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[This] talk really centers on complexity, because, while we tend to reductionism,
complexity is really where things are at. We have a tendency to reduce things to nil,
and they're empty. But complexity is really the name of the game. If you look at
psychedelic research, when it's reductionist it's boring and empty, and when it's
truly complicated, as it is, it's fulsome. So, I started, but I'm calling this a dance,
but I'm unfortunately dancing alone a bit, as a flamenco of exploration
and demystification that I hope will open the door to mystic elation.
So I begin...the title of this talk is The Varieties of Ketamine Experience.
I owe that title, of course, to William James, who was an extremely complex and interesting
human being. So William James, in his rational self...he had tremendously irrational selves...
he was into seances and he had terrible grief and he tried to contact the dead
and he was flim-flammed. He was an amazing human. So in his rational self,
he said, "The truth of an idea is not a stagnant property inherent in it."
"Truth happens to an idea. It becomes true. It is made true by events. Its verity is in fact an event,"
"a process, the process, namely, of its verifying itself, its verification."
"Its validity is the process of its validation." Well, I think that's true
in the era he was writing, to some extent. But it's also true for invalidation.
What James [really did not] pay attention to, nor could he, was the buttressed illusion
of validation because of the stamp of approval of an idea from an authority,
from special interests especially interested in obtaining a truth.
So, we look at complexity. Let me get to my presentation here, so I can work
from here. Pardon me...I can't use the slide.
Okay. I think we're in shape. So my argument about complexity is that the mind
remains irreducible despite the scientific creativity of assaying its mechanisms and parts.
Though science succeeds in providing us with information about [the] brain
with its ever-greater sophistication of technology and tools for exploration, the study of
the mind itself remains locked in our subjectivity and our reports of our experience[s].
In part, this is the result of the complexity of [the] brain itself,
and in far greater measure, [it is] because subjectivity by its nature is not knowable
by instrumental means. We'll be discussing [the] mind, and reporting about
states of mind and their contents. This is an amazing view...what you can see
of a travel through the cortex of a mouse brain. I'm going to let it
speak for itself. The green is the axons.
We're going deeper and deeper into the cortex of a mouse.
Q: What are the other colors?
A: The other colors are glial cells and cells that surround nerve tissue.
You can see on the left where you are in the cortex, coming down towards the white matter,
that little box. It usually says on the screen what layer it is. I can't tell you exactly.
It's like a universe. It's like a cosmos, like galaxies, it's like being in the realm of the
great cosmos, and this is a mouse brain.
So imagine, as we do this, the inside of your own cortex, the complexity of
your own brain, the complexity of your friends' brains. [laughter]
You're bigger than a mouse.
This is from Stanford.
We're using me now, or [do] you want to go back to you?
How about if we go back to you? You'll have the full slide,
unless I can get it. Let me try. And we can do the lights. Okay, so we're going to do you.
So...complexity, which I'm trying to highlight here, and we're going to have time issues
for sure, because we have a long way to go, complexity dictates a few caveats.
They're worth remembering, such as "never trust a single neurotransmitter theory as explanatory;"
none have ever worked out. All attributions of complex mental phenomena have been
irreducible so far to biochemistry, scanning, neuroanatomy, and our various
attempts at instrumentalism. Distrust the latest hype for an internal love substance.
They come every few years or months. The current one's oxytocin, but forget about serotonin;
it's more complex. The current real one now is glutamate, which we're going to
talk about today. It's a brain substance; it's not the whole answer.
So we remain at the level of observing interactions between drug, setting, and set
in the broadest sense. That's where we are. That's what subjectivity's about.
We haven't really gotten past it. So embrace complexity and enactivism,
which is a [Francisco] Varela-inspired theory of being in the world, which I urge you to look at.
Avoid reducing [the] mind to [the] brain itself. On a much lesser level,
never trust an investigator who is single-mindedly making a reputation and livelihood
on a single substance. Remember our friend [George A.] Ricaurte, who brought us [the] terror
of ecstasy which, fortunately, isn't true. People still live in that terror.
Next one. My setup is harder to read than yours. Recently there's been a great
resurgence of interest in ketamine. We're going to go through some of this much faster.
It's now touted as a significant new antidepressant with a novel mechanism of action,
and there are a bunch of congeners in drug company development based on these studies.
Ketamine was first synthesized in '62 and by '65 was noted to have psychedelic properties.
John Lilly, who we met in 1985 and was a wreck, and inspired people to avoid ketamine,
was by far the most potent explicator of ketamine. His book, The Scientist,
is really worth reading. It's novel. It's interesting.
