Dr. Nolan Williams: Psychedelics & Neurostimulation for Brain Rewiring

00:00:00.000 | - Welcome to the Huberman Lab Podcast,

00:00:02.280 | where we discuss science and science-based tools

00:00:04.880 | for everyday life.

00:00:05.900 | I'm Andrew Huberman,

00:00:10.280 | and I'm a professor of neurobiology and ophthalmology

00:00:13.340 | at Stanford School of Medicine.

00:00:15.200 | Today, my guest is Dr. Nolan Williams.

00:00:17.540 | Dr. Williams is a medical doctor

00:00:19.600 | and professor of psychiatry and behavioral sciences

00:00:22.280 | at Stanford University School of Medicine.

00:00:24.640 | His laboratory and clinic focus on depression

00:00:26.960 | and other mood disorders.

00:00:28.880 | They focus specifically on the use

00:00:30.560 | of transcranial magnetic stimulation,

00:00:32.880 | which is a brain stimulation technique

00:00:35.060 | that can either activate or quiet specific brain circuits,

00:00:38.620 | as well as circuits within the body,

00:00:40.540 | in order to treat depression and other mood disorders.

00:00:43.920 | Other laboratories and clinics use TMS.

00:00:46.560 | What sets apart the work of Nolan Williams and colleagues

00:00:49.400 | is that they combine TMS with other treatments.

00:00:52.440 | And some of those treatments are among the more cutting edge

00:00:54.560 | that you've probably heard about these days,

00:00:56.160 | including Ibogaine, psilocybin, MDMA, cannabis, DMT,

00:01:01.160 | and other drugs that at this point in time

00:01:04.320 | are experimental in terms of clinical trials,

00:01:07.240 | but that at least the preliminary data show

00:01:09.440 | hold great promise for the treatment of depression

00:01:11.740 | and other mood disorders.

00:01:13.220 | In the course of my discussion with Dr. Williams,

00:01:15.400 | we covered things such as the history

00:01:17.640 | of each of these drugs,

00:01:19.200 | how they came to be and their current status

00:01:21.320 | in terms of their clinical use and legality.

00:01:23.840 | We also talk about their safety profiles,

00:01:25.760 | both in children and in adults.

00:01:28.100 | And we talk about what the future of psychedelic research

00:01:30.720 | and clinical use really looks like.

00:01:33.400 | For instance, we discuss how a number of laboratories

00:01:36.460 | and clinics are modifying psychedelics

00:01:38.720 | to remove some of their hallucinogenic properties

00:01:41.340 | while maintaining some of their antidepressant

00:01:43.400 | or anti-trauma properties.

00:01:45.200 | You'll also learn about some fascinating research

00:01:47.020 | in Dr. Williams' laboratory focused on ketamine,

00:01:50.340 | which is a drug that is increasingly being used

00:01:52.700 | to treat depression.

00:01:53.880 | And contrary to common belief,

00:01:55.640 | the effects of ketamine in terms of relieving depression

00:01:58.760 | may not actually arise from its dissociative effects.

00:02:02.200 | One thing that you'll find extraordinary about Dr. Williams

00:02:05.080 | is that not only does he have vast knowledge

00:02:07.040 | of the various treatments for depression,

00:02:09.040 | but that he and his laboratory

00:02:10.940 | are really combining these treatments

00:02:12.480 | in the most potent way.

00:02:13.560 | That is combining psychedelic treatments

00:02:15.320 | with brain-machine interface

00:02:16.720 | or combining brain-machine interface

00:02:18.200 | with particular learning protocols,

00:02:20.060 | that is neuroplasticity protocols,

00:02:22.240 | which can directly change the brain in specific ways.

00:02:25.020 | So today you're going to learn a tremendous amount

00:02:27.640 | about the neural circuitry underlying depression,

00:02:29.880 | as well as positive moods.

00:02:31.300 | You'll also learn about all the various drugs

00:02:33.040 | that I described,

00:02:34.080 | and you're really going to learn about the current status

00:02:36.520 | and future of the treatment of mood disorders.

00:02:39.060 | Today, you'll also learn about a number of ongoing studies

00:02:41.540 | in Dr. Williams' laboratory.

00:02:43.400 | I should mention that they are recruiting subjects

00:02:45.380 | for these studies.

00:02:46.620 | If you go to BSL,

00:02:47.940 | which stands for Brain Stimulation Laboratory,

00:02:49.800 | so that's bsl.stanford.edu,

00:02:52.280 | you have the opportunity to apply

00:02:54.100 | for one of these clinical trials

00:02:55.400 | for the treatment of depression and other mood disorders.

00:02:58.200 | I confess that the conversation with Dr. Williams

00:03:00.300 | was, for me, one of the more stimulating

00:03:02.600 | and informative conversations I've ever had

00:03:05.200 | about psychedelics,

00:03:06.500 | which is simply to say that his breadth

00:03:08.860 | and depth of knowledge on that topic is incredible,

00:03:12.360 | and his breadth and depth of knowledge

00:03:13.900 | in terms of the underlying brain science

00:03:15.640 | and how it can all be combined with clinical applications

00:03:18.940 | is also extraordinary.

00:03:20.480 | I'm sure that by the end of today's episode,

00:03:22.180 | you're going to come away with a tremendous amount

00:03:24.160 | of knowledge about the clinical

00:03:25.380 | and nonclinical uses of those substances,

00:03:27.580 | and you're going to understand a lot more

00:03:29.660 | about how the healthy and diseased brain work.

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00:08:37.160 | On many episodes of the Huberman Lab Podcast,

00:08:39.200 | we talk about supplements.

00:08:40.740 | While supplements aren't necessary for everybody,

00:08:42.880 | many people derive tremendous benefit from them.

00:08:45.400 | Things like enhancing sleep and the depth of sleep,

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00:09:13.000 | And now for my discussion with Dr. Nolan Williams.

00:09:16.080 | Thanks for joining today.

00:09:17.600 | I'm really excited to have this conversation.

00:09:20.060 | It's been a long time coming,

00:09:21.840 | and I have a lot of questions about different compounds,

00:09:25.960 | psychedelics in particular.

00:09:27.720 | But before we get into that discussion,

00:09:30.120 | I want to ask you about depression, broadly speaking,

00:09:34.120 | intractable depression, how common depression is or isn't.

00:09:40.120 | I heard you say in a wonderful talk that you gave

00:09:43.240 | that depression is perhaps

00:09:45.360 | the most debilitating condition worldwide.

00:09:49.040 | And yet in contrast to other medical conditions like cancer,

00:09:54.040 | we actually have a fairly limited number of tools

00:09:57.240 | to approach depression, and yet number of tools

00:10:00.920 | and the potency of those tools is growing.

00:10:03.200 | So if you could educate us on depression,

00:10:05.160 | I would really appreciate it.

00:10:06.320 | - Yeah, absolutely.

00:10:07.160 | Depression is a condition that

00:10:09.560 | it has a lot of manifestations.

00:10:14.240 | So you can have kind of a depression

00:10:16.620 | that's primarily loss of interest.

00:10:18.500 | You can have folks who feel very anxious

00:10:21.320 | and they're kind of overactive.

00:10:22.620 | You can have people who don't have any anxiety at all,

00:10:25.280 | and they're very underactive

00:10:26.400 | and they have low motivation to do anything.

00:10:29.000 | So you have this huge range of symptoms

00:10:30.920 | that are in that umbrella of depression.

00:10:33.480 | And some of our work is to actually work

00:10:35.480 | with folks like Connor Liston and Cornell

00:10:37.920 | and try to actually get biotypes based off of neuroimaging

00:10:42.280 | to see if we can kind of parse out

00:10:44.040 | the different depression kind of presentations

00:10:47.680 | and see that clinically and also see that in the brain.

00:10:51.220 | Depression is the most disabling condition worldwide.

00:10:55.400 | What's interesting about depression

00:10:56.800 | is it's both a risk factor for other illnesses

00:11:00.920 | and it makes other medical

00:11:02.580 | and psychiatric illnesses worse, right?

00:11:04.640 | So recently the American Heart Association

00:11:08.020 | added depression as the fourth major risk factor

00:11:11.400 | for coronary artery disease, right?

