unfortunately. An extremely
Extremely Generative. Place in its era. And he said If you gave Cernal.
Which was the company name for Then Cyclodine PCP Angel Dust. If you gave it to people It produced something like schizophrenia in them. The thing was
That's nineteen fifty nine. And the mechanism The fact that it blocked the N MDA glutamate receptor wasn't Identified until the mid nineteen eighties or Eighty three, eighty four.
So It was this Fascinating observation. Which couldn't go anywhere scientifically. But they did research and this is gonna bring us to other topics that we'll probably talk about.
In which they compared The effects of Pencycladine. to the effects of LSD in people. Mm-hmm. Good old psychometic. Yeah.
But just Unbelievably courageous and creative trailblazing psychopharmacology. At a time when they just had no idea what was happening in the brain, the neurobiology. And In the early sixties.
Another Trailblazing scientist also associated with that group was a guy named Ed Domino. Who was a pharmacologist Great name too. Yeah.
My Cousin. I apologize for mentioning his name. Who is a medical student
At the University of Michigan. brought me to sit in one of his classes when I was applying to medical schools. And it just happened to be Ed Domino. And my friends, my my cousin and his friends Ed Domino.
came up to talk saying a bit of the Van Morrison Song Domino. Uh which you which you may may be familiar with. Anyway. Okay.
Unforgettable to me because Ed became a very dear friend. And colleague uh over the years. But And Was the first to give
Cadmine. Two. Animals and humans. Because it was a shorter acting Safer version of a
Small structural modification. In the Thencycladine chemical structure. that made it possible. to be shorter acting, more manageable, easier to control.
And for what reason was he administering the ketamine in those particular studies? For anesthesia. For anesthesia. Got it. There was a A fellow
Corson, who was working with him on some of those studies. So there's a line that I love. I love Portentious lines. In scientific literature.
I think it's the last line in the Watson and Crick discovery. Of DNA where they say It has not escaped our notice that the elucidation of the structure of DNA may have relevance for
the transmission of genetic traits or something like that. Something unbelievably understated. There's a line in one of the The first papers on ketamine May maybe the first paper.
Yeah. And Domino wrote, which was When you give ketamine to humans we notice that sensory information can get
To sensory cortex unimpeded. But is altered or blocked in its transmission to association cortex. We call this Dissociation.
And the Process dissociative anesthesia, something like that. And Wow. What a profound
section of a paper in an anesthesia journal. But really what happened was that This group of pioneers Had
An incredible tool. But no conceptual framework. To use it. To generate Real deep scientific insight.
And that's because they were Thirty years. ahead of the field. And You know, it wasn't even known that there was a binding site.
For Fancyclade. So First studies published in nineteen fifty nine. Wasn't even known that there was a binding site for fencyclidine.
Now by binding set you mean a receptor. That it could Some kind of something. That where the drug act in a They didn't know that it acted in a specific way, but
At a specific target in their brain. What that target was, they didn't yet know until n the early nineteen eighties that it was a glutamate receptor. But in in the just didn't even know that there was a binding site for fencycleating until uh landmark paper in nineteen seventy nine from Steve and Suzanne Zuckin. So It was
Darkness, right? It was like The middle ages. Of neuroscience. And so they they had a brilliant insight, but they couldn't Take it anywhere because there was no
Framework for it. So Around eighty eight eighty nine. Join the faculty in eighty eight.
Uh yeah. And I wasn't sure what I was going to do. And my boss said to me, D Doctor Chinese said. Well
You can be the Chief of the Schizophrenia program. Or the deputy chief of the PTSD program. And I said, Well I like the idea of being the chief.
That's why I went into the field of schizophrenia research. And so I found myself as a new Completely Inexperienced. Schizophrenia researcher.
Setting up a research program. related to the neurobiology and treatment of schizophrenia. And It happened. to be just at that time that clozepine, which is an antipsychotic
medication that's a little bit more effective than other Antipsychotics. Was introduced. And I've been raised studying monoamine pharmacology. That's what I knew that's really
What I a had anticipated studying. I treated patients with clozepene and and I thought it was a pretty good medication. But I didn't want my legacy after forty years. of schizophrenia research to be that
He figured out why clozepine was a little bit more effective than other antipsychotic medications. So I I I felt like I just had to Go out of the box. And
This is where my father's legacy really had had a big impact. It's like Well If you could do anything. What would you do?
And it was like well I don't want to study These few cells. Contributing to Dopamine or norepinephrine.
I wanna study the main information highway of the brain. And Just a few years before they figured out. That Drugs like ketamine, PCP.
blocked this receptor for glutamine. And so What brought me to Cadmine The effort to probe glutamate synaptic function in higher cortical
Circuits. As a way of understanding the cognitive impairments, negative symptoms, and other aspects of schizophrenia. So our path in our institution Might. Was
the development of a research program on glutamate psychopharmacology. Developing Circuit and mechanistic hypotheses. And one of my collaborators in those days.
Was A pharmacologist named Beta Mogadum. And in nineteen Ninety seven. She published a paper.
That showed That Ketamine released glutamate in the brain. Yeah. The very same doses that we were using, the equivalent of the very same doses.
That we were using to Produce. Changes in cognition and psychosis. related to schizophrenia.
And You know, that line of research has its own story because we began using the Cadmine administration as a platform for trying to identify novel Alternatives medication for the treatment of schizophrenia. And and that has had its own life in story in. Maybe some day we'll
We'll talk about Yeah. One of the things Beta found which turned out to be profoundly important. For the antidepressant story. Was
If you give it at the sub anesthetic dose that we use To study cognition. Yeah. Release glutamate. If you give it at anesthetic doses, it depresses glutamine, and it's not antidepressant at those doses.
And if you give it a little bit more. At even a little bit lower level. It doesn't stimulate the glutamate release. There's this tiny narrow window. Where it's reducing dissociation, psychosis, and a number of the other effects that we're really interested in. Where it works.
And Turns out that that little narrow dose window is the dose range where it works for the treatment of depression. We just Stumbled on that. Because it was optimal.
You know, the thing was we couldn't give higher doses to people. Because we needed them to Perform cognitive tests and be able to answer our questions. When we gave people Much higher doses of ketamine.
They would have Pretty interesting experiences. But they couldn't answer any of our questions, so it wasn't any good for me as a research tool. I mean, I remember one person that we gave this higher dose of ketamine too.
Who Couldn't answer a lot of our questions. But he was holding on to the bed really tightly. And um and I said.
Well, that's interesting. Why were you holding on to the bed? He said, Well Basically the dress the blue in the dress of the interviewer had become outer space The white polka dots in her dress had become planets and solar systems.
And his bed was flying among the planets. And the and the uh You know, uh the outer planets. And he was afraid that if he let go of the bed that he'd be cast adrift in outer space and and not make it back. Well That was really fascinating. Seems seems reasonable. Yeah. Was really, really interesting. But
Useless. I couldn't get him he couldn't do any tests, he couldn't perform anything. So what that essentially did was Create The upper bound of the dosing that we were using with ketamine. And then the lower doses Just Turned out to be completely ineffective and they have have repeatedly
uh been shown to be so in single doses and antidepressant trials. So that's how we got to ketamine. And that's how we got to the dose of ketamine and the route of ketamine that we use. in the treatment studies because what we did was to adapt The dose and the duration of administration. Like you could have said
Why forty minutes? Well Because ketamine is such a short acting drug. We administer it for forty minutes. To give us a time window.
Where people are having The subjective effects of ketamine where we can test behavioral incognition. That's Why we had the slow infusion in the initial study. And we just Imported that into depression and that has become
The standard Treatment. infusion paradigm for Recema Academy administration for the treatment of depression. So John, may I may I interject for a second? So I wanna talk about I think we'll we'll get to this pretty quickly.
Basically what you consider best practices in terms of format. Dosing schedule, et cetera. For And if you want to
Take But I would love to Have you just translate an earlier definition which was in more let's just call it science speak for the lay person, and that is a definition of dissociation. And then
Whether that is a feature of Or a bug, whether that is important for the clinical outcomes or it is a side effect. to be removed. And this is highly relevant to the broader conversation, including psychedelics, because there are many Efforts. in different camps, some who believe the say psychedelic effects are critical to
Could you define dissociation and then Share your perspective on whether It is helpful. Aka desirable or undesirable.
In the effects that we see. The antidepressant effects. You know, sometimes I Have started papers on dissociation and stopped. Because
I would get hung up on what the definition of dissociation is. But Our Consciousness. Our experience of the world.
Our sense of ourself in the world. Our sense of our bodies. Our sense of ourselves Embedded in time. All of these things which
People take for granted. Are constructions of our brain. Active constructions. And When these fundamental
aspects of the organization of consciousness. Are perturbed. We experience ourselves As disconnected. From
Ourselves. Other words depersonalized. Or in an artificial state. Which is also called derialization. In other words, that you're in an altered Reality.
And those States of derailization and depersonalization. As well as distortions. In R
Perception of ourselves. And the perception of the world as integrated. are collectively what we tend to refer to as dissociative states because Dissociation meaning disconnected from what's going on around us. But really it's a much more profound
And nuanced. idea. Because you can have some Distortion. of dissociation in some dimensions and not others.
And it can be very nuanced. I got interested in dissociation. Because Of working with
Vietnam veterans. with post traumatic stress disorder. For whom Dissociation is a Complication.
or a part of the syndrome of post traumatic stress disorder for many people. And it's a whole nuanced range of things from these states of feeling disconnected and That things are not real To sensory distortions. Two
What people know as a very dramatic aspect of PTSD which are these flashbacks where people are completely absorbed in another state. and lose touch with what's happening around them. And so One of the things that was exciting about the initial ketamine research
Was It was not only Providing us a way A new way to think about the neurobiology
of psychosis and cognitive impairments associated with schizophrenia. But it was also at the same time providing us with really the first Pure neurobiological path. to studying the neurobiology of dissociation and PTSD and that's a whole other
Kind of. Discussion which we can come back to. So What about dissociation in the antidepressant effects academy? This is really an interesting and complicated question. Because to really answer your question you have to acknowledge
I have to acknowledge that I come from I'm a Translational neuroscientist and psychiatrist. I do work And
Trying to understand the most basic aspects of Biochemistry, synaptic signaling, network function, computational modeling, whatever. So There are aspects of engaging in treatment. That are not.
So close to that. Like what did it mean? To me to go through this experience. And so a lot of people say that the dissociative experience is a very meaningful
experience for them. particularly if there's some kind of guided experience to do that. And I have no argument with that whatsoever. I Why not? In fact, that's great.
But I've seen a lot of people who get ketamine. For treatment. And a lot of people who just get ketamine. I've given
Well over a thousand doses of catamine to people. For him, it's not really that much. I've had People say things like Well
My parents scrimped and saved to send me to medical school and now Um Losing control of my thought processes during ketamine. Um Throwing away my parents' investment.
These kinds of scary thoughts. My organs are being replaced with machine parts. That sounds unpleasant. Yeah. You know, stuff like that. And that is not a productive insight and it's not Healing, it's not important for them to even remember that after the ketamine is worn off. So
I would say the dissociation is clearly not A necessity in terms of producing attitude change and things like that. I would also say that some people they get the ketamine.
And I once had a g treated a guy or it wasn't tr it was a research study, but I gave him a dose academy He had never He had come from a Mormon background, he had never had coffee, he had never had tea, never had alcohol, never smoked, never used any drug. And he described
Cadmine as the most fun he ever had. Since he arrived at Yale. So it was like a roller coaster of doing all these things. And so I mean it clearly has that Part to it. As well.
So the question is Is dissociation telling us something important? And I think There are ways that it does. On my side of the street.
Which is That as I've mentioned. It just so happens. Yeah. The dose of ketamine that is optimal.
For inducing the antidepressant effects. is for many people the dose at which they experience. dissociative symptoms. I mean the dose that produces therapeutic effects. The does that produce. dissociation overlap.
And so that if you're giving a dose of ketamine that is is not producing any dissociative symptoms. For some people it will mean you have underdosed. The Academy. And there are exceptions to this. In that some people are just not very sensitive to the dissociative effects of ketamine, but still get the antidepressant effects. And examples of those people are people who have a person or family history of alcohol use disorder, who seem to have a built in
Tolerance to the effects academy. As they do have a built in tolerance, some of them. to the effects of Alcohol. That's another story which we we can get to if you want sometime.
Uh my colleagues Arena Estel des and Sophie Holmes. And the broader group of collaborators with the Yale Pet Center. Did a study which I think is incredibly Important and interesting related to the Neurobiology Academy, which sheds light a little bit on dissociation.
And that is They had previously reported that a subgroup of patients with relatively more severe depression had reductions in synaptic density. And they could show that with PET scans with using a a molecular tag. For synapses.
And so okay, so there are the these depressed patients who have reductions. Yeah. Snap Dick Duncy. Great. So far that
could be relevant to translating the animal work to the human. Work. So you give a mixed group of depressed patients, some who have synaptic deficits, others who don't have synaptic deficits, and you give them a dose of ketamine, what happens? This paper was from this.
Same group published. This year. Turns out. That the people who have synaptic deficits Which are the more treatment resistant, the more severely ill.
More chronically ill. Exeter, et cetera. The more hardcore Depressed patients. They get a Dust Academy. They get us an increase in synaptic density.