[Dennis S.] Charney, who is one of the NIMH [National Institute of Mental Health] founding fathers
of ketamine research, published in 1994 in the archives, and what Charney did
was to actually at that point, though he later suppressed it as we'll see,
Charney talked about the psychotomimetic, perceptual, cognitive, and neuroendocrine
responses, in other words that there was psychedelic activity, even at the
low dose that he and others purported to use, and did use in research.
So in the later papers, as you read them, there's been a tendency to diminish the
psychotomimetic experiences of subjects. That is to say, the attempt is to make
ketamine a docile little creature, which most of us know it's not,
but of course that's dose-related.
He refers...in 2010 to minimal positive psychotic symptoms, which refer to
hallucinations, delusions, etc. So that's again part of an understatement
of what ketamine's about. Again, sorry for my little technical struggles here.
So, all of this leaves us in a...reason for really being here. They postulated a low-dose scheme
of 0.5 milligrams intravenous per kilogram, which people have been taking. Their
last review was 163 subjects in all, over time. Of course, that left the riddle
of "what are people experiencing? What are they getting out of this?"
"Why is it an antidepressant? Why is it called that?" So I get to the next one.
Next one, please. So this is marvelously difficult.
So that's the emotional origin of this study. Add to that...I had a *** of James Fadiman
yesterday. James was giving wonderful first-person analyses, and I realized
how flattened I had become, reading journal article after journal article in which
there was no human reportage. So you read all this literature, and I went through
dozens and dozens of papers, there's nothing about what happens to people.
That was where we were coming from. The intellectual origin is somewhat different.
Having known non-abusing ketamine transformationists, people who go for the
transformational effect over many years of use, my sense is that ketamine use
has played a valuable and indeed transformative role in their lives.
But there have been episodes of significant and sometimes sustained depression,
despite ketamine's use. As a clinician, my interest in exploring what happened to people
in this IV [intravenous] ketamine series was related to "is it a tool? Can I use it? Can I bring it to my patients?"
"Do I want to do that?" So in my view, coming into the study, because I think
it's good to do biases, what I'm really thinking about, what as a practitioner I'm looking at [is that]
I think it's a transformative egolytic interruption from obsession and despair.
Ketamine has a more lasting and valuable impact than just the antidepressant thing.
So we did a study and it's qualitative research. It's not a double-blind.
It's not an attempt to definitively outline what ketamine does. We did it with
seven people, who were experienced [with] greater than 5 experiences of moderate-dose ketamine.
Next. Next, please. The procedure was a straightforward replication of the NIMH
protocol, 0.5 mg IV administered over 40 minutes. Our findings are as follows.
Let's go to the next one. I want to share mostly the comments of people, because
that's what we were looking for. That's in the descriptive comment section.
As usual, pulse rate was stable, but blood pressure increased, as it does with ketamine.
There's no suppression of respiration; it's very safe there.
So let me just find where I can read it.
So the descriptive comments during the experience included: metallic taste, the 2 "plus four"
on the Shulgin [Rating Scale], after Sasha [Alexander Shulgin], very pleasant, from E.K., warm,
no hallucinations, paper baggy, crinkly, could read or make phone calls, floating,
not particularly psychological, no spice, detached, no loss of intellectual function, shouldn't drive,
but could, relaxed, very gentle, not particularly insightful, could walk with support,
couldn't drive, very tuned into all sounds, mild, +- high, rather keep eyes closed,
a bit anesthetized, door almost open, anesthetic is predominant.
This is not an antidepressant, and of all the people in this study, only one person
...next slide, please...who came into it in a somewhat grief-ridden depressed state
had a bit of a transformative experience.
Interestingly, she was the biggest person in the study group and received 50 mg.
That, I think, is an important factor, and you see my conclusions here,
that body weight and effect are not linearly correlated, but related.
Humans have a range of sensitivities, irrespective of their actual state,
and hence only a correlation with peripheral levels of drug concentration.
I think that's one to bear in mind for any kind of substance, that our responses
are not uniform. Milligrams per kilogram doesn't mean a hell of a lot.
It puts you in a range, but it doesn't mean you're high or low. So, the conclusion of that is:
the more I do, the more intoxicated I get, but one human's point of intoxication
is another human's neutrality or another human's big high. A fifty mg IV dose has
a significant anesthetic impact irrespective of body weight. The depth
of the experiences in the study [is] related to the depth of the anesthesia,
that is, the reduction in access to sensation through external senses.