00:11:13.160 | So alongside the risk factors that we know,

00:11:16.560 | hypertension, high blood pressure, hyperlipidemia,

00:11:19.520 | high cholesterol, and diabetes, high blood sugar,

00:11:24.100 | those three have been on the list for a long time

00:11:26.820 | and depression ended up being added to the list

00:11:29.200 | as the fourth one.

00:11:30.580 | And really interesting, right?

00:11:33.040 | So in addition to taking medications

00:11:35.640 | to address those other three risk factors,

00:11:37.640 | we really have to be thinking about

00:11:40.000 | how do you treat folks with depression

00:11:41.980 | to reduce the risk of having a heart attack in the future.

00:11:45.720 | And some of that's being worked on now,

00:11:48.700 | but we don't have a complete solution

00:11:50.480 | to thinking about that at this time.

00:11:52.880 | And then the other thing that's interesting

00:11:54.880 | is once you have a heart attack

00:11:57.280 | and in the individuals that end up having a heart attack,

00:12:00.640 | the risk of having depression after the heart attack

00:12:04.060 | is higher than the normal population, right?

00:12:07.080 | And so a lot of what we're doing in the lab actually

00:12:09.960 | is measuring kind of brain heart connections

00:12:13.320 | and we can actually with transcranial magnetic stimulation,

00:12:16.200 | a form of brain stimulation,

00:12:17.540 | we can actually decelerate the heart rate.

00:12:19.340 | We can capture that heart rate deceleration

00:12:22.320 | over the mood regulatory regions.

00:12:24.000 | And so actually a direct probe of that connection.

00:12:27.100 | So it's interesting.

00:12:28.360 | And so as you said a second ago,

00:12:31.560 | it's a very disabling condition, moderate depressions,

00:12:34.680 | about as disabling as having a heart attack,

00:12:37.840 | acutely having a heart attack,

00:12:39.440 | severe depressions as disabling

00:12:41.520 | as having cancer without treatment

00:12:44.440 | and dying from a cancer without treatment.

00:12:47.000 | And so it's kind of underappreciated

00:12:51.200 | just how disabling depression is in that way.

00:12:54.120 | And I think important as stigma is consistently

00:12:58.600 | kind of being reduced over the years for mental illness,

00:13:01.840 | for mental illnesses than the idea

00:13:03.640 | that we can start really putting more funding

00:13:06.040 | and putting more focus at the federal level,

00:13:08.560 | private foundation level, whatever it is

00:13:10.640 | at a given university to thinking about

00:13:13.840 | developing treatments.

00:13:15.400 | We've been very interested in a very particular

00:13:19.240 | clinical set of problems around the most severe

00:13:23.440 | and the most high acuity settings

00:13:26.420 | that folks with depression end up being in.

00:13:29.400 | And that's in emergency settings

00:13:32.260 | where they go into inpatient units.

00:13:34.260 | And in the rest of medicine,

00:13:37.180 | if it's talking about heart attacks,

00:13:38.780 | if I start having chest pain right now

00:13:41.560 | and you bring me to a primary care doctor's office,

00:13:44.400 | they're gonna have a certain number of tests

00:13:46.080 | and treatments, right?

00:13:47.240 | But very limited 'cause it's an outpatient facility.

00:13:50.520 | If you bring me to the emergency room after that,

00:13:52.600 | there are more tests and more treatments.

00:13:54.320 | If you put me in the ICU or in the cath lab

00:13:57.680 | where they do invasive procedures to the heart,

00:14:00.800 | there are more tests and more treatments.

00:14:02.800 | In psychiatry, as we elevate the acuity of an individual,

00:14:07.800 | you go from being just depressed to being depressed

00:14:10.200 | and now thinking about ending your life,

00:14:12.080 | the number of treatments actually go down on average.

00:14:16.480 | I mean, in some scenarios they go up,

00:14:17.900 | but on average they go down and there are no tests, right?

00:14:21.080 | And so we've been very focused on that particular problem.

00:14:24.520 | Somebody that maybe was doing fairly okay

00:14:28.520 | with a pretty moderate depression

00:14:30.080 | and then their depression gets worse

00:14:32.000 | and then they end up in an emergency setting

00:14:35.040 | and the field really hasn't developed a way

00:14:38.320 | of consistently being able to treat that problem

00:14:42.040 | and folks end up getting the same standard

00:14:43.960 | oral antidepressants that they've been getting outpatient.

00:14:47.640 | And I came to this because I dual trained as a neurologist

00:14:51.800 | and psychiatrist, went back and forth

00:14:53.680 | between neurology and psychiatry,

00:14:55.640 | saw that in neurology we have all of these ways

00:14:58.000 | of treating acute brain-based problems

00:15:01.040 | and really wanted to emulate that in psychiatry

00:15:04.000 | and find ways to develop and engineer

00:15:06.320 | new brain-based solutions.

00:15:08.780 | - There's a lot to unpack there.

00:15:11.020 | One thing that you said is I'd like to focus on a bit more

00:15:14.840 | because I think we hear that the brain and the heart

00:15:17.960 | are connected, but you described, I believe,

00:15:21.240 | a direct relationship between areas of the brain

00:15:24.600 | associated with emotion and heart rate.

00:15:28.520 | And that makes perfect logical sense to me,

00:15:32.040 | but I think at the same time, many people out there

00:15:36.600 | probably think of the relationship between the heart

00:15:39.280 | and the mind as kind of woo or kind of a soft biology,

00:15:43.400 | but here you're talking about an actual physical connection

00:15:46.600 | between what area of the brain is it?

00:15:49.040 | - The first place where the stimulation goes

00:15:52.560 | is called the dorsolateral prefrontal cortex.

00:15:54.760 | It's kind of the sense of control,

00:15:57.020 | kind of governor of the brain.

00:15:58.600 | And then what we know is that when you use a magnet,

00:16:02.560 | use kind of what we call Faraday's law,

00:16:04.480 | this idea of using a magnetic pulse

00:16:07.820 | to induce an electrical current

00:16:10.560 | in electrically conducting substances.

00:16:12.840 | So in this case, brain tissue, but not skull or scalp

00:16:16.480 | or any of that or hair.

00:16:17.920 | You avoid all that, just the brain tissue.

00:16:20.160 | Then you have a direct depolarization of cortical neurons,

00:16:24.920 | the surface of the brain's neurons

00:16:27.360 | in this dorsolateral prefrontal.

00:16:29.720 | And if you do that in the actual scanner, which we can do,

00:16:33.360 | you can see that that distributes down

00:16:35.860 | into the anterior cingulate and the insula and the amygdala.

00:16:39.920 | And ultimately, the tract goes into something

00:16:42.720 | called the nucleus tractus solitarius

00:16:45.080 | and ultimately into the vagus nerve and to the heart.

00:16:47.760 | So the heart very consistently seems to be the end organ

00:16:52.760 | of the dorsolateral prefrontal cortex.

00:16:55.960 | If you measure heart rate in standard ways

00:16:58.760 | that cardiologists measure heart rate

00:17:00.860 | and you stimulate over this left dorsolateral,

00:17:03.360 | you get a deceleration of the heart rate

00:17:05.200 | and it's very time locked to the stimulation.

00:17:08.400 | So it's a two second train of stimulation.

00:17:10.760 | At one second, you see the deceleration.

00:17:12.920 | It goes down about 10 beats per minute

00:17:15.040 | and then it'll drift back up and there's a break

00:17:17.080 | for eight seconds on the stimulation.

00:17:18.640 | It drifts back up and the stimulation goes back in

00:17:21.360 | and then the heart rate goes back down.

00:17:22.960 | So you see the heart rate just do this,

00:17:25.320 | 10 beats per minute every train.

00:17:27.480 | And so we know if you do that over visual cortex,

00:17:30.760 | you don't get that or motor cortex,

00:17:32.400 | you don't get any of those findings.

00:17:33.740 | It's really specific to this kind of control region

00:17:38.040 | of the brain.

00:17:38.880 | So, yeah, it seems to, you know, it's our work,

00:17:42.280 | other folks work, Martin Arens in Europe,

00:17:46.200 | the Netherlands work showing the same connections.