And the more dissociative symptoms they get. The bigger the increase in synaptic density. And the bigger the increase in synaptic density The greater their clinical improvement. Pilot data really preliminary, but very interesting. So it suggests that in people who have synaptic density,
Deficits. That dissociative symptoms produced by ketamine can be A marker.
That you've gotten enough ketamine into the brain and you're triggering The therapeutic. Antidepressant effects. But what about those Other depressed patients. The other half of the patients with depression who are getting ketamine.
They don't have synaptic deficits. What happens to them? They get dissociation too. But Dissociation in those patients is unrelated to their clinical response. And if anything, it's not really so meaningful, but there's a little bit of a trend.
That the more dissociation they get. The less. Improvement again. Not meaningful. Maybe it's there, Louis.
So Dissociation in these two groups of patients. During Cademy. means two different things. In one.
It's a signature of clinical improvement. And another it's not. And what that highlights Is really Number one.
Ketamine is doing. Different things. Because the people who don't have synaptic deficits are still getting clinical improvement overall. But they're not getting clinical improvement.
That's related to the restoration of structurity. They don't have that kind of depression. They don't have the deficit in synaptic density and it's not re growing. So what could it be? So I'm gonna
Take a a step back. Two Point out that reduction in the density. of synaptic connections in the brain isn't the only kind of glutamate abnormality that we have in depression.
Another kind of abnormality that we've seen in people with PTSD and depression. And that was published. This year also. From The first author is a Cali.
Chaddy Abdullah who's now at Baylor College of Medicine. Using a really newfangled Clever Technical technique.
Where We can Give a Isotopically tagged. Infusion.
of acetate or glucose. and then track its incorporation into a variety of metabolic intermediates in the brain. This technique allows us To measure two things. One is
How much glutamate's being released? And how much metabolic activity is triggered. So you can say amount of metabolic activity. Per glutamate. It's a measure of the effectiveness.
Of that synaptic connection. How much is glutamate able to activate the brain? Lo behold. In some circuits in the frontal cortex. There's a reduction in the effectiveness.
Uh. Synaptic efficiency in Depression in the frontal cortex. Pretty Crude measure.
Not necessarily a deficit in synaptic. Density. But just a decreased efficiency. Exactly. Another
Deficit. So One of the Ideas related to that. Is
That probably that reduction in Efficiency. Efficacy. is present more broadly in depression.
And only a subgroup of the more severe chronic more treatment resistant depression. Have the Redu in Synaptic density. So
Maybe The reason That You get Some people getting better with depression.
When they get ketamine. Is For some people it's unrelated to the restoration of the synapses. And it has to do with An increase In the efficiency or effectiveness of these
Synaptic connections. What is the Evidence to support that hypothesis, a wonderful study conducted by Alison Nugent and Carlos Zerati. They used another cool Technique called magnetoencephalography. If you will, EEG but with a magnetic signal rather than an electrical signal. Gets a little deeper into the brain, a little higher sensitivity. And what they showed is that
You give a dose academy. Well first That sensory evoked potential is the ability of a sensory input to activate the brain, and you can measure that electrical or magnetic signature, if you will, using this technique. That's a little bit blunted in depressed patients. And
If you give a single dose academy to patients with depression, They'll discover. That there are two groups. Those people who don't respond don't show any change in the magnitude of this evoked response in the brain. But the people who do respond
Щоен? In the evoked response. The synaptic Connections get potentiated. Functionally.
Now not structurally. And so What we Take from these kinds of studies and others, like fMRI studies and other things from ketamine, is that ketamine has the ability both to increase The functionality of synapses
Something that probably happens very rapidly within hours of Cademan administration and for some people will be the Bulk of their antidepressant response. And restore synaptic connections. And that happens in a more delayed way. And is involved in sustaining for many people the antidepressant response.
And We know a lot about The mechanisms directly emerges out of
Ron Duman's work and Peter Mogadan's work, you know a lot about The biology of The restoration of structural connectivity and We know much less at this point about how ketamine. restores the efficiency of the network. But it's kind of
My sense is that both are probably contributing to the Clinical effect. So let me hop in for a second because uh I'm enjoying this so much and learning so much. And a few things come to mind for me. The first is that We're talking about the neuroanatomical changes, or maybe not neuroanatomical, but the certain activity changes. in some cases structural changes that you observe
And the clinical outcomes that you see Yeah. Different breeds of depressed patients, right? Those with lower density. I wouldn't use that word. Well subtypes. Subtypes. There we go.
I feel like kind of allowed to play it fast and loose since I fit into the broad category of someone who who has treatment resistant depression, so I f I feel like I can sling loosely. But you have different responses to different Types of depression and part of me wonders if their subjective experiences are also different. And just by way of analogy, I'll say
I think the that labels can be so reductionist that it's easy to run into confounding factors or to run into confusion. And this is true in many, many areas, not just psychiatry and it and I think about, for instance, cardiology and dealing with lipid markers that are out of whack.
And how Brute force. And non specific certain approaches are. High cholesterol statins.
Instead of automatically doing that, which can be a tool in the toolkit determining if one is a hyperabsorber of cholesterol versus a hyperproduction of cholesterol, versus fill in the blank, in which case your first line approach might be, say Something like Azetomibrazetia instead of a statin, which could then be looked at later if the sort of clinical changes aren't achieved. And Similarly, I can imagine that in a group of depressed, self described depressed patients, even if they take an assessment.
Like a not sure what the proper assessment would be, like a ham D or something like that. That The subjective experience, as you noted earlier in this conversation, for one of these subgroups could be and hedonia, right? So they have an inability to feel joy.
But they're not Stuck in a Endless loop. of perseverating Negativity.
And to just again I'm speculating here, but To to the to then jump from that. I can imagine that for some people Perhaps those who also respond to the dissociative effects or
Let me be clear. Have a high correlation of positive improvements. to achieving those dissociative effects with dosing, that maybe they're the ones who have this self-hatred on endless loop and the Dissociative effects have impart some of the subtraction of that. So they feel what it is like to exist without that loop playing.
endlessly and this is one of my And I am such a Tourist. So I wanna dive into this. Further with you, but Having gone through a five infus well, I was supposed to be six, I ended up doing five infusion sequence myself.
I was struck by how You can experience what it is like to not have. A loop. or a repetitive thought pattern. And that sometimes that subjective experience Putting aside that there are certainly other things happening in the brain.
can feel tremendously therapeutic even in the moment. Versus say perhaps that those who had positive outcomes, but didn't seem to need the dissociative effect. I'm simplifying here. Perhaps Just didn't have that loop issue. It was a it presented differently for them. These are just thoughts that are occurring to me as we're talking.
And We're gonna dig into all sorts of this. Let me ask If I may. Just because I think people are are chomping at the bit for this and then we're gonna go in a bunch of different directions.
If you had say close friend ended up working with you or a doctor you trust in a clinical capacity. With treatment resistant depression. What would the formatting Dosing, et cetera, look like
might it look like for that person, recognizing that maybe it's, you know, Migs per kigs or weight dependent or whatever. But what might it look like because uh before we start recording and also based on what you said perhaps 10, 15 minutes ago. There's a response curve. Well Too little Doesn't do the trick.
Too much also doesn't seem to do the trick. There's this Goldilocks. Narrow. Dosing window. But also there are all these other questions. Intravenous versus intramuscular versus something else. Is there therapy during the session or only before and after? So could you speak to sort of what that friend With
Someone who's highly competent with perhaps your input. What that experience of Kemy might look like. The first thing is The choice of As ketamine.
versus intravenous cateman. And It's really not clear. How They stack up against each other in terms of efficacy and tolerability.
There's a clear difference in Ease of use. Which is If you're the sort of person who doesn't like needles getting the medication intranasal is a huge
Benefit. And if you're the sort of person who doesn't like sticking things in your nose Then getting ketamine. intravenously would be a benefit. And that sounds like a trivial thing.
But There are a lot of people who don't get a lot of treatment because they're afraid of needles. And that can be a problem for For some people and as ketamine. can be given intranasely and that's really
It can be given in more settings that might be more congenial and all has all kinds of other implications. And for the sake of our hypothetical, let's say this person is not averse to needles, so I V or intramuscular is okay. So then there are some differences. That favorite. The intravenous.
One is that The intravenous dose is dosed on a milligram per kilogram basis. Whereas there's a fixed milligram dose for the Asked me. And because of the fixed milligram dose of acetamine.
Some people start It's recommended that you start At fifty six milligrams of academy. And then work your way up. If you tolerate that.
Two eighty four milligrams. And That means that for many people they're gonna start on a dose which is not the maximally therapeutic dose for them. Or maybe even
An ineffective dose for them. Before they get to A therapeutic test. And that means that they For some people that they have to wait till they get to the higher dose to get
Much in the way of clinical benefit. So that is a subtle point. But if you're if someone is getting to ketamine as a treatment because they want the rapid response. that there's a little bit of an advantage for getting the full dose of ketamine.
intravenously. It's a theoretical advantage, whether it's a real clinical advantage. Still early to say because we don't We'd only have good head to head. Data it's mostly derived from Secondary Comparison of secondary data, secondary analyses.
But for some people there may be an advantage of the intravenous dose. I'd love for you to also just speak to the cost differences, potentially. The cost differences As ketamine is a little bit expensive. Medication's about six hundred
A treatment. Maybe. You know, depending on where you're getting your treatment can be. Can be more. But it's usually covered by insurance.
at least in in many places covered by insurance, so it's More of a cost for the overall health system than it is often for the individual. But sometimes it's the individuals pay out of pocket. And ketamine is obviously generic and much less expensive.
So Let's say they are Suffering from acute depression. Maybe suicidal ideation. I mean putting aside the other precautions it might be taking in such a situation. But let's just say it's acute.
Depression. They're looking for Rapid antidepressant effects. What then? How many sessions over what period of time? What does a session itself look like? I would just love to
to know what's the the current State of the art without some of the forward looking stuff, we'll get to what the future might look like, but just as it stands right now, if someone wanted to go to a clinic today. This is an evolving Story?
And when we're talking about ketamine for treatment resistant depression It tends to be administered. In many clinics without any attendant psychotherapy? So for example, people will come in They'll get the ketamine.
They'll hang around for You know, another hour or two. And then head out. And They'll do that.
For the initial four weeks. At least four weeks. They'll do it twice a week. Most people after four weeks of twice a week will go to once a week. And if they tolerate that, eventually they'll go to once every other week.
And after a longer Term treatment several months. Some people will go to every three weeks, sometimes as infrequently. As once a month and be able to be maintained on ketamine after that. People will come in.
Do a short term Um Course. Six treatments. Ten treatments, twelve treatments. And they'll do that course
To get back. to a remission of their depression. And some people are able to then just stay on their on their ongoing treatment. Usually people are in some kind of ongoing treatment before they come to ketamine. We don't stop their standard medications basically. If they're taking a sedative medication during the day or anxiolytic medication like a benzodiazepine, we'll ask them to hold it on the mornings that they get their ketamine so that there's not an interaction there. So some people will just do a course and and then they'll be done, but others will need ongoing some kind of ongoing maintenance treatment to sustain the benefits.
So let's just say With someone who again friend of yours that you refer to a clinician you trust, would you in such a case tend to lean towards the four weeks of two times a week, then one time a week or Would you tend to lean Towards and again.
We said this in the introduction, or I will have recorded this by the time this comes out. This is not medical advice. This is for educational purposes only. So obviously speak to your own general practitioner or physician before considering anything like this. But Would you tend to lean towards four weeks, two times a week, and then the tapering, so to speak. Not tapering, but the greater distribution after that. Or the more perhaps aggressive higher frequency per week.
And then what does an individual session what might an individual session look like in terms of duration, milligrams per kilogram? psychotherapeutic rapper, if one. There's very limited data. Comparing modes of Academy administration.
There was a small study that suggested that three times a week, or modest study, that suggested that three times a week is no better than two times a week in terms of the effectiveness Or the duration of the antidepressant effects. So the the twice a week startup tends to be the standard Frequency There are some people who think that masked
ketamine treatments in other words. three consecutive days or multiple days in a row might produce more lasting benefit. I don't think we can conclude that yet from the from the evidence that we have. So we tend to do twice a week. In my view. For treatment resistant depression, this is a a pretty good strategy. The question about
How to wrap up Psychotherapy around this is really an interesting one. And and there are some important points to make About ketamine generally. Before going into the wraparound treatment because In my view, ketamine is an intervention.
And it's part of an overall treatment. In other words. Yeah. It's really. Important
That somebody is thinking about the overall well being of the patient. Providing support. Providing oftentimes psychotherapy. And thinking about
how the other medications that patients are taking are interacting with academy, and looking out in a big picture way. For the overall well being of patients. Kid means an intervention embedded in overall treatment. And for for many people There's some kind of ongoing psychotherapy. And there's evidence that because ketamine increases the neuroplasticity of the brain.
That there may be synergy between ketamine and other treatments that are given outside of the ketamine session, in other words, oftentimes sessions twenty four hours after. And that these sessions can both potentially extend and augment the effectiveness of Academy and such uh paper by Sam Wilkinson here at Yale suggests that. But there's also this interesting question about what do you do during the ketamine infusion.