Next one, please. So, the greater the dissociative effect, the more interesting the experience.
Take out the transformative element and subjects are unable to understand the effect
or value of the experience, save as it might relate, to naive subjects, to a
partial break from the usual afflicted mind. So in consensus, the group recommendation
was for threshold transformative work. That really means IM [intramuscular injection] 40-50 mg.
We'll go on. Next slide. In all of this, I want to think with you about "what is the nature of"
"a dissociative anesthetic?" My view is that, with increasing doses, much like with
nitrous oxide, not just with ketamine, the sensory inputs and perceptual integrations
are turned off at the cortical level, leaving consciousness more and more subject
to its own view, experience, and creativity. Next slide. We got the whole thing; good.
The next slide is an extraction I made form the Abhidharmakosha. The Abhidharmakosha
is the third basket in the tripitaka of Buddhism, the philosophical basket.
It's later than the first two and it's very comprehensive. What it offers is a view
of perception in the six paths. When you look at it, you can start to think about
"where is ketamine really acting?" We know from experience that the first place
it begins to act is visually and tactilely; it's an anesthetic. It produces analgesia.
You don't want to keep your eyes open. We know very little about its effect on taste and smell,
...and we know that auditory perception is pretty well kept, since we listen
to music, we like music. It's altered, but it's there as the anesthetic level rises.
Then we have [the] mind more and more isolated unto itself, as per
the preceding slide. What we're looking at, I think, is both the stimulation effect of ketamine
[and] also that it provides a narrowing of our sensory apparatus so we're more and more
like in a dream state. It's like going to sleep, where your senses are a bit alive,
perhaps even more than ketamine, depending on dosage, but what is produced is
the mind-only function without much sensory input. That's, I think, how dissociative anesthetics
work. They cut us off from our perception and the integration of that perception.
Next, please. So, now I wanted to look with you at dosages. There are many routes:
you can eat it, you can...insufflate it, you can do IM [intramuscular injection].
This is from Erowid[.org]. Just one comment: the IM dose is a bit low in Erowid;
really the anesthetic dose is 6.5-13 mg/kg. So this gives you a range.
Then, for anesthesia, it's 1-4.5 mg/kg, but that's administered over 60 seconds,
so it's a bolus. It's not about doing ketamine by an IV drip over time.
Is the message for me? No. Then there's a review of the literature. We're not
going to have much time to do it. Next slide, please. The review of the literature
is fairly comprehensive. What is shows is transformative experiences,
in the beginning especially, [Evgeny] Krupitsky's work is transformative. He's still around,
good work. He did it in Russia in a 3-month long inpatient study, using high dose[s]
even at a comparator of 0.2 mg/kg, which did very little. He got, with all of that,
very successful results of *** and alcohol abstinence, which [were] not totally reproduced
in the United States in his association with Colp. Next, please.
So, there's a very interesting study which goes to the nature of how you might
administer ketamine. This is in very treatment-resistant anorectics who are given
10 hours of ketamine IV in multiple sessions. Nine respond in up to 5 sessions,
and six don't respond. The outlier has 17 sessions. So, can imagine? [If] you're basically
on ketamine for 10 hours frequently, you get over not wanting to eat over time.
At least 9 people of 15. Then we have a bunch of studies labeled as antidepressant
ketamine research. That shows us very short-acting results in numerous subjects up to
7 days in treatment-resistant depression people, next slide please,
[or] three days in the bipolar I and II study that Zarate did. Zarate's one of the main people.
What you see is very short acting results; not everyone responds.
So this is what's inspired the work. I think we missed a slide which had the
quote from Science, but the quote from Science was in late October 2012,
that ketamine was the breakthrough of antidepressant research for the first time in 50 years.
I'm arguing that's not true. Then, I just wanted to show you a tool. Next slide.
That one, the next one, and the next one, and the next one.
This is the major evaluative tool that Zarate has been using. It's called the MADRS.
It's the Montgomery Asberg Depression...Scale.
It's about asking the same question over and over again. I wanted to demystify myself,
because I thought, "okay, rigorous tools being used." But this is a questionnaire
administered by people at various intervals, who then ask the same questions.
It's like saying, "how do you feel?" in ten compartments.
"How do you feel? My mother used to ask me that.
"How do you feel?" And I'd answer in one of those 10 compartments, usually not suicidal ideation...
when she got angry with me. [Is this] qualitative research or quantitative research?