00:17:48.960 | I think it's been replicated like four or five times.

00:17:51.800 | - So you mentioned left dorsolateral prefrontal cortex.

00:17:56.160 | Anytime I hear about lateralization of function,

00:17:58.240 | I get particularly curious because obviously

00:18:02.040 | we have two mirror symmetric sides of the brain.

00:18:07.280 | There are, you know, rare exceptions to this,

00:18:09.580 | like the pineal and things of that sort

00:18:12.080 | that are only, there is only one pineal.

00:18:15.900 | What is special about the left dorsolateral

00:18:19.160 | prefrontal cortex?

00:18:20.000 | Does this have anything to do with handedness,

00:18:21.720 | right-hand or left-hand?

00:18:22.920 | Because we know right-hand and left-handedness

00:18:24.480 | has a lot to do with lateralization of function

00:18:26.280 | for language, a topic for another time.

00:18:30.480 | But why do you think that left dorsolateral

00:18:33.820 | prefrontal cortex would be connected to the heart

00:18:36.920 | in this way?

00:18:37.920 | - Yeah, yeah, I think so.

00:18:39.580 | So left dorsolateral, you know,

00:18:42.680 | is thought to be the side that when you excite it,

00:18:46.320 | when you kind of do excitatory stimulation,

00:18:49.700 | potentiating sort of stimulation,

00:18:51.360 | that you can reduce depressive symptoms.

00:18:54.760 | And a guy by the name of Mike Fox at Harvard

00:18:57.040 | has demonstrated that if you have strokes in the brain

00:19:00.400 | that cause depression and you put them

00:19:03.000 | on the human connectome 100,000 patient map,

00:19:06.960 | and you ask the question what they're all

00:19:08.280 | functionally connected to, left dorsolateral.

00:19:11.880 | If you take lesions that cause mania in individuals

00:19:15.680 | and you put those all on the human connectome map

00:19:17.800 | and ask what they're all, the one common area

00:19:20.840 | they're all connected to, it's the right dorsolateral.

00:19:24.120 | And so there seems to be a hemispheric, you know,

00:19:28.840 | balancing of mood between these two brain regions.

00:19:31.840 | And we know this from an experimental standpoint too,

00:19:34.600 | because you can take individuals with depression

00:19:37.140 | and you can excite the left or you can inhibit the right

00:19:40.920 | and they're both antidepressant.

00:19:43.480 | You can excite the right

00:19:45.880 | and that's anti-manic in some studies.

00:19:48.640 | And so this idea that there is this hemispheric balancing

00:19:52.320 | of mood is quite interesting, right?

00:19:54.600 | - It's incredibly interesting.

00:19:56.520 | And just so people know if you're curious

00:20:00.000 | what the connectome is, connectome is a term

00:20:02.160 | that was built out of this notion of genomes

00:20:04.600 | of being a large collections of sequencing

00:20:07.680 | and mapping of genes.

00:20:08.960 | They're proteomes of proteins of connectomes

00:20:12.360 | as a so-called connectomics of connections between neurons.

00:20:15.360 | So the Human Connectome Project is ongoing.

00:20:18.940 | And I find that incredible that within the connectome

00:20:22.120 | project, they can identify these regularities

00:20:24.220 | of right versus left dorsolateral prefrontal cortex,

00:20:27.400 | especially since I've looked at a fair number of brains

00:20:32.400 | from humans, certainly not as many as you have.

00:20:36.240 | And if you look at the architecture, the layers,

00:20:39.820 | the cell types, and even the neurochemicals

00:20:42.620 | of which cells are expressing say dopamine or serotonin

00:20:45.560 | or receiving input from areas that make dopamine

00:20:47.640 | or serotonin, they don't look that different

00:20:49.960 | on the right and left side.

00:20:51.360 | And yet here we're talking about a kind of an accelerator

00:20:54.800 | and a break, if you will, on depression and mania

00:20:59.140 | using what at least by my eye and I think other people's eye

00:21:03.240 | look to be basically the same set of bits,

00:21:06.280 | the same parts list, more or less.

00:21:08.360 | So what gives these properties to the right

00:21:12.400 | and left dorsolateral prefrontal cortex?

00:21:14.080 | Is it the inputs they receive?

00:21:16.040 | Is this something that we learn during development

00:21:17.800 | or do you think that we come into the world

00:21:19.640 | with these hemispheric biases?

00:21:22.240 | - Yeah, it's a great question.

00:21:23.720 | And it hasn't been worked out,

00:21:26.000 | which your original question was around,

00:21:28.360 | in a left-handed individual, which as you know,

00:21:31.760 | 25% of those folks end up having a right brain dominance

00:21:35.480 | or 1% of right-handed people have a right brain dominance

00:21:38.880 | if it's flipped, right?

00:21:40.100 | And unfortunately that study still hasn't been done

00:21:44.000 | at the level 'cause that would be probably pretty helpful

00:21:46.380 | for teasing some of this out.

00:21:48.320 | But it's still being sorted out, right?

00:21:52.560 | We know enough to know this phenomenon exists

00:21:56.960 | because we can use TMS as a probe

00:22:00.520 | and do these sorts of manipulations.

00:22:03.200 | But to my knowledge, there hasn't been anybody

00:22:06.580 | that's gotten so interested in it

00:22:08.080 | that they've been able to get a mechanism of why that is.

00:22:12.400 | But it's kind of empirically true

00:22:16.320 | in the sense that you can push and pull on those systems

00:22:19.160 | or in the case of strokes that folks have

00:22:22.800 | and then you kind of get their brains and their brain images

00:22:25.520 | and look at where the strokes landed,

00:22:28.000 | those kind of causal bits of information

00:22:30.060 | point to this asymmetry.

00:22:33.340 | - Interesting.

00:22:34.180 | Well, in that case, going with what we do know,

00:22:37.280 | that stimulation of dorsolateral prefrontal cortex

00:22:39.840 | slows the heart rate down transiently, but it slows it down

00:22:43.200 | and seems to alleviate at least some symptoms of depression.

00:22:46.840 | Leads me to the question of why would that be the case?

00:22:50.360 | Does it tell us anything fundamental about depression

00:22:53.480 | that anxiety is inherent to depression?

00:22:56.520 | I think a faster heart rate

00:22:58.000 | is part and parcel with anxiety.

00:23:02.160 | In my laboratory, we've studied fear a bit

00:23:07.040 | in animals and in humans,

00:23:08.240 | and we often observe brachycardia

00:23:10.920 | where somebody or an animal is afraid of something

00:23:14.200 | and rather than the heart rate speeding up,

00:23:15.940 | it actually slows down,

00:23:17.520 | something that most people don't think about or recognize.

00:23:21.520 | But given that stimulation of dorsolateral prefrontal cortex

00:23:26.000 | slows the heart rate down

00:23:27.080 | and can alleviate depressive symptoms

00:23:29.540 | and that there are other ways to slow the heart down,

00:23:31.740 | I have two questions.

00:23:32.920 | What do you think this tells us

00:23:34.420 | about the basic architecture of depression

00:23:37.720 | and its physiology at the level of the heart?

00:23:40.500 | And does the circuit run in the opposite direction too?

00:23:43.340 | If one were to have or find other ways to slow

00:23:45.820 | the heart rate down, say with a beta blocker,

00:23:48.600 | does that help alleviate depression?

00:23:50.520 | - Yeah, that's a great question.

00:23:51.660 | So I'll answer the second question first.

00:23:55.360 | So we know that there are ongoing trials of this.

00:23:59.360 | If you stimulate in the vagus nerve

00:24:01.720 | and an implanted vagus nerve stimulator,

00:24:04.440 | you can actually have the afferent parts of the vagus

00:24:11.280 | project ultimately up to the DLPFC through the cingulate,

00:24:14.860 | through these anterior insula,

00:24:16.080 | so obviously the same tract, right?

00:24:18.900 | And you can stimulate there and alleviate depression,

00:24:22.180 | which seems very unusual, right?

00:24:24.240 | You're stimulating a cranial nerve down on the neck,

00:24:27.140 | but if you can get up into the brain,

00:24:29.340 | you actually can improve depressive symptoms.