And I think that this question is particularly relevant. When you're In a way treating the impact of maladaptive memories. What do I mean by maladaptive memories? I mean things like early life trauma. Current
Traumatic experiences Addiction. Which is a kind of reward learning, if you will. And What we have found in a study led by
Elon Harpaz wrote him. Is that If you activate trauma memories during the ketamine infusion. then the potency of those trauma memories is greatly reduced.
You know, people with PTSD Have a lot of concern. that treatment would in some way rob them of their trauma memories and and impede their overall ability to be Advocates for the groups
That they're often committed to. In other words say combat veterans to their fellow combat veterans, or Rate. survivors to other rape survivors. And oftentimes They believe that the
Trauma memories are A burden, but In some ways. valuable to them. And I would want to reassure anybody who is in that kind of state. That we're not talking about removing or deleting memories in any way. That all we're trying to do is to reduce the intensity of these memor so that they don't interfere with
the ability to achieve things in life and and they don't fear with quality of life. So If you activate a trauma memory or an alcohol or say for alcohol use disorder memory during ketamine, you tend to reduce the potency of that memory and For a long period of time, surprising period of time.
After the event. And what we don't yet know. Is how it fits in the overall treatment of these folks. In the sense that There are some signs that you can reduce the potency of a particular trauma memory.
So that you can talk about the worst event that ever happened and now it doesn't trigger a whole exacerbation of their PTSD symptoms, but it doesn't necessarily resolve the broader issues. And this is partly a bit w about what I'm talking about about the broader psychotherapic context for Ketamine, which is that there's an overall treatment process and then there's the intervention and what it what we can reasonably expect from it. But w you you can There is a sign that not only craving for alcohol, but actually alcohol consumption may be reduced from a preliminary study conducted by a group in London, Ravi Das's uh
lead author on that paper. It was in Nature Communications a few years ago. And people are trying to develop that into a treatment for alcohol use disorder. Quick question on that. Is that independent of the content? of the session, in other words, is that a
pharmacological effect, or is that in combination with, say, bringing up maybe early trauma that they attribute their Alcohol. Use disorder, alcoholism. Two.
This is one of the kind of really interesting byproducts of Ketamine. In relation to other drugs like the psychedelics. So ketamine.
Because it blocks the NMDA glutamate receptor. block certain forms of neuroplasticity in the brain. And we think That every time you activate a memory You put it
that memory into a somewhat labile state. In other words, you can strengthen the impact of that memory. uh by rehearsing it in a negative way. And in fact, we think that's part of how PTSD develops. You have a negative trauma memory, you bring it up You rehearse it, it gets more powerful, it has a bigger impact on your life. You do that over and over again, and the whole narrative starts to be integrated in your life like a bad habit and and your reaction and expectation of trauma becomes triggered every time that memory gets activated. Yeah.
The same thing as like an addiction. Use the alcohol you like it. Use it again, you like a little bit more. And you are using it over and over and over in those alcohol related memories. Have more and more power in the way you think and the way you act. And so by interfering with neuroplasticity and preventing that strengthening process, you actually weaken Yeah. Impact of those memories.
And we think that that can be helpful. That's maybe relevant. To some addictions it may be relevant to PTSD. And particularly relevant to PTSD because in a large For its kinda large study that we published this year. With about fifty patients in the group.
Where we compared standard dose ketamine to a lower dose ketamine to placebo in people with military related PTSD. That we found that there was a robust antidepressant effect. But a really weak and and didn't quite meet statistical significance effect on the core PTSD centers. So it may be that
If you want just the antidepressant effect. You can just give a dose academy to people with PTSD. But if you want the full blown maximal impact on PTSD, you may have to activate the trauma memories in the context of the ketamine infusion to get the full benefit. And that seems to be different than major depression, where a lot of people or a reasonably large number of people with not PTSD but major depression. will have a major clinical response just to the pharmacologic effect of the drug, even if no
Reactivating of memories happens during the infusion. All right, John. We've been talking about best practices. Let's get into some of the nitty gritty of dosing because it seems like Too little. Doesn't do the job. Too much
Also counterproductive. Yeah. What are the milligrams per kilogram? Best practices to achieve that. Let's call it optimal or at least land in the narrow therapeutic window.
We have the most information. For A forty minute intravenous infusion. So The forty minute intravenous infusion. Dose that we most commonly use is zero point five milligrams per kilogram.
And I'm told that there are some people who are very unresponsive to the zero point five milligram per kilogram dose and I've heard that there are some cases where you would go to point six or point seven and can sometimes Get a good effect.
But People generally don't go much higher than that. And similarly Generally speaking If you go much lower
Then zero point five milligram. For example down to zero point two Milligrams. It's Hardly effective for anyone.
There are some people who are extremely sensitive to zero point five where you can dial it down a little bit. Maybe point four milligrams per kilogram. And have less side effects and still get some efficacy. So it's a really narrow range. I mean if you think about almost any
medication that you take take aspirin. People take two aspirin, right? So It would be as if If you went down to one aspirin, you get no effect. And if you took two aspirins, it would knock you out. So the it with the forty minute in intravenous infusion academy.
It's really a very narrow window where it really works. And this is really important. Because uh there are some preparations that are being developed. That might be Oral.
Where The whole point of the treatment is to achieve a lower dose. Not to achieve the kind of blood level. that you get with the zero point Five milligram per kilogram intravenous dose.
And We don't know if those treatments are effective for various conditions or not really at this point. But whatever they're doing, they're not doing what the traditional antidepressant dose of ketamine is doing. So let me ask a few follow up questions. Well actually let me just
maybe explain for folks. If uh my audience is, as I imagine, a lot of Yanks meaning Americans. So Pounds. So for me Again, this is not perfect math. I weigh about a hundred and seventy, hundred and seventy five Let's just call it roughly eighty.
For the The zero point five Milligrams, so half a milligram per kilogram of body weight. What is the
rate of infusion. So if we're talking about a forty minute IV Is it equally distributed? In other words, is each minute, the first minute, second minute, thirteenth minute, fortieth minute, the same amount, or do you front load in some capacity a bolus so that a larger percentage of the total is administered In the earlier phases of administration. It depends really whether it's a clinical or research.
Procedure. So when we do research with ketamine we give a bolus and then a slow infusion to maintain that peak level of ketamine throughout the test period because this gives us a a longer period of time where the brain has a steady exposure for ketamine where we can really do brain imaging studies or psychological testing and things like that. When you get a bowl of academy.
It's like jumping into a cold pool of water. One person Told me he felt like he was rocketed out of the universe. Uh when when he got a big bolus of right up Because you get the full effects within about Thirty. Seconds or a minute of the infusion.
Whereas if you get the slow infusion in the traditional way, it's like wading into a pool. And so you gradually, gradually get the effects and it's much Less disorienting for people. People tend to like that a little better. From a clinical outcome perspective.
And just as a as an example. For folks because bolus may be a fancy word. If we say hypothetically Since it's a forty minute IV. For the sake of making the math simple, let's say somebody weigh forty kilograms.
So they're getting Point five milligrams per kilogram. So that would be twenty, if I'm not screwing this up, twenty milligrams total. One option would be the point five milligrams. Every minute. For forty minutes.
And if it were a bolus. Certainly there are some clinics I've observed. Who might administer twenty or thirty percent of that total in the first
So my question is For you if You think there are putting the Patient. Comfort aside, which
Maybe a silly thing to do. Well, if we put patient comfort aside, let's just say getting rocketed into a different universe or out of the universe is acceptable. If you're looking at clinical outcomes with depressed patients. Do you think there is a difference between the Continuous. administration, the waiting into the pool.
versus the bolus in the beginning and if you do use a bolus for a clinically depressed patient What does that potentially look like just as a percentage of the total over what period of time in the beginning? We don't have data to really
Inform us. But In theory, what we want to do is to get Up to a certain Occupancy of the NMDA glutamate receptor.
And as far as I can tell. That's the critical thing. So if we get there quickly Or if we get there a little more slowly. So far it seems like both have the potential to produce an antidepressant response.
What is Different is that If you took the infusion rate and doubled it. And so you said, We're gonna give you the same and I think the my math if my math is correct, eighty kilograms, half a milligram per kilogram would be forty milligrams. I'm gonna stick to my math should be right. Should be right.
Yeah. If you took those forty milligrams And you infuse them over eighty minutes. Then y you would get the same total dose, but the peak blood level. Would be half.
That would be as far as we can tell, that would be more like giving A lower dose. I don't think that would be as effective. And that's because we think that the antidepressant effects are kind of triggered. Bye.
A relatively rapid change in glutamate synaptic function. As opposed to a slower, smaller, more gradual effect in in in glutamate function. Is the choice for Ivy Over
Say. intramuscular injection, which is another Let's just call it common means of administration, at least by some therapists or facilitators, clinics, et cetera. What are the
upsides and downsides of that. Is it simply less predictable, less trackable? The sort of pharmacokinetics are more erratic and therefore for a scientific context it makes more sense to do IV. What are the pros and cons of one Versus the other. So as far as I can tell, the main pro of I am
is ease. In other words. You go up to somebody, you give them an injection And then it takes You don't know.
need an intravenous line. You don't need to wait around. And so in some context that's a little easier. But the main drawback is That With I injections typically people get the entire injection at once.
And That's not optimal for everybody because sometimes When people get upset during a ketamine infusion, or if they get a headache, or if they get nauseous, or if they even start to vomit. We'll stop the infusion and hold it. And
those side effects will go away on their own. But Once you've given the dose intramuscularly, you can't take it back. Yeah, once you hit the golf ball, he can't unhit the golf ball. Exactly. So then you're counting on the person being able to write out whatever uh side effect they get from the medication. What are some of the
side effects in session and how do you mitigate those side effects. For instance, when I had my own experience with Series of infusions. It was standard operating procedure to give I think it was eight milligrams or so of zoophren, so for sort of anti-nause. So nausea does appear to be quite common for folks, but it can be attenuated with Some type of medication beforehand.
Are some of the more commonly observed side effects in session and post session for that matter. And How do you attempt to address some of those? The one that's probably most disturbing to people is nausea. Nobody likes to get nauseous. Nobody
Likes to vomit. That I know of. So this is our friend. Which is an anti nausea medication works pretty well for most people. And
The nausea that you get with ketamine is a little bit like the spins that you get if you drink too much. I don't know if it was for you, but that for some people that Is the experience that they describe. And these are frameworks. Pretty well for that.
Medically. The People watch very carefully is blood pressure. So ketamine produces a small increase in blood pressure. And if you start with an elevation in your blood pressure before you get ketamine, it can boost your blood pressure up in a range where
You wouldn't want it. So When that is a risk, we pre treat e people with a Drug that blocks the Later. Adrenergic receptor drug like perpanolol, and that works pretty well.
Those are the main side effects that we have to manage. People often think that The main concern is the side effect of dissociation or Transent psychosis or Cognitive impairment.
And The main way we manage that When we're Administering the drug intravenously. is by stopping the infusion.
And so we can stop an infusion within thirty minutes a person is pretty much back to themselves. In even if they get the full dose, the side effects usually don't last that long. And in my experience. Of administering ketamine. A very large number of times.
The main thing that's helpful is getting right up to people and talking to them. So that they have a kind of visceral sense of your presence there and Assuring them that they're gonna be okay and that this isn't gonna last. Because one of the things that can happen during uh ketamine infusion is that people lose the perspective that the drug is causing
the change in their consciousness. And the best way to prepare people for that Is Remarkably. To prepare them for that.
So what we do before we give anybody ketamine is spend a a fair amount of time Telling them what ketamine effects could be like. Preparing them so they're not surprised when it happens. And then when it does happen, say if they Happen to have uh prominent
feeling of unreality or Changes in environmental perception. Or perception of the body. We tell them you remember before the session we Talked about how you might have these kinds of effects.
Well, it's happening. And it's gonna go away. And most people find that very comforting because they kind of knew it was gonna happen all along. And and you tell them this is what we're talking about, it does change their frame of reference. But they usually tolerate it pretty well. That makes me remember.
A sign that at one point was inside a Yurt at Burning Man, which was associated with something called Zendo, which is sort of pure support. harm reduction mostly related to psychedelic use. So if people are having a difficult psychedelic or drug experience. Their friends will bring them to this yurt where there will be sober sitters and volunteers and managers and so on to look after them.
And I don't think they have it there anymore. But there used to be a sign, huge sign on the wall where everybody could see it that said You took drugs and the good news is they're working. Exactly. Just a big reminder. Now let me share a few things from my experience which I'm sure Just to be clear, format wise diverged quite
a bit from what you're describing in terms of best practices, duration of IV, et cetera. And I chose a clinical setting for a number of reasons, and I think we'll come back to a few of them. One was I wanted to make it as inconvenient as possible for me to use ketamine. We'll come back to that. The second was I really wanted to standardize the experience and have the versatility that IV provides.
Which is not The case with Hitting the golf ball. with intramuscular injection. So I wanted to be able to, which I did, ultimately have the ability to dial up the rate of administration in the middle of, say, a
Therapy conversation. With a Therapist. And then At one point I remember very very clearly dialed up the rate by about
twenty, twenty five percent, and suddenly things got very strange and there seemed to be a distinct lag between my thought my mouth moving and me hearing any sound, which makes it very hard to talk. It's kind of like having a delayed reverb on a microphone or a set of speakers when you're trying to talk. It's extremely challenging. And I remember saying John, that was the name of the technician or medic who he former medic who was administering Academy and I said, John, things are getting a little bendy. Could you please dial back? And he was able to dial back and then I could resume the session and I I wanted that type of ability to experiment. The session itself And this is where I'd love to hear a bit about the setting.