When you really look at how people put things together, it's totally dependent on
subjectivity. It's just me reporting on the same questions to you about what people answered
in those questions. That's not very deep. Next. Recent developments are interesting.
They're moving towards repetition of ketamine sessions. There's always been a
comparison with ketamine and ECT, because it's intravenous in this way.
ECT is episodic, and relapse rates for ECT and ketamine are similar after first dose.
In this study, an ECT-resistant woman got to a maintenance phase,
where she's getting IV ketamine every three weeks. That's pretty novel, intense.
But what's happening, really, is that people aren't able to extend the benefit of ketamine
as an antidepressant. They've looked at drugs for it [and] haven't been able to find one,
and they're looking at multiple sessions. It's becoming like that.
Next, please.
...Let me get back to my side...What I'm basically saying is, there's a method
to the madness, and it serves institutional psychiatry, and really when you look at depression,
it's extremely complicated. It's extremely complicated both in its drug treatment,
in how we treat depression...There are so many ways to treat depression;
it's not simple and straightforward, and there are many recoveries without
psychotherapy or medication. Most depressions stop without psychiatrists
and therapy, and some depressions start with psychiatrists and psychotherapists.
There's a continuum between anxiety and depression and mostly they are mingled.
If you look at the list of issues when we really evaluate a person, they're extensive.
I won't repeat them all. Next, please. That's Dürer's melancholia, 499 years ago.
[It's] pretty complicated. Then let's go to the "view, path and fruit," again,
from Buddhism. We've looked at the view and we've done the path of research, quickly.
Now we're at the fruit. What do I think? The effects of ketamine are related to dose and
subjects' sensitivity. In general, the higher the dose, no matter what the route of administration,
the greater the anesthesia and interference with sensory modes,
the greater the internal stimulation and isolation of consciousness to [the] mind only.
The so-called antidepressant effect is short-lived and has only been extended
by repeated administration of IV infusions. The rapid action of ketamine is due to its
disruption of ordinary consciousness and its anesthetic properties.
The mechanism of action as an antidepressant has not been elucidated,
inasmuch as the complexity of the state of depression is enormous,
and so are the brain chemistries involved, etc. There have been
other mechanisms proposed than the glutamatergic method which is so high
[at] present, and even Zarate is having trouble making that one stick.
Next, please. We look theoretically, and I hope you're interested in this,
at how the antidepressants are administered in the substance sense,
[and] we can see that there are different modalities. One is the disruption of consciousness.
That's famous with ECT and the sleep studies, and narcoanalysis, and if you look,
a second one is this mild disruption of consciousness with the IV protocol of ketamine.
The disruption egolysis and transformation towards the k-hole, or in the k-hole,
and [with] other psychedelics. Ketamine's not unique in every aspect.
Then there's the direct shifting of mood and new experience of affect, such as [with]
empathogens, because they can be great antidepressants.
That's what we were doing before it was made illegal, amongst other things:
helping couples who were anxious/depressed, helping all kinds of people.
Then there's the show shifting of affective and anxious obsessional states.
I call that the continuous brain bath, and that's antidepressants like SSRIs.
Then we have things like marijuana, which in some people have the effect of
smoothing, refocusing, and obsession release. We're almost done. Next.
Conclusions: I don't think much of the IV administration route, as you can tell.
I think it results in a mild disruption of consciousness. I believe this...you have the slide.
That's why transformation is...I believe that, in essence, the IV route was chosen
because of the illegality of substances, the War on Drugs, and [the fact that] NIMH research is
concerned to keep it without psychotomimetic effects. The lower the dose,
the happier they are, but I don't think the effects are robust or lasting.
That's why transformation remains the attractive way to really use ketamine.
If you really think of psychiatric use of ketamine, it's to help people change personality,
grow in a fairly safe way. [It] pushes you towards the IM route.
Next one, please. I think the IM route is the way to go and will be the way to go.
People are going to do it much more because the IV route pushes you to hospitals,
institutions. While it's good for business, because you['ve] got to do repeat after repeat,
it's awkward and people aren't going to really want to do it. So can you get the whole slide in,
or not? No? Okay. Anyway...my argument, in conclusion, is that ketamine is a valuable substance
for transformation. It has risks: bad trips, some small risk of addiction,
but otherwise is a safe and widely used anesthetic. We should value it and use it
for transformational work. See where the whole thing goes in antidepressant work,
but I think it's dubious. Last slide. If you're interested, these are things I have at the
back of the room: my book, and I have some papers if you want, [to] distribute.
Sorry for all the technical difficulties, but thanks for putting up with it.
[applause]