00:24:31.820 | And so more evidence that this is

00:24:35.380 | kind of a whole tract and system,

00:24:37.840 | and if you stimulate in part of that system,

00:24:40.620 | it appears that you can improve mood.

00:24:44.100 | - And what if I were somebody who did not have

00:24:46.220 | a stimulating electrode in my vagus nerve

00:24:48.700 | and I was dealing with minor depression

00:24:51.420 | and I decided I wanted to take some other approach

00:24:54.440 | to slow my heart rate down via the vagus.

00:24:56.480 | For instance, exhale emphasized breathing

00:24:59.620 | or deliberately slow cadence breathing, things of that sort.

00:25:04.220 | Is there any evidence that behavioral interventions

00:25:06.100 | of those kinds can alleviate depression

00:25:10.380 | or some symptoms of depression?

00:25:12.980 | And is there any evidence that it does indeed feed back

00:25:15.320 | to the dorsolateral prefrontal cortex

00:25:17.060 | to achieve some of that alleviation?

00:25:19.100 | - Absolutely, yeah.

00:25:19.940 | So there's a number of studies implicating the dorsolateral

00:25:24.400 | and say meditation, mindfulness, that sort of thing.

00:25:29.320 | And they're small studies,

00:25:31.500 | but pretty well designed studies suggesting

00:25:34.580 | that behavioral interventions in mild depression

00:25:37.720 | actually work quite well.

00:25:39.580 | There seems to be a volitional threshold for depression

00:25:43.100 | where at some point you start losing,

00:25:46.180 | you go from being completely in total volition

00:25:49.100 | to having kind of semi-volition.

00:25:51.180 | You have thoughts that you really have a hard time

00:25:53.500 | controlling and that sort of thing.

00:25:54.780 | And when you go through that threshold,

00:25:57.120 | at some point it gets harder and harder

00:26:00.220 | for those sorts of things to kind of kick in and work.

00:26:03.160 | In the extreme form of that is catatonia,

00:26:05.380 | where people in a very severe form of depression

00:26:08.300 | get kind of stuck motorically,

00:26:10.320 | and they obviously can't, they have no control,

00:26:12.820 | and so, or very limited control.

00:26:16.220 | And so I think there's a threshold

00:26:19.160 | in which these sorts of interventions will work.

00:26:21.860 | Exercise seems to really be a good treatment

00:26:24.860 | for mild depression,

00:26:26.580 | and it may work through the mechanism you're describing.

00:26:29.200 | As we all know, athletes hold a lower resting heart rate

00:26:33.660 | than folks that aren't, if you were an athlete,

00:26:37.900 | you had a lower resting heart rate,

00:26:39.260 | you stopped exercising, and a couple years later,

00:26:41.980 | your resting heart rate in many cases goes up, right?

00:26:44.580 | And so maybe that's part of the process.

00:26:48.340 | I'm not aware of any studies specifically

00:26:52.460 | looking at dorsolateral prefrontal physiology

00:26:57.300 | pre, post exercise, but it would be a great study.

00:26:59.860 | I think that would be really helpful to understanding this,

00:27:02.600 | especially if you had a correlation of changes

00:27:06.080 | and kind of lowering of, say, heart rate

00:27:07.460 | with mood improvements.

00:27:09.200 | There's been a lot of work with heart rate variability

00:27:13.220 | and depression, and studies kind of point towards it.

00:27:18.220 | Not every study is positive for this,

00:27:24.300 | but quite a few studies say basically

00:27:27.700 | that lower heart rate variability

00:27:30.720 | is associated with moderate to severe depression,

00:27:34.820 | and that may be part of that mechanism

00:27:36.980 | of that heart brain risk.

00:27:40.140 | - So I'm both intrigued and a little bit perplexed

00:27:42.180 | by this relationship between heart rate and depression.

00:27:45.860 | On the face of it, I would think of depression as depressed,

00:27:48.820 | so lower heart rate might make somebody more depressed.

00:27:51.140 | You even mentioned catatonia or somebody

00:27:52.740 | that just doesn't seem motivated or excited to do anything.

00:27:56.260 | I think of mania as elevated heart rate and being excited.

00:27:59.760 | On the other hand, I realized that anxiety,

00:28:02.840 | which brings about ideas as elevated heart rate,

00:28:07.300 | is also built into depression,

00:28:09.020 | which brings me back to what you said earlier,

00:28:10.740 | which is that when we say depression,

00:28:12.660 | are we really talking about four or five different

00:28:15.220 | disorders, for lack of a better word?

00:28:19.220 | And for what percentage of people that have depression

00:28:23.260 | does some approach to reducing heart rate work?

00:28:28.260 | Whether or not it's stimulation

00:28:29.500 | of the left dorsolateral prefrontal cortex

00:28:32.900 | by way of transcranial magnet stimulation,

00:28:34.820 | or by taking a beta blocker, or by stimulating the vagus,

00:28:38.900 | can we throw out a number, a rough number?

00:28:40.900 | Does that help 30%, 50%, how long lasting is that relief?

00:28:45.340 | - Yeah, and to be clear, the deceleration of the heart rate

00:28:50.060 | is in the moment when the stimulation is happening,

00:28:52.980 | but it's not something

00:28:54.980 | that's necessarily maintained chronically.

00:28:57.820 | It's more of an indicator that you're in the right network

00:29:01.140 | more than it appears to be itself central to the mechanism.

00:29:06.060 | The heart rate variability piece may be,

00:29:08.680 | and there's some studies that link the two,

00:29:11.020 | but the actual deceleration seems to be much more

00:29:13.260 | of a marker that you're in the right system,

00:29:16.020 | but it very well could be that the heart rate system

00:29:19.020 | and the mood system just sit next to each other

00:29:21.060 | and the stimulation hits both.

00:29:23.100 | If you look at how much of the variance in the mood

00:29:26.380 | is explained by the heart rate deceleration,

00:29:28.460 | it's not a huge amount, right?

00:29:32.220 | So it only explains a small percentage.

00:29:35.580 | And so it's unlikely that simply reducing the heart rate,

00:29:41.380 | and in fact, for many years, propranolol

00:29:44.060 | and these sorts of drugs actually

00:29:45.300 | were implicating causing depression.

00:29:47.520 | And so that's been kind of debunked,

00:29:50.040 | but it's unlikely that simply decelerating the heart rate

00:29:53.540 | is gonna improve depression.

00:29:55.300 | But what it does tell you is that if you're in that area

00:29:58.780 | that is the mood regulatory area,

00:30:00.740 | there's some parasympathetic cortical kind of process

00:30:04.220 | that's going on that gets in and causes this to happen.

00:30:07.540 | And it's independent of mood.

00:30:10.140 | You can take a normal healthy individual and you can do this

00:30:14.540 | and they're gonna decelerate their heart rate.

00:30:17.460 | - I'm so glad you mentioned

00:30:18.400 | the parasympathetic nervous system,

00:30:19.900 | which of course is the,

00:30:21.120 | most people think of as the rest and digest

00:30:22.780 | or the kind of calming side of the autonomic nervous system.

00:30:25.620 | As I'm hearing you say all of this,

00:30:27.300 | and in particular, what you just told me,

00:30:30.100 | which is that it's not as if having a lower heart rate

00:30:33.620 | protects you against depression

00:30:34.920 | or a higher heart rate is associated with depression,

00:30:37.420 | although at the extremes, that might be true,

00:30:39.860 | but rather it's something about the regulatory network,

00:30:42.980 | the ability to control your own nervous system

00:30:46.040 | to some extent.

00:30:46.980 | And when I think about the autonomic nervous system,

00:30:50.060 | I like to think about as a seesaw of alertness and calmness.

00:30:53.500 | And when you're asleep, it's a lot of calmness.

00:30:55.300 | And when you're panicking, it's a lot of alertness.

00:30:58.100 | But that, and I don't think this has ever been defined.

00:31:01.060 | And when I teach the medical students

00:31:03.620 | at Stanford Neuroanatomy,

00:31:04.920 | my wish is that someday I'll be able to explain

00:31:07.540 | what the hinge in that process would be, right?

00:31:09.980 | Not the ends of the seesaw.