The session itself There was an intake process. And I was in a room Sitting in a comfortable chair recliner, effectively.
Big screen TV and you got to choose your effectively Let's call it a nature video with scenes of nature with music overlaid. And I standardized on one Redwood video. And I should say that was the first time I had ever watched a video. In a Any type of
clinical or serious setting with drug administration. So I found that in and of itself quite novel. We can come back to the pros and cons of that at some point. And My experience post session Was
And we were gradually escalating dose. I mean starting well below let's just call it the minimum effective dose that you're outlining and then probably exceeding it by quite a bit by the end. And My experience after the session became a running joke with my girlfriend because I would always forget something at the clinic. I would leave my wallet. I would forget my phone. I would forget my backpack. I would come home. I'd put something somewhere, forget where it was, and it seemed like my short term memory was just
Gone. For a period of time. And That leads me to two questions. So number one How
common is that that one experienced some cognitive deficit or short term memory impairment for a period of time. And What does the actual setting look like? Yeah. The
clinical setups that you've supervised or observed. Is it in a blank room? Are they staring at the ceiling? Do they have eyeshades on it? Are they listening to music? Et cetera. You know, I've seen all of the above. In terms of settings.
And We've always used blank rooms partly because What we're trying to do is to make ketamine available to as many people as possible and have the most um efficient settings. So In our clinic, which is led co led by uh doctor Robert Ostroff and uh Gerard Santacora.
Both experts in in this work. It would look like a surgical recovery room. With a number of bays. And everybody has their own space. They're shielded from seeing other people by curtains and things like that. So they do have some privacy.
But the doctors are moving and the nursing staff are moving from patient to patient to patient in the session. So it's more of a strange in some way, uh almost a communal Experience Not that people are wanting the communal experience per se, but it is a very efficient way to uh deliver the treatment.
One of the things about ketamine is That It distorts. Perception in exactly the way that you described.
Some groups try to keep the level of stimulation limited. Because the more Intense the sensory input on catamine. The more you get distortions. of of the experience.
And It is said. By mentors of mine who worked the emergency rooms when you would get P C P and and L S D. people intoxicated people come to the emergency room that the management strategy was
the opposite for those two medications because PCP like ketamine is a causes distortions of the input. So the more input that you get The more Distorted things become.
But with L S D There's almost like a battle for control of your Perceptual world. So when you put the blinders on and produce sensory
deprivation you tend to augment the intensity of L S D. You're you're withdrawing the Organizing. effects of the sensory world and so You tend to have a little bit more stimulation in the emergency room setting with with the psychedelics than you do with P C P.
Is there Well, actually, I think you answered the question. I was gonna ask you if cost and scale were no consideration, I suppose I didn't frame it this way. For the purposes of scaling, it makes perfect sense that you would want The list cost The least on some level least space required, least training, right? You don't want it to require a four string quartet or something.
But if cost and scale were no consideration, do you have any thoughts on How you might Design. the setting would it be any different? I understand the point that you made, which I think probably applies whether cost is a constraint or not. about minimizing
Inputs. But do you have any other thoughts on What that might look like. My general feeling about Cadmine. Like
Most clinical experiences is That when the patient is comfortable. And feels well cared for and supported. That outcomes tend to be better. So the whole
setting that you described, a really comfy chair, a really relaxing video. That's not too stimulating. Privacy and quiet. is pretty close to an optimized Setting.
Because Not much happens. for you know, that's uh uh describing a treatment where not much is happening during the Infusion. If you're gonna reactivate
A trauma memories or if you're going to reactivate alcohol memories. That itself is gonna be a pretty engross intervention and probably Will occupy a a lot of the kind of Sensory space of the in of the infusion. And it sounds like you had some version of that.
The problem with video. Well one of the many potential complications with video is that Not all content. may provoke the warm and cozy feeling that you may be seeking. So I remember watching for the first time this video. And it's like beautiful redwoods and rivers.
Kinda creepy, not creepy, but like minor tone melancholic music, which I didn't love. I didn't expect that or see that coming, but I was already kinda strapped to the seat and on the ride. So couldn't couldn't get off in the middle of Pirates of the Caribbean Disney World ride. So I was I was in it. But I remember at one point on a higher dose. There's this one scene. That popped up out of nowhere and it was just this fox. This little fox
It looked like maybe it was freezing cold beach. It was sitting on this sand and it just looked miserable. It wasn't doing anything. I was like, why is this fox here? It looked Really unhappy. That was not conducive to an optimal.
Clinical experience. And Let's talk. Not about necessarily the side effects in session, but some of the
risks of ketamine and I'm gonna lead into that in a few ways. So one of the A parent. One of the apparent benefits of ketamine as contrasted to some other Drugs that
People may have heard about on this podcast. Let's just say ayahuasca as an example. There appear to be fewer contraindications. For ketamine. I'd love for you to speak to that, but there appear to be fewer contraindications versus say ayahuasca plus SSRI could mean
serotonin syndrome, possibly fatal. Certainly I began with cardiac risk. People die from these things. In contrast to some of these Very powerful psychedelics. And there are certain psychedelics to be fair, Silicine and L S D being two of them that seem to have
Almost No identifiable L D fifty. From a physiological basis they they seem relatively low risk. Not true psychologically, perhaps. But
Ketamine for me. has two huge advantages relative to many other psychedelics. Number one, there are legal options you can explore. That is non trivial.
Right. Legal options you can explore. Which means you can operate through In many cases regulated Vetted. practitioners on some level.
So there's a practitioner risk that we're going to do. To a certain extent. you can remove if you're proactive about focusing on that. The second would be contraindication. And contraindication risk.
However. One of the things I mentioned earlier I want to come back to and that was I wanted to make it as inconvenient as possible for me to use ketamine. Yeah. And the reason I decided to do that Is
Well, there are multiple reasons. The first is And most important is that I had seen Multiple friends. And there are at least a handful of friends right now I know of who will fit this description.
Who had decided to stop using one dissociative An aesthetic, certainly at high enough doses. Alcohol. and switch to using ketamine four or five nights a week. Alcohol without the hangover. And
I found this very deeply concerning. And certainly new friends who were using ketamine hundreds of times. A year. Uh in some cases. And these are
Also to paint a full picture experienced psychonauts with a lot of psychedelic experience, but psychedelics And you see this in animal models as well. For most people, self-regulating or self-limiting capacities. I mean, if you give LSD to a rat in a bottle, it hits it once and it never touches it again. Uh so I would love for you to speak to some of the Risks of ketamine.
Maybe outside of the lab or even inside of the lab. Sh And How you think about mitigating some of those risks? If there's addictive potential, speaking to that. And out of my own personal curiosity, I would I would also be fascinated. No. Is the behavior that I've seen in humans the addictive behavior
Also found in Animal experiments or is it not? First. I I think your point's really well taken, which is To think about a drug like ketamine.
most people gravitate to the risks that are the most flamboyant part of it. In other words What's the risk of dissociation, what's the risk of uh transient psychosis. from single doses. And To tell the truth, I have found
That those risks are really quite Limited. People have undersold The addiction risk of Cadmi in the United States. But
In some parts of the world, ketamine is known as a very significant commonly abused substance, often as an alternative to alcohol. Or sometimes as an alternative to cannabis. So
I have visited clinics where ketamine abuse was being treated. And these were really heavy Users of ketamine. They were hospitalized in patient unit. They were persistently psychotic. And those psychoses didn't.
Clear. Even After a time when they had stopped using the ketamine. And so ketamine abuse carries with it risks that have to be taken very seriously. All the way from drunk driving to really high dose academy use. We said earlier that the typical therapeutic dose
For an eighty kilogram man was about forty milligrams. And in China And in Taiwan. I've met with people who were using
Eight. grams a day intranasely and orally. So in other words. That's eight thousand milligrams. That's
A hundredfold or two hundredfold times. The dose. And they used it every day. One of the things that happens when you Use ketamine every day. is that its effects on the brain.
Turn out to be the opposite. So when we give a dose. And we Let the brain react. The brain.
responds in ways that are helpful. We get regrowth of synaptic connections. We get potentiation of synaptic function. And in animal studies there's some evidence that the inhibitory cells which are sometimes atrophyed in depressed patients will come back to life and all kinds of Beneficial effects happen. The effects of a single dose don't seem to be permanent. Those are all kinds of effects that we hope to see and hopefully over time with treatment will become stabilized.
And When we space the doses apart. We don't get tolerance to the effects of Ketemy. We don't have to give higher and higher doses academy. And if anything The fact that we can space it apart suggests that the brain has become more responsive or the brain's reaction to ketamine has in some way adapted in a positive way.
When you use ketamine regularly, when you use it every day It produces the opposite pattern of adaptations. instead of becoming sensitized to the effects of ketamine, And having the ability to give doses that are spaced farther and farther apart. You become tolerant to the effects academy.
You need more and more acetamine to produce the same effects. And people tend to use the dose. More and more frequently. So I've spoken to people who started Using ketamine to
Self treat their depression. They would take it once a month. And that would Initially Hold them just fine. And then they take it.
maybe if they were heading into a stressful time and a stressful weekend, they would take an extra dose before the weekend. And maybe they were Having a down day they take an extra dust academy. And some of these people with the best of intentions and no interest whatsoever in developing a ketamine habit, found themselves taking it.
More and more frequently, every day. These were people who were given bottles of ketamine to use at home and who had the ability to take it whenever they Whenever they need it. And some of these people ended up taking it. Every day.
And some of these people ended up taking it. Four, five, six times a day. in order to maintain their equilibrium. And one of the things that
That happens. If you take high doses of ketamine every day. As opposed to lower doses of ketamine sporadically. is that ketamine can increase your vulnerability to depression.
When used in this compulsive manner. as opposed to decreasing your symptoms of depression. And if you look at the brains of people who use ketamine very regularly, They have rather than enrichment of synaptic connections, they tend to have loss Reductions in white matter, you know, the marker of neural connections in the brain on MRI in parts of the brain. they tend to have impaired function of the brain with functional magnetic resonance imaging. They tend to have cognitive impairments, and those cognitive impairments tend not to
resolve rapidly when ketamine use is stopped, but rather have a very slow response and in some cases There may be residual Impairments in memory or attention. And then the most extreme cases for this group of people that are using extremely high doses of Cademy for a long period of time, you have this Risk of persisting psychosis.
And as I mentioned earlier, that's particularly scary because these Persisting psychotic symptoms that you see with high dose long lasting ketamine use, they don't respond very well to antipsychotic medications. Those psychotic symptoms don't necessarily go away quickly when ketamine use is stopped. So Ketamine is a drug. Yeah.
has to be given A lot of respect. And treated with a way that recognizes Yeah. Careful thought.
Needs to go into Protecting people. From Developing. A problems related Academy News.
And the group that people worry about the most are people who have Already not only depression, but some kind of substance use disorder. Whether it be alcohol use disorder, stimulants, opiates, things like that. And that's a problem in terms of access to ketamine as an effective antidepressant because Out of this concern about the addiction risk of ketamine or the risks of ketamine for people with addiction,
A lot of programs that would otherwise be prescribing ketamine for the treatment of Depression will exclude people who have these substance use disorders. And that turns out to be a lot of people who are depressed in the first place. So you're cutting out a large group of people and there's I believe and I think others believe that there's a need to really think about how what the optimized way
to treat these patients who have depression and and comorbid substance use disorders. So one strategy is the strategy that was developed by the group in England that I mentioned earlier at University College London and that is extended to I think it's Manchester, but I I may be wrong. Trying to activate the drug memories during the ketamine infusion to try to counteract whatever aggravating effect ketamine might have on addiction and in fact have produced beneficial effects on drug craving.
The biggest step is to limit the availability of ketamine to the clinic setting. And That protects people f Not only from
Taking more and more acetamine on their own. But it also helps to limit the possibility that the ketamine that they're given would be diverted to others who wanted to use it for recreational purposes. And That's really something that needs to be thought about really carefully. Because
Let's say a person got a bottle of ketamine that had a thousand milligrams of it. Or let's say they got pills of ketamine that had a thousand milligrams. Because A thousand milligrams might not be that many oral doses because your body metabolizes. Cadmine so rapidly that if you give it early, you have to give a lot. And so giving a thousand milligrams might not be that much for someone who was just going to use it orally.
But what if they gave that a thousand milligrams to someone who was gonna dissolve it and administer it intravenously? Person can get high on maybe ten milligrams. Yeah. Or stored it. Or snorted, exactly. So you just given The person who maybe just got a few doses of oral ketamine.
All of a sudden maybe just got like a hundred doses. So the risks of diversion when you give ketamine To people. For home use. You have to really
Be you know, thoughtful and careful about thinking about that. in strategies to deal with this. So for example there's a company out there That's developing uh intranasal delivery system to deliver controlled substances in a manner that has less risk. How do they decrease the risk with the nasal administration? Is it like a childproof lock that just locks it for a period of time, or how does it work?
It's s sort of a more elaborate version where there there's some external regulation of the dosing and external monitoring of the dosing so they can the person only is able to use it to administer The Cadmine at certain times. It's not for A hundred percent protection, but for most people it would be very protective against the the diversion of Academy.
Another strategy is to try to Develop. A Cademy That is Got less abuse potential.