00:31:11.100 | We know what the sympathetic nervous system is

00:31:12.820 | and what it's to wake us up and make us panic

00:31:15.400 | or make us feel nicely alert and calm.

00:31:17.980 | We know what puts someone into sleep or a coma

00:31:21.440 | or makes them feel relaxed.

00:31:23.360 | But what shifts from one side of the seesaw to the other

00:31:26.260 | and the tightness of that hinge

00:31:28.100 | seems to be what you're describing,

00:31:29.540 | that depression is sort of a lack of control

00:31:32.720 | over inner state so that when I'm stressed,

00:31:34.780 | I can't get myself out of it.

00:31:35.860 | But when I'm feeling completely collapsed with exhaustion,

00:31:38.780 | I can't get out of bed and get motivated

00:31:40.700 | to do the very things that would help me

00:31:42.320 | get out of depression, like a workout or social connection

00:31:45.060 | or eat a quality meal, these kinds of things.

00:31:48.040 | So this is perhaps the first time that I've ever heard

00:31:52.240 | about a potential circuit for the hinge,

00:31:55.120 | as I'm referring to it.

00:31:55.960 | Does that make any sense at all?

00:31:57.420 | - Yeah, absolutely, absolutely.

00:31:58.260 | - Okay, I just want to make sure

00:31:59.100 | that I'm framing this correctly in my mind.

00:32:00.620 | - Yeah, absolutely.

00:32:01.460 | And in some studies, if you do the same identical stimulation

00:32:05.160 | on the right dorsolateral, you can get an acceleration.

00:32:07.900 | You know, just kind of further confirming this idea

00:32:11.740 | of lateralization, right, that even it appears

00:32:15.420 | that even the prefrontal cortical areas

00:32:18.600 | seem to be lateralized in this way.

00:32:20.940 | And I, you know, it's less, the right finding

00:32:25.740 | is more variable depending upon the study.

00:32:28.160 | The left's very consistent in this way, so.

00:32:31.780 | - So we've talked about Czern's cranial magnet stimulation

00:32:34.220 | for getting into these networks.

00:32:35.900 | And I also just want to take a brief tangent and say I,

00:32:38.860 | 'cause I've heard you say this before,

00:32:40.260 | I think it's so vital what you're saying

00:32:42.540 | that it's really not about stimulation of areas.

00:32:45.680 | It's, or any specific brain area or vagus nerve

00:32:49.200 | being important per se.

00:32:51.280 | It's really about a network, a connection,

00:32:53.420 | a series of connections.

00:32:54.980 | I think that's really important for people to understand

00:32:57.100 | and is kind of a new emerging theme really.

00:33:00.000 | The other thing that to me seems extremely important

00:33:03.600 | for us to consider is what are these lateral prefrontal

00:33:08.600 | cortices doing?

00:33:11.420 | Are they involved, for instance, in sensation,

00:33:14.020 | sensing the heart rate?

00:33:15.100 | Are they involved in thinking and planning?

00:33:17.780 | And this gets down to a very simple question

00:33:19.780 | that I know a lot of people have,

00:33:20.900 | which is can we talk ourselves out of depression

00:33:24.380 | if it's mild?

00:33:25.660 | Can we talk ourselves into a manic state

00:33:29.740 | or an excited state, a positively excited state

00:33:31.860 | that doesn't qualify as mania?

00:33:34.200 | Other areas of the brain, I think of they is responsible

00:33:36.900 | for perception or for motor control.

00:33:39.660 | But here we are in this mysterious frontal cortex area,

00:33:42.480 | which people say executive function, planning, et cetera.

00:33:45.400 | Are we talking about thoughts?

00:33:47.540 | Are we talking about structured thoughts?

00:33:49.380 | Are we talking about dreamlike thoughts?

00:33:51.380 | What in the world is going on in the prefrontal cortex?

00:33:55.520 | And here I spend my career in neuroscience

00:33:57.620 | and I still can't really understand what it's doing

00:34:01.820 | and maybe it's doing 50 things.

00:34:03.700 | - Yeah, no, it's a great question.

00:34:05.420 | So one of the studies that we've been working on

00:34:10.420 | in addition to the depression work

00:34:11.820 | is actually trying to change trait hypnotizability.

00:34:15.060 | So David Spiegel and I have been working on this

00:34:17.520 | and he's found and published this 10 years ago

00:34:21.740 | that a different part of the left dorsolateral

00:34:25.660 | is functionally connected with the dorsol anterior cingulate

00:34:30.340 | with a lot of functional connectivity and high hypnotizables

00:34:33.180 | and not much in low hypnotizables.

00:34:35.720 | And that's a different, kind of a different sub-region

00:34:38.780 | within this bigger brain region we call

00:34:40.980 | left dorsolateral prefrontal cortex

00:34:43.340 | than the part that seems to be important for regulating mood.

00:34:47.020 | And so the left dorsolateral seems to have connections

00:34:52.020 | that are location specific within the overall

00:34:56.280 | kind of named brain region that connect to various parts

00:34:59.460 | of the cingulate and seem to regulate it, right?

00:35:03.260 | And so if you knock out the left dorsolateral

00:35:06.300 | prefrontal cortex and you have people do the Stroop task,

00:35:10.180 | for instance, which is a task where you have,

00:35:13.100 | it's a simple task, you probably know this,

00:35:15.300 | you have people name the color of words.

00:35:19.140 | And so if I look at one of the cards that they'll show you,

00:35:24.140 | it'll have the word red in red and that's very easy

00:35:28.780 | and that's called a congruent.

00:35:30.660 | And then the incongruent is red in the color blue

00:35:35.660 | and you have to name, you have to say the word,

00:35:39.860 | you don't name the color.

00:35:41.960 | - So you have to suppress a response.

00:35:43.460 | - Yeah, yeah, exactly.

00:35:44.500 | And so, I'm sorry, you name the color

00:35:47.740 | and you see the word written in a different way.

00:35:50.700 | And so basically, if you stimulate in a way

00:35:55.380 | that inhibits the left dorsolateral prefrontal cortex

00:35:57.940 | or either one, you can actually knock out the ability

00:36:01.220 | to do that well and it'll take longer for people

00:36:04.220 | on the incongruent cards to be able to name it.

00:36:08.720 | And so they have a kind of a time delay

00:36:11.700 | that's greater than they had before they got stimulated.

00:36:14.740 | So that's a part of the prefrontal cortex

00:36:17.940 | that's different than the part of the prefrontal cortex

00:36:20.140 | that's involved in mood regulation.

00:36:22.420 | The nice thing about TMS is that you can go through

00:36:25.460 | and you can find these areas that are functionally defined

00:36:29.460 | through brain imaging and you can perturb them

00:36:32.020 | and answer the question you're talking about.

00:36:33.700 | How do I understand this part of the prefrontal cortex

00:36:36.900 | and its function, this part?

00:36:39.040 | And so we were able to stimulate in an inhibitory way

00:36:44.040 | within the left dorsolateral prefrontal cortex

00:36:47.420 | that's involved with this sort of cognitive control area

00:36:52.100 | and we were able to knock that area out

00:36:55.140 | and an increased trait hypnotizability.

00:36:58.340 | So people had greater hypnotizability

00:37:03.100 | after they got active stimulation

00:37:05.520 | versus when they got sham.

00:37:07.300 | And so it suggests that that brain circuit is involved

00:37:11.620 | in the process of what therapeutic hypnosis ends up being

00:37:16.620 | but it's a very different region

00:37:18.960 | within the left dorsolateral than say we do

00:37:21.260 | when we do these very intensive stimulation approaches

00:37:24.500 | to treat severe depression

00:37:26.420 | and we're able to get people out of depression.

00:37:29.300 | With the part of the dorsolateral,

00:37:31.300 | it seems to be lower in the kind of more lateral

00:37:35.060 | and inferior on the DLPFC

00:37:40.820 | and connected with this subgenual anterior cingulate.

00:37:43.380 | So the part of the anterior cingulate

00:37:44.620 | that processes emotion.

00:37:46.900 | - I'd like to take a quick break

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00:39:01.140 | Based on what you told us about the Stroop task

00:39:03.300 | and the role of the prefrontal cortex in the Stroop task,

00:39:06.580 | to me, the Stroop task is a rule switching game.

00:39:09.620 | You're saying in one moment,

00:39:10.880 | the rule is you read whatever the word says

00:39:14.100 | and then you switch and then you say the rule now

00:39:17.040 | is you tell me what color the word is written in

00:39:20.380 | and you suppress whatever it is the word says, okay?

00:39:23.240 | - Yeah, that's right.

00:39:24.080 | - Okay, a rule in some sense like that

00:39:27.580 | is a transiently adopted belief system.

00:39:31.220 | So I could imagine that in depression,

00:39:33.180 | which has all sorts of backstory to it,

00:39:37.520 | that of course the psychiatrist or psychologist

00:39:39.560 | or friend can pull on that thread.

00:39:41.040 | Like for instance, somebody might believe that they are bad

00:39:45.340 | or that they don't deserve love.

00:39:46.900 | I'm trying to bring this into the typical language

00:39:49.020 | that people talk about.

00:39:49.860 | - Absolutely.

00:39:50.700 | - That they will never succeed

00:39:52.040 | or that even if they keep succeeding,

00:39:54.340 | it's just going to get harder and harder

00:39:56.160 | and it will never feel good.

00:39:58.020 | These are sort of rules like the Stroop task at some level.

00:40:01.420 | They're rules that are more pervasive

00:40:02.800 | over time, unfortunately.

00:40:04.500 | But I could imagine that if the PFC is also contains

00:40:08.900 | some sort of maps or algorithms related to rules

00:40:11.860 | of emotionality or self-representation

00:40:14.420 | or things that we've heard,

00:40:15.540 | I think there must be data out there

00:40:17.580 | that saying that whatever we heard in middle school,

00:40:19.800 | when someone made fun of us, we can remember that.

00:40:21.940 | 'Cause I can remember things that people said

00:40:24.140 | about a jacket I wore one day

00:40:26.840 | or something in the fourth grade, crazy.

00:40:28.820 | I didn't even like the jacket.

00:40:30.360 | Now I think it was kind of cool.

00:40:32.500 | But anyway, the point being that we have an intense memory

00:40:35.540 | for these things that set up a sort of rule or a question,

00:40:38.220 | like maybe I don't really know how to dress for instance.

00:40:42.340 | Maybe that's why I always wear the same black shirt.

00:40:44.780 | But in all seriousness,

00:40:45.940 | it seems like the dorsal out prefrontal cortex

00:40:48.220 | is in this amazing position to access rules,

00:40:52.300 | which are beliefs and beliefs are rules.

00:40:54.700 | And then for moments or longer to switch those rules.

00:40:58.680 | And so for somebody who's depressed

00:41:01.200 | to just simply look themselves in the mirror and say,

00:41:03.000 | you are great, you are fantastic.

00:41:05.160 | It feels like a lie if you feel like garbage to say that.

00:41:08.340 | It doesn't fit with the rule.

00:41:10.120 | It's like saying that card is not red.

00:41:12.860 | That card is green when your eyes tell you that it's red.

00:41:17.780 | And it seems like there's something about prefrontal cortex

00:41:21.500 | that in principle gives flexibility to rules

00:41:25.060 | based on what we know on this Stroop task.

00:41:27.020 | So given its connectivity,

00:41:29.620 | can we assume that the talk therapy that occurs

00:41:33.420 | in the psychiatrist's office or with a friend

00:41:36.180 | or through journaling out something,

00:41:37.980 | because we do know that reporting things about trauma

00:41:41.660 | or difficult circumstances or the rules that we contain

00:41:44.260 | and tend to hide inside of us about how we feel miserable,

00:41:47.620 | about ourselves or anything really,

00:41:50.540 | that in re-scripting that,

00:41:53.300 | that somehow it allows us to do a sort of Stroop task

00:41:56.980 | on our beliefs, is that a tremendous leap?

00:42:00.500 | I'm just really trying to frame this in the context

00:42:02.380 | of what I and most people think of as depression.

00:42:04.900 | - Yeah, totally.

00:42:05.960 | - Because the network components are vitally important,

00:42:07.900 | but I guess what I'm trying to figure out is like,

00:42:09.720 | what are the algorithms that govern prefrontal cortex?

00:42:14.720 | - Yeah, absolutely.

00:42:15.820 | So in a kind of standard cognitive

00:42:18.100 | behavioral therapy session, right?

00:42:20.300 | What the therapist is just trying to do

00:42:23.600 | is identify those beliefs and kind of determine

00:42:28.380 | how fixed they are, if they're flexible, as you're saying,

00:42:32.060 | and then help folks to find another explanation for them

00:42:37.060 | and to kind of reintegrate that potential other explanation

00:42:43.420 | into their memory system, right?

00:42:46.220 | Where I think TMS is really interesting, actually,

00:42:49.620 | we had a lot of patients who've told me,

00:42:51.140 | like my therapist told me that I wasn't trying hard enough

00:42:54.960 | in therapy and I really am trying hard,

00:42:59.440 | but these are moderate, pretty severe depressed patients.

00:43:03.140 | And as soon as we get them well with the TMS approaches,

00:43:06.860 | kind of rapid five day approach,

00:43:09.180 | and the next week we come in and see them

00:43:10.940 | and they'll say, you know what I did all weekend

00:43:12.300 | as I looked at my therapy books

00:43:13.660 | and now I can understand it.

00:43:15.600 | And so I actually see TMS as a way

00:43:18.980 | of having kind of exogenous sorts of cognitive functions

00:43:23.980 | that in milder forms of depression,

00:43:27.020 | we can pull off with psychotherapy,

00:43:29.940 | this idea of being able to kind of turn

00:43:32.000 | that prefrontal cortex on and have it govern

00:43:35.780 | these deeper regions, and depression,

00:43:37.980 | the deeper regions govern the prefrontal cortex,

00:43:41.900 | they precede the prefrontal cortex timing-wise,

00:43:45.260 | and we've got some data in review now

00:43:46.940 | where we're seeing that in depressed individuals

00:43:50.180 | that are responsive to our rapid TMS approach,

00:43:52.720 | what we call Stanford-accelerated intelligent

00:43:54.860 | neuromodulation therapy, or S&T, or SAINT,

00:43:58.960 | if you look at the brain before people get this,

00:44:02.700 | they will have a temporal delay

00:44:06.300 | where the cingulate is in front of the DLPFC.

00:44:11.580 | And in people that are normal healthy controls,

00:44:15.380 | no depression, the dorsolateral prefrontal cortex

00:44:18.740 | is temporally in front of the anterior cingulate.

00:44:23.000 | With effective treatment, we can flip the timing of things

00:44:28.000 | so the dorsolateral is in front of the anterior cingulate,

00:44:32.140 | just like in a normal person.

00:44:33.920 | - So you're not talking about, obviously,

00:44:35.260 | physically moving these structures,

00:44:36.500 | you're talking about in time, their activation.

00:44:38.660 | So in one case, it's like the coach telling the player

00:44:41.580 | what to do, and in the other case,

00:44:43.020 | like a player telling the coach what to do,

00:44:44.660 | and you restore order to the game.

00:44:46.820 | - You restore order to the game.

00:44:48.140 | And what it looks like is depression, to your point,

00:44:52.020 | is a bunch of kind of spontaneous content

00:44:55.300 | that's semi-volitional, that's being kind of generated

00:44:58.700 | out of this conflict detection system,

00:45:02.180 | the cingulate that seems to sense conflict

00:45:06.420 | and kind of feed that information, gets overactive

00:45:09.420 | in depression, and then in depression,

00:45:13.300 | it looks like the left dorsolateral

00:45:15.420 | does not sufficiently clamp down on it.

00:45:19.120 | And what therapy appears to do is to kind of restore that.

00:45:23.320 | What we see with TMS over that region

00:45:26.340 | is that we just exogenously do the same sort of thing.

00:45:28.980 | We restore the governance of the left dorsolateral

00:45:33.240 | over the cingulate area, and that is correlated

00:45:36.660 | with treatment improvement.

00:45:38.440 | So the degree in which you can re-time, re-regulate in time

00:45:43.440 | the left dorsolateral over the cingulate,

00:45:46.680 | the more of an antidepressant effect you have.