So a company that that I've been working with called Freedom Biosciences is trying to do just that by combining ketamine with a drug that might reduce its abuse liability to come up with a version of ketamine that has less abuse risk uh associated with it. And that's still early days with that, but it's it's an interesting idea. On that
Last point and we don't have to get into any specifics you don't want to get into, but is it By changing the ketamine itself or is it by lowering the minimum effective dose required of ketamine by Combining it with other drugs. There are a variety of companies that are
Approaching a variety of different strategies to try to get to this Point. For example, one company that believes that their version of ketamine has uh r less abuse liability is Using the opposite isomer, in other words, the mirror image of S ketamine is called R ketamine. And so they believe that that version of ketamine might have less
Intrinsic abuse liability There are other drugs that block the NMDA receptor that are being explored or being developed for the treatment of depression that may or may not have similar degrees of abuse liability with Cadamine. There's the strategy that Freedom is trying, which is combining an anti addiction medication with ketamine to reduce it's interesting. It's abuse risk. And yeah, so there are a variety of strategies that people are Taking to try to reduce this risk.
Abuse is the greatest risk associated with ketamine. Ketamine has been around since the sixties. It's medically safe and well tolerated by most people. When given in the ch in the way in which it's given for treatment, we don't see much evidence of Persisting medical risk. The only persisting medical risk is when people are exposed to ketamine in the context of You know, the persisting medical risk that we
can't prevent is the one when people are developing uh addiction. So we want to Think about ways to broaden the pool of people who would be considered for ketamine and And maybe to take advantage of the fact that Treating depression is good for addiction, just like treating addiction is good for depression, so providing a an avenue for the safe treatment of these patients is uh it it we think is really important.
I wonder if there is a drug and there may be, I just don't know my My biochemistry, my pharmacopia, but There's a drug that would increase the nausea and other undesirable side effects of ketamine in between sessions and therefore Act as a
biological policing function. Of sorts. Because I know these drugs exist for other things, for other compounds. But it's just I'm allowing my mind to go wild with all the different options. I mean there are a lot of different options here. Let me come back to the Animal model question for a second, or the animal testing model because It's sometimes easy to forget that humans are not just really large mice. But uh in fact we are quite different.
Are addictive properties of ketamine observed in animal use or self-administration? Or is that seemingly unique to higher primates or humans who have all of the sort of attendant weaknesses of Let's just call it higher functioning and neuroses and so on. Is the abuse witnessed in animals?
What's interesting is that There are some drugs of abuse. Like Cocaine. Yeah.
Animals. You know, love. And humans seem to Like as well. But ketamine is more like alcohol.
So there are some strains of rodents that naturally consume alcohol and or naturally consume ketamine. But generally speaking you have to kind of gradually introduce them to alcohol or to ketamine and then they can become compulsive Alcohol consumers or acetamine consumers just like humans and
It's bad. And the animal models Very between very patient. you know, escalation of alcohol or ketamine and you give it to them at times when they're most active like in the dark, and the rodent mice and rats are more active in the dark. And you Give it a little bit and you take it away.
And then the animals will when you give them access again, they'll drink a little more, take a little more and so they go through bouts of exposure to the drug and then they tend to develop heavier versions of alcohol or Cadmine Self Administration. The self administration.
Cadmine the suffering PCP. And and other substances from that class. I was speaking with an acquaintance. who was commenting on a few subcultures, I'm I won't name them, but few subcultures in the US that seem to Use
Cademine. extensively as a drug of abuse. And he said, if anyone claims they're not addicted to ketamine, ask if you can borrow their look at their inhaler for a second or their their insufflator, their nasal applicator, and just uh stick it in your pocket and see how long it takes them to get really agitated. and insist on getting it back like Schmeagle from Lord of the Rings. And I will also just Add one
Comment which is I think it is very dangerous for people to Say or believe or assume. I do not have an addictive personality, therefore this is not a risk because my feeling based on all my experience
There is a molecule that will get you. There is a molecule that will get you. So I I think an ounce of prevention is worth a pound of cure for sure in this instance and Many of my friends
Who our experienced psychonauts, at least a few of them, had no prior Abuse history. With any drugs. outside of in this in this case ketamine.
So let's talk about you mentioned The R ketamine versus S ketamine. There are a lot of urban myths around From
avid consumers of ketamine as to the differences between these two. And who knows? Maybe they know what they're talking about. I think most of them are just bullshitting, frankly, but good at storytelling. And that's their new way of showing off is talking about how Deep there. expertise in in ketamine consumption goes as connoisseurs, but This is just a a question that I'm sure I will embarrass myself at asking. But so you're talking about R ketamine versus S ketamine. And
Is it right to say they're kind of mirror images? They're like enantiomers, is that the word? I'm probably correct. You you you got it. You got the linga. Just for people who are looking at video or not looking at video, on the audio, what I'm doing is I'm holding up both of my hands open, palms facing me. So thumb pointing different directions. Another way to think of it would be like the state of Michigan, the glove, flip it the other way. Okay. So we have these two mirror images, but then I'm thinking to myself, wait a second. Well these are not two D Images, these are three dimensional molecules. So if I rotated one of my hands 180 degrees, would they not be the same thing? So I'm just very confused by this right and left handed
shorthand that is sometimes used to describe the differences in these two because it seems like, well, if I flipped one to 180 degrees, you would have Effectively the same molecule. the same series of hydrogens and carbons or configuration, would they not bind in exactly the same way? Could you Just uh shed some light on that. Well first
I think you do a great job of portraying the R and S uh in the ancient years. That was uh very impressive. Thanks. But secondly. You said something which is extremely important, which is that what really counts for these molecules binding into the nooks and crannies is the three dimensional space. So what you couldn't portray
is that when you overlaid the two hand your two hands in a way that made the sequence of the molecules in the two And the two eyes are similar, was that in one case the first carbon might be sticking into the plane, but in the other case The carbon was sticking out of the plane. Right. And and so that when you saw the actual structure in three dimensional space. They actually
occupied them in in ways that were not ac couldn't be one where you couldn't superimpose one on the other. They're actually in turning in o opposite directions. And that turns out to make a big difference because R ketamine. is somewhere between three and five times less Potent in its ability. To block what we perceive to be the
What we think is the primary target of ketamine in the brain, which is the N MDA glutamate receptor. Yeah. And It's a really complicated story, too complicated. For us to go into in detail.
But the reality is That there are at least four subtypes of N M D A glutamate receptors and ketamine binds with a little bit different affinity to each of the four types of the NMDA receptors. Affinity for academy.
has been taken up by the pharmaceuticals industry where you have different companies Developing alternatives to ketamine that target us just a subtype of the N MDA glutamate receptor to block and that's a whole other area that's being developed by the pharmaceutical industry. But uh when we go back to R versus S And John John may I interrupt for one second. So when people just say ketamine.
Is that a third molecular configuration versus R and S or Is it just a lazy shorthand that is omitting? One of those. So when people say ketamine
These days. They're talking about the mixture of the R and the S molecules. I see. So the standard Ketamine that we studied was a mixture of R and S. And when people say S ketamine, which is the version of ketamine that was developed. by Jansen Pharmaceuticals. That's the S isomer, which is more potent
at blocking the N M D A glutamate receptor. The idea being ketamine Has a more potent and less potent blocker. Let's develop a treatment that blocks the NMDA receptor more potentially and And logic goes something like Then we can give less
Total dose. And maybe that'll be safer in terms of side effects or better in terms of tolerability. The alternative. idea which is being developed in relation to our academy is
Still I'd say From where I sit, which is A bit at a distance from the R Academy is One of two strategies. And it's not clear to me which strategy will be followed.
One strategy says Our academy has a different binding profile at N M DA receptors and other targets. And so the ratio of its affinity For N M D A versus these uh targets is different than Escadine.
So if we bring our ketamine up to the same dose as S ketamine the same o comparable occupancy of N M T A receptors, maybe it'll be a little bit more tolerable. The alternative idea is What is Ar ketamine works through some other target.
Maybe it doesn't work. Through the NMDA receptor. In which case you might be able to get some kind of effectiveness at at a low dose that doesn't produce dissociative effects. You know, that would be if it really is just as effective as S ketamine and doesn't produce abdiction liability and doesn't produce dissociative effects and doesn't have other medical effects.
That would be super. But The problem is If our Calmine is working by Some other mechanism.
What is it? How does it work? Does it have any of the properties. That we ascribe to Racimic R S Kademy. Yeah, lower uh N M D A receptor occupancy. And the answer there is we have no idea.
So as our ketamine gets developed, it has uh shown effectiveness in animal models. in studies in Japan by Kenji Hashimoto and some other groups. So there's interest in our ketamine and how it should be dosed and what it would be like. It it's still kind of Um getting sorted out. But It's really important to understand that there's a way to use our academy that's Not that different than the way we currently use Haskademy.
And then there's a way to use our ketamine that's Some kind of lower dose. Treatment that If it works. would be working through some other
Pathway that we don't yet understand. So I have a few things just to Bookmark for folks or mention for folks, and then I have a question about other applications of ketamine because I would be remiss if I didn't mention my own Personal experience.
A bit of trivia. People should look up another piece of trivia, the origin, the etymology of the word trivia. Uh Three roads. meeting. In any case, people should look it up. It's it's pretty fun.
Separately. I have read A theory, a description of a theory That has postulated that the origin of
human tendency to alcohol abuse originates from our Simeon ancestors who would find fruit that was fermenting and consequently become somewhat intoxicated, but that it was an evolutionary Driver was a a fitness advantage for natural selection to be able to not just identify and find fermenting fruit
But to Consume it. and to be inclined to consume it. So I I don't know if there's any scientific consensus or acceptance of this. But relatively recently came on my radar, which I thought was at least Interesting as a thought exercise.
Uh the Application. Potential application. I'd like to get your two cents on the scientific support for this that I experienced firsthand was going in for my series of catamine infusions, which just as a a comedic side note In these intake
uh questionnaires they would always ask, you know, anxiety on a scale of one to ten. And I I mean I starting from nothing What I always do with these one to ten questionnaires because how the hell do you know on some level. I mean, if it's a pain scale, I think it's a little bit easier, right? It's like okay, one is I can't feel it. Ten is I need to go to the emergency room immediately. Okay, fine. But on the anxiety, I always choose five. If it's the first session for Anything, I choose fives that that I can go above or below on subsequent Intake forms. And
I was doing I think it was three a week. I was coming in without any Depression at the time.
I don't know hacked schedule of podcast recording. And so my anxiety kept going up over time because it was screwing up my ability to prepare for the podcast because my short term memory was vanishing. And and the uh the nurse practitioner said, I've never seen anything like this. You just keep getting worse. And I'm like, well, it's not the full picture, but yeah, that's fine. However. What I did realize about a week after
My Two infusions. My or I should say my two weeks of infusions. chronic pain that I'd had on my the left side of my thoracic region of my back.
Had completely vanished. And It remained gone for probably Five or six months minimum. And it was the first time in my adult life that I had gone pain free for that period of time.
With this. Thraci. carry over from an uh severe injury. Many, many years ago. Is there much
Published literature to support using ketamine, and I don't know if this I would imagine it was related to N MDA receptors. to reboot or otherwise. Treat chronic pain. Yeah.
And the answer is yes. And this is actually There are two kind of interesting parts of this. One is The NMDA receptors are in the pain pathways. It's in the spinal cord. The NMDA receptors are in the spinal cord and involved in transmitting the the pain messages up to the brain. And they're in the higher Executive pain centers like in the thalamus.
And And so It both can reduce the experience of pain and it can reduce how much pain is upsetting to you. So in both ways ketamine can be helpful via its action in blocking the NMDA glutamate receptors. And it's now being already used commonly in pain centers for the treatment of pathological pain. There's another part of ketamine that from the pharmacology point of view is extremely interesting.
And this goes back to the work of Keith Trujillo and Huda Kill Maybe in the nineties, I think in the late nineties. And what they found is that You could
Prevent the development Uh Tolerance. to the anti pain effects of opiates. By co administering
Cadamine or an N M D A antagonist. I think they used it a different way. Intermittently during the Exposure to opiates. And so one of the big problems as you know with opiates there Very helpful for controlling pain for many people. But if you have like You know, neuropathic pain, uh old sports injury, back pain, or you know and you get that kinda chronic
Grading Nerve pain. Sometimes people will be on opiates for a long time and they're not really getting much benefit from those drugs. And so N M DA antagonists can be a path for reducing
The pain that Can't be reduced by the opiates. and restoring sensitivity to the opiates. So that people don't need to use so much opiates to control their pain afterwards.
And The third thing that they ketamine can do that's really interesting. Is Prevent The sensitization of
Pain pathways. So let's say you're going to have A knee replacement. And you know that when you have a knee replacement You know, you're gonna do some things to the nurse to make it possible to replace the knee and and that there's a risk for some chronic pain related to that knee replacement. As you know, because you've just said it.
That ketamine interferes with neuroplasticity and and while the ketamine is in your system can interfere with the encoding and the neuro adaptations associated with memory and so produce a some temporary memory impairment. Well, it does the same thing for learning in the pain pathway. If you Pre treat people. with ketamine and have ketamine in their system when they undergo
the knee replacement, the chances that they're going to develop this nagging long lasting pain in neuropathic pain goes down. So it's very common. To have a drug like ketamine. given during an an operation like that to reduce the development of neuropathic pain. So it can be used to treat pain and to prevent it.
What I found most incredible about the experience was the durability. Of The pain relief.
And this is not a scientific explanation because I haven't done my proper homework to be able to speak to that, but it seemed like there's certain motor patterns that we learn to associate with pain. Even if The mechanical dysfunction or damage has ceased to be an issue. Right. Now in the case of my mid back, there are actually some spinal issues, but let's just say you do a squat. You blow out your knee.
And then for six months it hurts to squat after that point. Mechanically you're intact, but y you have learned that a certain motor pattern is dangerous, and so your body Delivers a learned pain signal in some capacity. It it seems like
At least to me, that there was a as you mentioned, a learned aspect to this that was over sensitizing. And that that was rebooted or disabled. With the use of
ketamine, maybe to use a different analogy or metaphor for folks, like imagine if you got severely sunburned. after the sunburn had passed, you would retain Certain sensitivity to the sun, an over sensitivity. as a like prophylactic learned
precaution so you would not get stun burned again. You know something like that. It's not the best comparison, but you get the idea. How do you explain the durability? of the effects because the the half life of ketamine is long gone. pretty quickly. But the pain relief, I mean complete pain relief, it wasn't 10% better. It was a hundred percent better.
lasted at least six months, and that I found just staggering. Um How do you explain that? I don't know that I can explain six months. But what I can't say Is
So the first thing you said Which was That Your whole body adapted. to having pain in in your knee.
And you change the way That you moved In ways that were probably Sparing acute pain. But we're probably a burden
And maybe not good for Your overall health. And The second thing I would say is is that There's a close tie between depression and anxiety.
Yeah. And A lot of what we're managing when we're managing pain. is our emotional response to the pain. And if you tone down the depression and anxiety
Then you discover that the pain is actually much more manageable. Because Anxiety depression focuses our attention on pain and makes us Vulnerable to
Blowing the pain out of proportion. It's not that we don't feel the pain more intensely, but we feel the pain more intensely because our attention tends to get drawn in such a focused way to it. So I think that there are many levels. Where
In many potential ways. the neuroplasticity part of it. The depression and anxiety cognitive part of it. The ability to engage. a variety of strategies to suppress
the pain signals through relaxation and other kinds of techniques. So I think chronic pain is like depression or PTSD in that It's often useful to think about Being resilient to the pain as opposed to making Whether or not you have it or not.
So I think W one of the things that you're describing is that ketamine helped you to be resilient in the face of a potential source of pain. And and so that you live the life of a person who didn't have pain. And you discovered that when you did that. You didn't have pain.
Yeah, I like I like the comparison to PTSD. I mean you can imagine and this is getting into an entire different uh class of the I guess it's not really a phenethyl, I mean, that would be more MDA, but if we're looking at MDMA assisted psychotherapy for PTSD. The memory is the same. The traumatic experience and the memory thereof may be the same, but it's how you contextualize it and relate to it. that seems to contribute to
the diagnosis or non diagnosis of PTSD. It's not a perfect comparison, but certainly the sort of phenomenology the the subjective experience that is reported by many patients is that they were able to go back, revisit this memory that would normally be re-traumatizing or make them hyper reactive and produce this huge physiological response. And
Calm engage with it. as their present day self as sort of an observer. To metabolize it such that it doesn't have that complete grip. It's not consuming for them afterwards. And
Just by comparison, in the same way that if somebody has acute pain, I know that when when I've had acute pain in my mid back, It dominates Everything. I mean it is It is the background colour. Of
Anything that is written upon it in my mind. And so to have that removed was just incredible. We talked about ar ketamine. Now here's one that I don't know anything about. But it's in some notes, so I would love to
Hear you Describe. In any capacity S methodone. What is S methodone? Yes, methadone. is yet another
drug that blocks N M D A glutamate receptors and is a a drug that has some potential to treat depression. So The other isomer of methadone is the methadone that we associate with opiate maintenance. So this is the inactive isomer of methadone, which bloc works by blocking N M D A glutamate receptors and and there's some preliminary data that's encouraging for the treatment of depression. You know, it's really important. That You know, we have many different
Drugs that block the SSRIs and it's been helpful to have a portfolio of medications Because for one reason or another, one of the family of the SSRIs will be tolerable or will work. Or it won't work.
for one patient versus another and It'll probably be the case. With N M D A glutamate receptor antagonists that ketamine works for some people and Some people they don't like the side effects, they
They go to another N M D A receptor antagonist and and maybe that one will work. So that's a drug that has some potential. In that regard. And coming back to S ketamine versus R ketamine, and this is a simplistic question, but I'm wondering If S ketamine is A more potent
Antagonists. If if I am Getting my terminology straight. Does that mean that S ketamine has at the same dose as our catamine more abuse potential. I'm wondering if if one or the other appears to have or hypothetically should have
More abuse potential. So the animal data. with our ketamine have been pretty encouraging about abuse potential, but we don't have enough experience in in humans to really be able to say. Yeah.
Ask Cademine. It it's true that it's more potent at n at the NMDA receptor, it's also a little bit more potent at the mu opiate receptor. Than our Academy. And and so there's been some discussion about the abuse liability That's because of the mu opiate receptor.
A fact or I think it's there's been a tendency to be more concerned About the mu opiate receptor. Activity. than the N MDA receptor antagonist activity. But in my view that's a bit of a distraction because
Cadamine as ketamine is much more uh potent at NMDA receptors than at mubiate receptors. At least it's more potent. Several fold to maybe uh uh Tenfold somewhere in in between there. And so But clearly we all No about
addiction risks of opiates. But we wanna make sure we don't Underestimate the addiction risks of R ketamine S ketamine S methadone, whatever the NMD antagonists is. You know, the rate of ketamine abuse has been going up. Since the rate of ketamine use disorders has been going up.
Since the uh About two thousand eighteen or so in the United States, so We do want to be careful about that. Yeah, I wonder how how much that is also correlated to just general increases in
Diagnosed. We have to be a little careful. About assuming that all these things are on an upswing, not referring to ketamine abuse, but just because the detec or reporting or diagnosis can also become a trend in itself, right? If you develop
Better technology. For Scanning and identifying brain tumors, lo and behold, brain tumors appear to be exploding, but it doesn't mean their prevalence wasn't the same. Beforehand. In any case, what I was gonna say is it it seems like with the advent of social media and
the sort of social proof Approval. Culture. That is so heightened by those tools. It seems to me, and this is also just watching my audience, that the
Chronic anxiety, depression, certainly we saw during COVID a sharp increase in suicide hotline volume. I wonder if ketamine and maybe alcohol abuse. Are Also correlated because people are just looking away.
Two numb themselves to turn off certain feelings. I don't know. The answer to that. But
You know, I wanted to mention one thing. Which is the only other Apart from alcohol and If I'm being honest, I don't really know how alcohol exerts its effects on the
psyche in the subjective experience. But the only other Dissociative that I have some familiarity with is Salvanor and A, which is a high efficacy kappa opioid receptor agonist. And I'm wondering
To what extent the dissociative effects of ketamine are dependent on that opiate receptor. Interaction versus Other than Receptors.
Let's back track and talk about these three For compounds. First alcohol. So alcohol is a That's all.
is a weak N MDA glutamate receptor. Antagonist. And and that we think is a major contributor about why the The subjective effects of a low enough dose of ketamine are often described like similar to a glass of wine. And
If you get Your alcohol dose. Uh high enough. Let's say it's been reported that you can get numbing, uh Distortions.
Impairments in cognitions, et cetera, et cetera, as as we all know. And some of those effects are thought to be similar. In fact We did a study where we gave ketamine to very experienced alcohol users who described the antidepressant dose of ketamine. Yeah, similar to the
On average to somewhere between six and ten drinks of alcohol. Hay item. It's quite quite a few. Depending on the time frame. Exactly. Exactly. So As a result of our interest in this NMDA opiate interaction, we did a study where we
Gave people. A high dose of naltrexone before we gave them. I do the academy. Okay, could you explain what naltrexone is? I mean I I know what it is, but Yeah, an opiate receptor blocker. It blocks At low doses it preferentially blocks the mu opiate receptor. The morphine receptor.
At higher dose, if you give a high dose, it also blocks the delta opiate receptor, which is the meaning. target or aiming target for the encafalons. endogenous opiates. And then if you give an even higher dose of naltrexone, you also block the kappa opiate receptor, which is the salvinurin receptor. So
If we give a pretty high dose of naltrexone and give ketamine, we don't change the dissociative. Facts of Academy at all. You do not. Do not. Not at all.
Wow. What what we do is we make we tend to make a low dose of ketamine less pleasant for people. They get a little more anxious. They don't like it as much. But they don't it doesn't block the dissociative effects. Now Sal the Norin
If you give it. Calvin Orns A very short acting drug in in humans, my colleagues Cyril DeSouza and Mohini Ranganathan dosed Salvinorin. And you can get this very intense kind of psychedelic state in people that is uh relatively uh short lasting. And
What's interesting. About Salvanorin. Is It's not such a positively euphoric experience as you get.
people uniformly rate even if they don't like the experience, they still rate the ketamine experiences as euphorogenic and they still rate a lot of the psychedelic Salvador A tends to be highly dysphoric. Most people will say I never ever in my life want to do that again. But what's so interesting is that it shuts down Dopamine related reward. signaling and some reward processing in parts of the brain. And so As we think about
Things like mood and addiction. All of the systems that we've talked about. end up being implicated. The N M D A glutamate receptor and synaptic connection. And the kappa opiate receptor Is thought to contribute to some of the anhedonic symptoms of depression. Yeah, the inability to feel joy. Yeah, inability to feel joy, and my brother
Who's a psychiatrist. You know, you know you know my family history. My father was a psychiatrist and psychoanalyst. My mother became a social worker. My brother's a psychiatrist, my cousin's a psychiatrist. I come from A genetically high vulnerability uh family for mental health uh professionals. My daughter's becoming a psychiatrist.
My brother did a study As part of a consortium. And gave Uh kappa opiate receptor blocker, in other words the reverse of salvanure.
and looked at the effects on brain circuit activity and anhedonia in patients with depression and showed that You could Affect the reward circuit activation and reduce anhedonia in depressed patients with this kind of mechanism, a capit an antagonist. And so people are actually interested in the capit receptor blockers has potential.
Treatments for some aspects of depression. Super interesting. Yeah, I will say Just to to also put Salvino Renee in context that more people may recognize Salvador and A is isolated from a ethnomedical plant called Salvia Divinorum that's been used
by indigenous populations, certain indigenous populations like the Mazatecs for hundreds, probably thousands of years. And Before you ever touch this stuff. Go on YouTube and search smoking Salvia Divinorum and you will see dozens of videos of people who just thought it was a good idea to set up a camcorder or an iPhone before they did such a thing. And they will
Try to escape by running into walls. Smashing through windows. flipping over couches because they're so terrified of this experience. So just uh The more you know.
Smokey the Bear. Definitely think about it at least thirty seven times before you uh casually partake in in any of these things. Okay. With that. Thank you for providing all that context. So fascinating to me.
Going from Risk of getting me into alternatives. Tychetamine or Compliments. Possibly, right? Not necessarily replacements for, but depending on the subpopulation, what works and what doesn't work. Let's talk about ways to optimize ketamine.
What are some of the means by which we might Extend the efficacy. Improve the safety. Wherever you want to take that. What are some of the potential ways or future ways to go about optimizing ketamine.
Let's start with the end, if you will. What do we really want in treatment? What would be the ideal antidepressant? Would be a drug
Yeah. Acted rapidly and lasted forever. We would call that Basically cure. And we never use the word cure in psychiatry.
We don't even think of the idea of cure. And That's partly because we don't really understand The brain well enough. to really know how to
completely undo the changes that we see there. So let's start just with a the shortest version of that, which is what if we could Take Catamine. Which is a very important thing.
Uh has a short a duration of antidepressant effectiveness at the beginning, somewhere between, say, three and seven days. And make it last two weeks or a little bit longer. And you might say, Well why would you think that that would be a reasonable Thing to try to do.
It's because when you give ketamine To patients In the long run. You can space out the treatments more and more. In other words, you start with
giving it twice a week, then you go to once a week, then you go to every other week, and then eventually many people will get to every three weeks or maybe even every four weeks. So It suggests that there are some mechanisms. That are Triggered when we give ketamine.
Or existing as a precondition for treatment resistant depression. That Shortened the duration of the effectiveness academy. And so we've been interested in that question for a long time. And we did a study
Yeah. That really spurred our interest in this question. And it was It was um Uh, led by at our site by uh my colleague.
Chaddy Abdullah. And what we did. Was To try to block A certain molecular switch that gets triggered when you give ketamine.
Downstream. S One of the proteins that gets activated inside nerve cells that Triggers the regrowth of those uh synaptic connections.
And that protein's called mTOR. And the drug we use to manipulate it is called rapamycin, it's a blocker of MTOR. Now you'll recall from the animal studies You may recall.
Yeah. MTOR activation was implicated in the antidepressant effects academy. And and so we did a study to try to show that that was somehow involved. In humans. We gave The highest dose of rapamycin, the M Tor blocker.