00:45:48.980 | - Can we therefore say in crude terms

00:45:54.500 | that the dorsolateral prefrontal cortex

00:45:57.920 | really is the governor of how we interpret

00:46:00.300 | physiological signals and spontaneous thoughts?

00:46:02.860 | - It is, it places a lens that the rest of the brain

00:46:07.280 | sees things through, and you can do these experiments

00:46:11.020 | where you can put a normal healthy control person

00:46:14.500 | in the scanner, and you can make them feel

00:46:17.640 | like they have a loss of control,

00:46:19.620 | and then you can see that region come offline, right?

00:46:22.820 | So you experimentally manipulate the system,

00:46:26.020 | and so kind of buffing it up, it's like almost,

00:46:29.400 | TMS is almost like exercise for the brain, right?

00:46:32.860 | You're kind of exercising this region over and over again

00:46:35.880 | with a physiologically relevant signal

00:46:39.200 | and kind of turning that system on.

00:46:41.360 | And what's interesting, I think really interesting

00:46:44.160 | for this show is to, we had a couple of folks,

00:46:48.320 | probably five or six folks that have actually told me this,

00:46:50.240 | where if they remit early enough in the week,

00:46:52.240 | we have this very dense stimulation approach

00:46:54.440 | where we can stimulate people really rapidly

00:46:57.440 | over a five-day block.

00:46:59.100 | We don't discriminate when they get better

00:47:00.880 | to when they stop, so if they get better on day one,

00:47:03.780 | we still give them the other four days

00:47:05.400 | because it's in the protocol to do that.

00:47:07.640 | We're getting to a point where we can tell

00:47:09.300 | how long it's gonna take, but we're not there yet.

00:47:12.180 | And so every time somebody gets better at day one or two,

00:47:15.720 | at the beginning when we first started doing this,

00:47:17.200 | we'd say, we're not sure, we think this is safe

00:47:20.200 | to keep going, but what do you wanna do?

00:47:22.780 | And everybody was like, no, I wanna keep going.

00:47:25.440 | And so by Wednesday, they're like totally zeroed out

00:47:29.140 | on the depression scales, even better

00:47:31.700 | than most people walking around,

00:47:33.220 | like really no anxiety, no depression or anything.

00:47:36.020 | By Thursday, the first guy that told me this,

00:47:39.260 | he came in and he said, I was driving back to my hotel

00:47:42.620 | and I decided to go to the beach and I just sat there

00:47:44.940 | and I was totally present in the present moment for an hour.

00:47:48.400 | And he's like, I read about this in my mindfulness books,

00:47:50.780 | but I experienced it last night

00:47:53.420 | and I've never experienced anything like this before

00:47:55.340 | and I was like, hmm, that's interesting,

00:47:57.240 | but kinda wasn't sure.

00:47:58.820 | And then I didn't tell obviously any more patients

00:48:02.020 | about that and then about five over the last couple of years

00:48:04.820 | when they were mid early in the week.

00:48:06.980 | By the end of the week, they're like going to the beach

00:48:09.140 | and they're like totally having what people describe

00:48:11.800 | as a pretty mindful present moment sort of experience,

00:48:15.960 | which is really interesting what that is.

00:48:18.080 | I mean, I don't have full on scientific data to tell you,

00:48:21.440 | but it's an interesting anecdote

00:48:25.180 | that folks, when you push them through this point

00:48:27.780 | of feeling kind of clinically well,

00:48:30.820 | that some people end up reporting

00:48:32.420 | this additional set of features, so.

00:48:35.320 | - Yeah, you mentioned the cingulate

00:48:36.580 | and the anterior cingulate in particular,

00:48:38.620 | because now I feel like for the first time in my career,

00:48:41.960 | I have some sense of what prefrontal cortex

00:48:44.580 | might actually be doing,

00:48:46.300 | besides providing a bumper for the rest of the brain.

00:48:52.060 | The cingulate it seems is a more primitive structure

00:48:55.220 | in the sense that it's under the,

00:48:58.820 | ideally it's under the regulation

00:49:00.500 | of this top-down control from prefrontal cortex,

00:49:02.700 | but what's mapped in the cingulate?

00:49:04.780 | And for the non-neuroscientists out there,

00:49:06.560 | when I say mapped, if we were to put someone in a scanner

00:49:09.380 | and focus in on cingulate or put an electrode in there,

00:49:12.100 | what makes the neurons in there fire?

00:49:13.980 | What sorts of things in the body and in the mind

00:49:16.900 | and out in the world light up, for lack of a better phrase,

00:49:21.100 | the cingulate, what does the cingulate like?

00:49:23.360 | - Yeah, yeah, so that Stroop task,

00:49:25.460 | those incongruent word color associations,

00:49:28.380 | the dorsal part of that.

00:49:30.540 | For obsessive compulsive disorder patients,

00:49:34.220 | certain kind of triggers you'll see,

00:49:37.340 | some of the neuroimaging studies

00:49:39.100 | will point to anterior cingulate.

00:49:41.500 | In the kind of very crude psychosurgery world

00:49:43.900 | 50 years ago, the anterior cingulotomy

00:49:46.460 | was a way of treating obsessive compulsive disorder, right?

00:49:49.540 | 'Cause that area seems to be overactive

00:49:52.220 | in people who are experiencing obsessive compulsive disorder.

00:49:55.400 | You can kind of walk, the cingulate wraps around

00:49:58.660 | this white matter track, like bundles,

00:50:01.660 | it wraps around that, and so there's a part

00:50:04.060 | that's above that, around that, and below that.

00:50:07.260 | And depending upon how much of the conflict task

00:50:12.260 | has an emotional component, the more ventral

00:50:17.700 | and subgenual that activation is.

00:50:22.700 | So the dorsal part of the anterior cingulate

00:50:26.780 | seems to be kind of more of a pure cognitive,

00:50:30.020 | maybe obsessive compulsive disorder sort of area,

00:50:34.160 | whereas when you start getting into mood sorts of triggers,

00:50:37.080 | like facial expression conflicts where you're supposed to,

00:50:42.080 | you know, there's an emotional Stroop task

00:50:44.160 | where you show the word happy,

00:50:45.740 | and then you have a face of a person that looks mad,

00:50:49.840 | then that's another way

00:50:51.100 | of having the same sort of Stroop conflict.

00:50:53.660 | That seems to be more perigenual, subgenual areas, right?

00:50:57.300 | So you can kind of, you can trigger the cingulate

00:51:00.140 | based off the level of emotional valence

00:51:02.540 | from none down to a lot,

00:51:05.060 | and that seems to be how it's distributed.

00:51:08.700 | There are, you know, heart rate kind of components to it,

00:51:11.180 | autonomic components in there too.

00:51:13.260 | There's something called akinetic mutism.

00:51:15.900 | You know, I'm a board certified neuropsychiatrist,

00:51:19.140 | behavioral neurologist, and I've seen, you know,

00:51:21.820 | a lot of these, what we call zebra cases in neurology

00:51:24.380 | where people have, you know,

00:51:25.900 | these unusual neurological presentations,

00:51:28.340 | and one of them is akinetic mutism.

00:51:30.780 | So if you have a glioma

00:51:32.980 | sitting in the inner hemispheric fissure

00:51:35.700 | and kind of having pressure on the cingulate,

00:51:39.580 | people can get into an almost catatonic looking state

00:51:42.220 | where they kind of get stuck and they don't speak,

00:51:44.580 | and so that tells you something

00:51:46.340 | about how the cingulate works as well, right?

00:51:50.020 | It's like if it's not functioning,

00:51:55.020 | then people have a hard time kind of connecting with reality.

00:51:59.340 | It seems to need to be constantly on, you know,

00:52:02.660 | online to be able to interact with the exterior world.

00:52:05.940 | - Is it involved in some of the dissociative states

00:52:08.180 | that sometimes people who are very stressed

00:52:10.740 | or depressed experience,

00:52:12.340 | you said catatonia being an extreme one,

00:52:15.200 | but I know someone, for instance,

00:52:16.860 | that when they get really stressed,

00:52:18.760 | and it can even be if someone yells at them

00:52:22.900 | or someone's angry, even if someone's angry with them

00:52:25.540 | or they perceive someone's angry with them,

00:52:27.140 | there's a developmental backstory

00:52:28.320 | to why they likely feel this way.