That we felt would be perfectly well tolerated by everybody in the study. Yeah. MTOR is an immunosuppressing drug. And and that was in our mind as well for a reason that I'm gonna come back to in a little bit. So we gave
Rapamycin. with Cademy. So in the same group of twenty patients with treatment resistant depression, they completed one ketamine day. Where they got Just kidding me.
Plus placebo, of course. And then the other day they got ketamine plus rapamice. And The remarkable thing was That the response rate at two weeks. When they got just Cademy.
was about thirteen percent. And when they got The same people, the same depression. If they had gotten pre treated with rapamycin, their response rate was over forty percent.
I'm no. No scientists, but that seems That seems non trivial. It seemed to us to be non trivial. And It was also a little bit perplexing.
I in the sense that We knew we were giving a drug. that had the potential to block MTOR in the brain. And if MTOR activation was critical, Then why
Didn't Wrap a mice in. Black. The antidepressant effects academy. Yeah.
And One of the Ideas. That we are wrestling with. is maybe the immunosuppressive effects of Rapovicein.
Which is a powerful immunosuppressant. are related to its ability to extend the antidepressant effects academy. Yeah. And In particular
You may recall that I said That the antidepressant effects of ketamine, at least in animals, seem to last about as long. as the newly created synapses. And so We assume that as those
Synapses are being gobbled up. that the antidepressant effects are going away. So what is doing the gobbling up? It turns out that one of the critical mechanisms that gets engaged are the primary immune cells in the brain. And these Tim, I think our maybe your new favorite cells, the microglia.
I'm fascinated by microglia. I just like saying it too. But yes. Microglia, please continue. So microglia are really interesting because they have different modes of function. In certain circumstances they can promote nerve growth in the brain. Another circumstances when synapses get immunologically tagged. They can Surround them.
And literally Eat them up. And so in fact over development. There are certain programmed ways that synapses are eliminated and microglia are involved in that. But when you have inflammation in the brain as you do in depression, microglia are involved and then we think they contribute to the initial deficits in in synaptic density in depression.
So One. Way that. Sorry to interrupt. correlated or is there a causal relationship between our subjective experience of stress and microglia activity?
So microglia tend to be activated. under conditions of severe And persisting stress like you have in depression. The paradox And I don't want to get us too distracted'cause
Frankly, I don't understand what we found. So I can't really explain it. But In patients with post traumatic stress disorder We find both
Inpatients while they're alive with pet scanning. and in analyzing postmortem brain tissue. That the mycoglia are suppressed. And I've been talking to
Colleagues about this and they think well Maybe at one point they were activated, but maybe There's kind of in a Burned out. State you know, an exhausted state. Exactly. Something like that.
Yeah, you know, I don't really know and I don't think anybody does what's going on with the microglia. But it's really interesting to me that you have these two stress related disorders. One like major depression, where you get a lot of cortisol in the body and the microglia tend to be activated in the brain. And you get the opposite pattern. in PTSD where You don't tend to get so much cortisol chronically. And you don't tend to get so much microglia activation.
So we've stumbled on to something that we think is important. That's different in these. Disorders that we don't yet quite understand. But for the antidepressant effects academy
What? We think is happening is that We might be preventing the microglia from gobbling up the newly created synapses. And so instead of lasting a couple of days, we get Yeah, like a full course of treatment.
How long does Rapamycin extend the antidepressant effects academy? We don't know the answer to that. Because Since we didn't expect to see it, we only designed the study with a two week window of follow up. So we'll have to do, you know, longer studies to figure that out. But we're really interested in developing this idea, both from the point of view of academic research and I have a A colleague that I've collaborated with for many years, uh Tom Su in Taipei. who is doing a study looking at this combination. And then
We're Developing a version of this idea use in the treatment environment. Within a company
Called the Freedom Bioscience Instead of I'm associated with. Touching again on the Rap mice in Plus ketamine.
Certainly people can go on PubMed and search MTOR and Cadamine and there are a lot of there's a lot to read. If you haven't published this Then of course no need to No need to get into it or if you don't want to disclose it, that's fine too. But what was the dosage range that you decided upon? Or maybe the the precise dosage. or protocol for the Rapamycin.
That you Determined or Hypothesized to be well tolerated. Think it's six milligrams. Six milligrams.
Okay. oral rapamycin. And we may have stumbled onto something by giving that dose. And what I mean by that is that We thought it should get into the brain at six milligrams and it's r we were pretty confident that it would get in the brain. It would have some effect in the brain. But
Rapamycin turns out to be actively pumped out of the brain. And so the concentration that we achieved was probably kept quite low by this act of Clearance mechanism. And so
What we think we did. Was to stumble on a combination that Was In a kind of sweet spot. high enough to interfere with gobbling up of the synapses, but not so high to interfere with the antidepressant effects.
A little bit of serendipity. Oh, I feel like a lot of science is serendipity and knowing when to pay attention to it. Seems like that's one of the more exciting pieces of scientific discovery is being able to spot those serendipities that matter. Actually Just mention something, please fact check me if I'm not getting this.
Correctly but First I want to emphasize what you said, and that is that Rapamycin is an immunosuppressant and at higher doses than we're discussing. for instance, organ transplants and things along those lines.
Was the frequency of administration of the oral wrapper? At five milligrams, was that once a week or Less was it a one time administration. How frequent in the intervention group. I don't know what the arms were in the study, but
Exactly, but how frequently would any one individual receive that rapamycin? So first Tim. This is a experimental procedure. It's not really not ready for prime time. The finding hasn't even been replicated yet, you know, this is what You do when you're trying to develop a new treatment and
It's very preliminary data in some ways, even though it's a ro very robust finding. But it was just a single dose of rapamycin given with that single dose of cadmium. And that was what was so striking to us because Rapamycin lasts a little longer than ketamine, but it doesn't last Two weeks. So really
The possibility that there's some synergy between the two treatments is really uh, you know, a possibility. Uh From the preliminary findings. Very exciting. It's very exciting. And the the reason I ask is that
For people listening. As you said. This is a powerful drug. You have to be very careful with it. You cannot just gobble this stuff like tic tac's and expect to turn out well.
And you know my very primitive understanding is that If one were taking Rapamycin as a monotherapy for say life extension which is very I mean I don't want to call it very speculative, but it's it's certainly not
mainstream at this point, or for other purposes. My very cursory understanding is that you're you're trying to have an effect on MTOR such that you trigger certain things like autophagy and sort of uh cellular cleaning and repair, but Not so much that you bleed into I think it's M Torque two territory where you start to
really experience the immunosuppressant effects because you then run the risk of Greater likelihood of infection. If you become infected, greater severity of infection, you have to be very careful with it. Uh So in any case, fascinating, fascinating drug. In case people were wondering, Rapamycin named after Rappa Nui, which is the native
term applied to Easter Island, where the bacterium I guess was first isolated. That relates to MTOR. Let me also just ask A novice question about
Microglia and glial cells. I assume they're related. But The description I read of the glial cells is that they're in a sense the connective tissue of the nervous system. They provide physical and metabolic support to neurons. So
How do you think about ensuring that the sort of Zambones of the brain are able to do what they need to do? while potentially inhibiting Microglia enough. To get these types of clinical outcomes that you're hoping for.
This has been the one of the most intriguing parts of the academy work and it is again one of the most intriguing parts of the Rapamecin work, which is that In both cases We're not trying to produce a chronic state of intoxication with ketamine. And we're not trying to produce a chronic state of exposure to rapomyces. We want the Zambones to clean up the ice
We want the m microglia to clean up the brain. Most of the time. What we want to try to do is to create an optimized environment so that in the time when these new synapses are particularly vulnerable to being engulfed that that we've protected them and and sort of optimizing that window of plasticity that's produced by the treatment. Exactly. And and enabling it to persist for for a longer period of time. And
one possible way this could play out, but it's certainly not by no means the only possible way, would be that Maybe the first time it lasts two weeks. And then maybe when you have uh repeated ex combinations of rapamycin and ketamine, maybe it can last longer and longer. From there, which would be really great. And It would be great for for a number of reasons. One is
As we say, and we keep coming back to both of us have have tried to make the point that no treatment, no medication is without risk. Every medication and treatment has risk. And so we want to Provide a treatment that has as few exposures to the drug as possible'cause that's a way of limiting risk.
And it's a way of ensuring At the same time. Increasing the likelihood that people will stick out to treatment. And it will increase the likelihood that People will get the treatment because it will cost less. So systems of care are more likely to adopt a less expensive treatment. People are likely to take a treatment that's less burdensome for them to take.
And if we can space out avoid that period of time when people are getting more frequent fusions, we reduce the cost, we increase the safety, improve the tolerability, and we provide a v uh greater flow through the clinic so that more people can get access to the treatment. So I think at at every level if we can If there is truly a potential to realize here and if we can realize that potential, then Then
I think A lot of people could benefit by that. Let's get to know Ketamine a bit better by Doing I don't want to say side by side comparison, but throwing it in the mix with a lineup
kind of usual suspect style. And the lineup consists of other psychedelics, and I should just take a second to say That in my subjective experience particularly I don't advise this, but at the doses that sort of push you through the looking glass, which I think no one really needs to do, but I consider ketamine much more of a psychedelic compound at higher doses than I do something like MDMA. If we uh
Take as characteristic of psychedelic experiences at higher doses. Ego dissolution, et cetera. Also, I wanted to harken back to something you mentioned, which was
Salvador and A being short lasting, short acting. And I just wanna emphasize for anybody out there who's maybe psychedelic naive or not experienced that Short acting is the most relative term imaginable when applied to psychedelic experience. And I would say short lasting in earth time, yes, but Let's just say s if it's in the case of N N DMT or five M E O DMT. Only fifteen to twenty minutes or ten to twenty minutes. Like put your hand on a hot stove and tell me only twenty minutes. Just not that you'd automatically have a hot stove experience, but It may not and very frequently will not feel like.
twenty minutes, so to be aware of that. But if we look at Other psychedelics. If we put ketamine in that class for the time being. Or even just Put ketamine by itself and then other psychedelics.
There seem to be some Not all. Not totally overlapping, but some similar effects. The release of glutamate activating say MTOR affecting MTOR BDNF, so brain drive neurotrophic factor. What are some of the closest comparables?
that you've seen and how are they most similar and how are they most different? I think you captured the the key point of convergence which is These are Structurally there's these drugs are not at all similar.
mechanism of action these drugs are are not at all similar. And where they converge. Which is Something you have to expect in the brain, which is this this enormously complicated organ. That where they converge is how they perturb the effects of
of micro circuits. And micro circuit being a cluster of a small group of excitatory and inhibitory cells That are You might say the transistor, if you will, of the transistor radio. In other words, the lowest level that has the superordinate properties that you're
You can study in relation to cognitive effects. So when you give a dose academy You do two things. Mainly. Three things. One is
You do activate inputs to the cortex from the thalus. You're really disinhibiting them. And you're inhibiting the inhibitory Nerve cells, the gab of nerve cells.
So you're locally reducing the degree of inhibition and you're increasing a little bit the excitatory Input. Could you just repeat the effect on the Thalamus and I'll just say this, I don't know if it's the best Metaphor again, but is it fair to say the thalamus is a bit like the traffic cop for sensory inputs going to the brain? It's like a relay station.
That's Through which everything or most things must pass before going to the cortex for processing. Could you just repeat the effect that ketamine has on the thalus? So what I'm gonna say about ketamine and the hallucinogens and the psychedelics, if you will. are going to be complementary at each stage of information processing. Ketamine is relieving inhibition in the thalamus.
In other words Resulting secondarily in excitation in And lucinogen psychedelics. Are stimulating. Polamic.
Neuronal act. You have sensory information coming in. And The ketamine is distorting that message to the cortex. And
Psychedelics are creating a new message. To the quote. And similarly. In the cortex. Ketamine is relieving inhibition.
And thereby increasing activation. And the psychedelics are driving Autonomously excitation. again creating it a new message. And so that Difference has been one of the reasons that people have thought
That ketamine sensory experiences tend to be more distortions of sensory experience. In other words, the walls are breathing in and out, and My arm is now A foot longer than it used to be, things like that.
Whereas Oh look, there's um A shining glowing orb in the middle of the room that wasn't there previous, you know, from the the psychedelic, right? Uh fully Fledged hallucination. So In that way they're not exactly the same in terms of the
Michael C but they both Have as a common property this. Increase of excitability. Increase in glutamate output, triggering the downstream neurotrophic effects. And triggering the regrowth of in animal models. The triggering the regrowth.
Of The key thing that we don't know yet. In terms of and so we see evidence hints of efficacy in the imperial college study and in the studies done
at Hopkins and some of the other trials. And A a little bit of a stronger signal In the Compass. Data that's been released in the press releases.
But we do not yet have Data in the Treatment resistant depressed population. And And there are a lot of reasons why we have
different populations being studied for the different ages. But to make a long story short, Even despite all the differences in the clinical data at the basic science level, we do have this kind of common effect on on micro circuits and regrowth of synapses and and that's encouraging as a potential foundation for the way people think about The potential therapeutic effects of of psychedelics.
How important is the role of BD and F again brain derived neurotrophic factor, I think I'm getting that right. Put a monkey in a suit and gets fancy. It's the equivalent of my my vocab that I use. But How important is BDNF? As far as we know. to the increase in
Synaptic. Or dendritic growth. Or synaptic density or Efficiency. If at all.
There are a whole family of neurotrophs in the brain. And when the different neurotrophs have tended to be studied, there has been some indication that other neurotrophic factors may also be involved in the antidepressant effects of ketamine and and psychedelics and and in fact the antidepressant effects of SSRIs and other antidepressants. And One of them.
Called Vaso endothelial growth factor. Rolls off the tongue. It does. It does. It's really a beautiful a beautiful Yeah. Nerve growth factor.
That or or growth factor that seems to involve the interface of neurons and glia with the surrounding circulatory. System and if you block The short name for it is Veg.
At least that's what people call it. If you block Ved Jeff. You can reduce the antidepressant effects of most antidepressants. Just like if you block BD and F you can block the action of most antidepressants. But BD and F does seem to be really important. It's a key thing. It affects
Raising BDNF. Affects both The synaptic efficacy And it affects the synaptic. Number.
and it affects the synaptic efficacy. Because One of the things it does in the depotentiated synapses, the less efficient synapses is when the BDNF levels goes up, it tends to drive more receptors for glutamate to the synaptic surface. In other words, it tends to make the
Neuron more receptive to glutamine. So that in in that way. Um compensating for the earlier deficits in synaptic efficiency. Yeah. And it tends to be involved in the regrowth of the synapses via the mechanisms we just talked about.
They know that MTOR is a part. So I I wanna mention a few things. Number one is if you're listening to this podcast and you're thinking I don't think I really want to I
Pretty sure I don't want to use Rapamycin. But Man, this BDNF stuff sounds pretty good. Sounds like it could be beneficial. I would That you
explore a few different types of exercise. There's actually a book that was published quite a long time ago called Spark that goes into some of the physiological Underpinnings. of psychological or mood improvement following exercise and you can go to PubMed where I spend uh
ridiculous amount of time. And I just pulled up one as an example. This is the the the the name of the paper. Exercise promotes the expression of brain derived neurotrophic factor of BDNF. Through the action of the ketone body beta hydroxy. Puterate. Now This is interesting on a number of levels. And this was just the first one I pulled up. This is from 2016. Seems to be pretty decently cited.
Uh but the the the point being that You feel better often after Certain types of exercise. Why is that? It's not magic. In fact
It is increasing One of the Let's call it, you know, agents or factors that we're talking about, BDNF. What's interesting about that particular favorite to me also is that And this ties into some other guests I've had on the podcast like Dr. Dominic Dagasino.
Is it raises questions and I'm sure Dom has a an answer for this because this is what he spends most of his time on, but could exogenous consumption of beta hydroxybuterate BHB, which is available. There are synthetic versions also provoke increases in BDNF. Actually I have something to show you, John.
So you might get a kick out of this. And this is before I even mention this. Say this is a really good case of do as I say, not as I do. But I've always enjoyed drinking
Alcohol with friends. Having a few drinks here and there. I don't think I have any abusive behavior with it. I mean, maybe in my early twenties I've like a lot of people in their early twenties probably didn't make the best decisions, but these days Maybe once.
every week or two I'll have a few drinks with friends, but it vastly disrupts your sleep architecture. It causes all sorts of sleep issues, in addition to other issues. And so I was looking for potential alternatives. I rolled out ketamine for all the reasons that we've Spoken about but Uh. It says R1 comma three ginger mule hard ketones. So this is R13 butane diol, which is
It's an ethanol free Alcohol. It's a ketone that produces Some of the I wanna say delirium, but some of the
effects that you would commonly associate with alcohol. I will say that it still seems to disrupt sleep if you consume it too close to bedtime, but not as much. least based on aura ring data and so on, not as much as ethanol itself. So Pretty interesting stuff. I wanna use this as a very indirect
Meandering segue to a question about Ketamine. Are you aware of any Impact of ketamine. On Sleep architecture or sleep.
Yeah, it does affect sleep. It's probably one of the ways that Alcohol intoxication at particularly at high levels affects sleep is by blocking N M D A glutamate receptors and And there's some E G s sleepy E G studies showing reduction in sleep quality after Getting ketamine and and so
Um When that Data was reported. There were some people who thought Well, maybe the disruption in sleep is actually contributing to the antidepressant response. Because for so many people
The full antidepressant response doesn't really appear until at least one night of sleep after After Academy. But we don't really know the answer to that yet. Just to come back to exercise. Exercise.
Shows dose related antidepressant effects. And My colleague and I actually analyze Uh my colleague led the study, Adam Shekrud, and This remarkable data about how
In a pretty dose related way, increasing exercise and Up to reasonably high levels, particularly in the context of team exercise, can be very helpful for For depression. It is possible to
Engage in such extreme exercise that you lose the protective or at least Some of the protective effects of exercise and uh We don't really know if that's a product of the exercise or who is the people who are choosing to exercise at those very extreme levels. Yeah. They know the stress that they're under. But the idea that uh that you say about raising BDNF and other beneficial effects of exercise.
And a possibility that that would synergize with Antidepressant treatment. Which also raises you know, SSRIs also raise BD and F in the brain and Yes. Academy and psychedelics.
John, are there any other pictures you'd like to paint of possibilities or Teasers for things that you see being explored or that you yourself would like to explore just uh forward looking, let's just say within the next five years. Yeah. It seems to me that
Ketamine along with some of these other more classically labeled psychedelic compounds. So the tryptomine psychedelics. Some phenethyl means, but to a lesser extent, you know, mescaline would be in that category. are not just being explored, but they're being taken apart, right? The car is being parked in the garage, every component is being removed.
And for therapeutic reasons and also for economic reasons things are being modified, repurposed in every which way possible. What are some of the more interesting explorations that you are aware of or that you anticipate seeing in the next Say within the next five years. So I think within five to ten years. The
current generation of N MDA receptor antagonists, N M D A receptor subtype antagonist, at least the One type. Subtype.
A selective group called the NR to be antagonists. The R Academy. And some of the combination therapies with ketamine, I think that will that will settle out and we'll know whether there's Uh meat on those bones. And
I think in parallel In the psychedelic space. There are certain key concepts that we're just getting into. Five.
At most ten years before we have a good sense of How helpful they are. And probably the best known in in some ways, perhaps the scientifically
strongest foundation is the idea that psychedelics can signal At the same receptor via different downstream mechanisms. And the work of Brian Ross. And
David Olson Now each of them have been associated with different pharmaceutical companies and other people Uh Pursuing this. And the idea is
Imagine You're driving a car. And instead of the car that we're used to, it has two gas pedals. And if you step on one gas pedal Maybe you have you drive the electric motor.
And if you step on the other gas pedal, you drive the internal combustion engine. And There are situations where you're driving where it's w much better. To drive the internal combustion engine, like There are no charging stations. But there are gas stations and you want to fill up. And we all know about that charge anxiety that comes with an electric vehicle.
Yeah. The other p gas pedal gives you electric. Power and that has all kinds of advantages uh as well. Well, a receptor is like that. Most receptors, including the serotonin two A receptor, which is the target in the brain.
can signal via two mechanisms. One. Pathway. Sometimes called the traditional pathway or canonical pathway. Internal.
Substrates that have names like cyclic A and P or Fossil Light Pacy, different kinds of signaling mechanisms, but particularly the cyclic AMP dependent pathway. And then the other gas pedal Signals by it. A Compound called beta arrest it.
And the idea Is that Different effects are mediated by these different signaling pathways. And if you could just selectively step on one gas pedal as opposed to the other.
That y maybe you can get the Antidepressant effects. Oh. Psychedelic drugs. Without getting the
Psychedelic effects. And So some people Like my friend. Roland Griffiths would say
That's the Wrong idea in the first place. that the psychedelic effects in the context of embedded in psychotherapy Adds to the intrinsic antidepressant effect that you would get just by triggering synaptic growth and doing things like that.
And others would say Well, it certainly would be a lot easier to use these drugs to take them and to prescribe them if they didn't produce These psychedelic effects. Those could both be true. And for people who don't know.
Is it fair to say that you are to ketamine research what Roland Griffiths' to modern psilocybin research? I mean, is that fair? To say. Yeah, I he Roland has been a just a tremendous leader in this space and and one of the Very first pioneers. You know, there have been a number of pioneers.
Names who we've forgotten who who in their own way pioneer this Science going back to The nineteen sixties People like uh Daniel Friedman, Danny Friedman and Sasha Shulgan and uh
I mean, Mark Guyer and Dave Nicholson. So on and so on and so on and But Roland has really been uh instrumental in moving this work forward and just a wonderful contributor. And pioneer in the field.
Yeah, he's uh A wonderful human and uh I feel also an impeccable scientist who's been such a gift to psychedelic research in part because he did not begin with psychedelic research. If that makes sense. I mean he was certainly at at one point considered One of the
the foremost experts, if not the foremost expert in caffeine metabolism and has studied so many different compounds and has been published so many times. prior to engaging with the space, to be clear when it was still considered Career suicide, by and large. It's just been Wonderful to get to know people like Roland and and yourself. And I've so much enjoyed this conversation. Dr John Crystal, thank you so much for making the time. And you are, as certainly I mentioned in the intro, the co founder and chief scientific
Officer of Freedom Biosciences is uh there a best website. Or a best way people can learn more about freedom biosciences. I'm sure there is. Yeah. Oh I love it.
We will put that in the show notes. So this will be a a teaser for people who would like the URL we're gonna put it in the show notes as per usual, in addition to links to everything that we've discussed. So all of the terms, all of the resources, all the people, so ranging from BDNF to Sasha's show again, there will be a link to everything in the show notes if you go to Tim.blog slash podcast and just search Certainly John may be tough, but Crystal will not be tough. That is K R Y S T A L And John, is there anything else that you would like to Say any closing comments, anything that you would like to
Request of My listening audience or Share with them before we Bring this. Epic, very comprehensive conversation to a close.
Well, Tim, first let me thank you for the opportunity to To chat about this stuff. You know, I think Cadamine and S ketamine are really extraordinarily important treatment advances and depression is so terrible. And that it's really important for people to know that there's hope out there and and even if the hope for them doesn't come from Ezamine or or from ketamine, there are still other things that can be done and and that treatment can be very helpful and it's really important to get
Connected if you're if you're struggling and don't give up. The second thing I'd say is I really appreciate The way
That we've talked about it today. These are Drugs, every drug has a risk. You have to take them seriously. You have to give them the respect That they need in terms of Making sure that If you're exposed to them, you're using them in the right way, in a way that doesn't put you at risk for harm and
A lot of the things we've talked about are very early stage development ideas. And really Not ready to be built uh into recreational practice and Let me just say it's been an extraordinary pleasure to hang out and
Yeah. I really appreciate the time. Absolutely. I hope we have another chance like we did after South by Southwest. uh some time ago to cheers and perhaps share a glass of my favorite neurotoxin, some type of wine, probably, or maybe Maybe I'll bring along some uh R one three butane dial for you to try. But for people who are listening who
Or prone to depression or experiencing depression. and want to learn more about ketamine assisted treatment options. Are there any resources you can recommend? Or websites or organizations
If you're interested in the S ketamine and in ketamine treatment generally, Jansen has a number of of um A lot of information on their website about S Academy. Right. People are welcome to contact we have the interventional psychiatry. service at Yale New Haven hospital, doctors Ostroff and Santa Cruz or my office, or
In most cities, most universities nowadays have academy service and Uh a place where you can get connected. So The availability of ketamine programs is growing and those are the places that I know of. But I'm sure there's some better centralized uh information sources. We'll try to pull a few things together, my team, and put them in the show notes as well. And I will just give
Yet another A warning, cautionary note, which is there are also a lot of flyby nights. Academy in operations or ketamine clinics that really push people through the system like cattle going through a cattle chute. And not all
Clinics or clinicians are created equal. And you may make certain assumptions about support and aftercare that will be misplaced with certain places. So I do think it's a great idea to first go to uh at least educate yourself with credible university sources if possible. And I will also speak to a few other folks and maybe follow up with you and we'll put things in the show notes for everyone. At Tim.blog slash podcasts. Crystal, like I said, easy to find. K-R-Y-S-T-A-L. And we will add the link for Freedom Biosciences. And
John, what a pleasure and uh what a gift to spend this time with you to learn so much. I've copious notes everywhere. And I think that this and I hope that this will be uh of great use. to people and as you said in your closing comments. Provide.
Some hope. Perhaps for those people who may feel Hopeless and helpless. Certainly I've been there before. And to reiterate what you said, there are tools. That can help there are people.
Who can help? So thank you very much, Sean. Take care. Thanks so much. Hey guys, this is Tim again, just one more thing before you take off, and that is Five Bullet Friday. Would you enjoy getting a short email from me every Friday that provides a little fun before the weekend? Between one and a half and two million people subscribe to my free newsletter, my super short newsletter called Five Bullet Friday. Easy to sign up, easy to cancel. It is basically a half page that I send out.
every Friday to share the coolest things I've found or discovered or have started exploring over that week. It's kind of like my diary of cool things. It often includes articles I'm reading, books I'm reading. Albums perhaps, gadgets, gizmos, all sorts of tech tricks and so on that get sent to me by my friends, including a lot of podcasts. guests and these strange esoteric things end up in my field and then I test them and then I share them with you. So if that sounds fun again it's very short a little tiny bite of goodness before you head off for the weekend something to think about. If you'd like to try out Just go to Tim.blog slash Friday. Type that into your browser. Tim.blog slash. Friday, drop in your email and you'll get the very next one.
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