00:52:30.240 | They sort of just kind of can't,

00:52:33.500 | this is a high, high functioning individual normally,

00:52:36.540 | and they just sort of can't function.

00:52:38.640 | They can't complete simple things like email or groceries

00:52:41.940 | or things for a short while.

00:52:43.600 | It's almost like a catatonia,

00:52:45.800 | and they refer to it as a dissociative state.

00:52:49.200 | Do you see that in depression?

00:52:51.840 | And I mean, we're speculating here

00:52:53.480 | as to whether or not that involves a cingulate,

00:52:55.080 | but what you're saying holds a lot of salience for me

00:52:57.920 | in thinking about this example.

00:52:59.200 | - Yeah, yeah, there's,

00:53:01.280 | so you see catatonia as an extreme outcome of depression

00:53:04.780 | and of, and sometimes schizophrenia and other illnesses.

00:53:09.060 | Dissociation is an extreme outcome,

00:53:11.460 | or even in some cases a less extreme outcome

00:53:13.780 | of PTSD and trauma.

00:53:16.380 | And it's also a phenomenon that happens naturally

00:53:21.020 | in some people that are highly hypnotizable.

00:53:23.680 | And so if you ask David Spiegel,

00:53:25.020 | he'd say that some of the work that he's been working on

00:53:28.200 | is around posterior cingulate

00:53:29.980 | and the capacity to dissociate.

00:53:32.400 | But yeah, with our stimulation approach to DLPFC,

00:53:37.400 | dorsal anterior cingulate,

00:53:39.380 | one of the subscales that moved the most

00:53:42.440 | was the dissociative subscale for hypnotizability.

00:53:46.400 | So even in a normal individual,

00:53:49.540 | you see that change in that kind of experience

00:53:53.440 | of dissociation.

00:53:54.560 | - I am highly hypnotizable.

00:53:56.820 | David's hypnotized me a number of times.

00:53:58.400 | In fact, we have a clip of that

00:53:59.540 | on our human life clips channel.

00:54:01.460 | I've always, well, always starting in my early teens,

00:54:05.860 | I started exploring hypnosis.

00:54:07.080 | I'm extremely hypnotizable.

00:54:09.260 | And self-hypnosis or assisted hypnosis.

00:54:13.580 | I don't know that I ever go into dissociative states.

00:54:16.240 | I'll try and avoid forcing you

00:54:18.420 | into running a clinical session right now,

00:54:20.320 | but to assess anything like that.

00:54:22.580 | But this brings about something really interesting, I think,

00:54:26.180 | which is I'm aware that some of the more popular

00:54:29.820 | emerging treatments for depression include things

00:54:33.420 | like ketamine, which is a dissociative anesthetic.

00:54:36.940 | Is that right?

00:54:37.780 | And my assumption is that as a dissociative anesthetic,

00:54:42.440 | that it leads to dissociative states

00:54:44.380 | where people can sort of third person themselves

00:54:46.760 | and feel somewhat distanced from their emotions.

00:54:50.220 | I've also been hearing that there are emerging treatments,

00:54:55.700 | psilocybin being one of them,

00:54:58.000 | but some other treatments, MDMA, et cetera,

00:55:00.460 | that we'll parse each of these in detail,

00:55:02.900 | that lead to the exact opposite state

00:55:05.140 | during the effect of the drug,

00:55:06.700 | which is a highly engaged emotionality

00:55:11.060 | and heart rate and sense of self,

00:55:12.980 | and can also lead to relief of depression.

00:55:16.640 | Now, whether or not this, again,

00:55:18.100 | reflects that depression has many conditions

00:55:20.700 | as opposed to just one, or whether or not somehow tickling,

00:55:24.620 | or in some cases, pushing really hard

00:55:26.260 | on the opposite ends of the scale really matter.

00:55:29.160 | I am absolutely fascinated,

00:55:30.780 | and again, also perplexed by this.

00:55:33.220 | Why would it be that a drug that induces dissociative states

00:55:37.520 | and a drug taken separately

00:55:39.460 | that induces hyper associative states

00:55:42.960 | would lead to relief of the same condition?

00:55:45.100 | - Yeah, that's a great question.

00:55:46.900 | Yeah, so for ketamine, the level of dissociation

00:55:51.900 | appears to be correlated with the therapeutic effect.

00:55:55.280 | It appears to be necessary,

00:55:57.960 | but not sufficient to produce an antidepressant effect,

00:56:00.920 | and so folks that don't have any psychological change

00:56:05.920 | from the ketamine or don't experience any dissociation

00:56:10.580 | typically tend to have less potent

00:56:14.080 | antidepressant effects from ketamine.

00:56:16.240 | We did a study a couple of years ago,

00:56:17.700 | it was really interesting,

00:56:18.540 | so we gave folks naltrexone, which is an opiate antagonist,

00:56:23.360 | a mu and kappa opiate receptor antagonist,

00:56:26.400 | and we gave the same individuals a pill of that

00:56:31.180 | or a pill of placebo,

00:56:32.400 | and they had no idea which one they were getting.

00:56:34.160 | - Was this low dose naltrexone?

00:56:35.760 | - 50 milligrams, so it's pretty high dose.

00:56:37.360 | - Okay.

00:56:38.200 | - Yeah, and so we gave a typical ketamine therapeutic dose,

00:56:41.360 | and then we gave 50 milligrams of naltrexone or placebo,

00:56:45.120 | and then in the same individuals,

00:56:46.960 | we gave two infusions, one with each of those conditions,

00:56:51.320 | and if they had an antidepressant effect,

00:56:53.200 | we waited until they relapsed,

00:56:54.960 | and then we gave them the other condition,

00:56:56.760 | and then we looked to see

00:56:58.760 | what effect of blocking the opioid receptor,

00:57:02.560 | what effect would you see on the antidepressant effect

00:57:05.640 | of blocking the opioid receptor,

00:57:06.720 | with the idea that if ketamine works the way

00:57:09.260 | that a lot of researchers at the time thought

00:57:11.980 | that it completely worked in,

00:57:14.060 | which is the glutamate system,

00:57:15.880 | then you would have no effect of naltrexone,

00:57:19.280 | 'cause naltrexone just interacts with the opiate system,

00:57:21.800 | it doesn't do anything with any other systems.

00:57:24.360 | Ketamine has a lot of effects over,

00:57:27.240 | it has clear opiate effects in mice

00:57:30.640 | and various ways of looking at that,

00:57:32.880 | and NMDA receptor antagonism and glutamate effects,

00:57:37.600 | and so if it's just that the glutamate part

00:57:40.520 | is the part driving the antidepressant effect,

00:57:44.000 | you shouldn't have any difference

00:57:46.240 | in the antidepressant effect between the two conditions,

00:57:49.180 | if, however, the antidepressant effect is primarily,

00:57:53.020 | is the opioid properties of ketamine are necessary

00:57:58.020 | for the antidepressant effect,

00:57:59.780 | then you should have a loss of antidepressant effect

00:58:02.420 | during the ketamine plus naltrexone condition

00:58:05.320 | that you observed in the ketamine plus placebo condition,

00:58:08.940 | and what we saw was that there was a dramatic blockade

00:58:13.940 | of the antidepressant effect when naltrexone was present

00:58:17.500 | in the people that had an antidepressant effect

00:58:22.500 | with ketamine plus placebo alone,

00:58:26.440 | and then some friends of mine did a TMS study with pain

00:58:31.440 | and they stimulated over

00:58:33.700 | the left dorsolateral prefrontal cortex

00:58:35.440 | and they gave IV naloxone,

00:58:37.240 | which works basically the same way as naltrexone,

00:58:39.640 | and they were able to block the anti-pain effects of TMS

00:58:43.840 | with a opiate blocker,

00:58:45.380 | so this idea that, another kind of convergent point,

00:58:49.460 | this idea that the opioid receptor

00:58:52.040 | may have a role in mood regulation,

00:58:55.440 | what's also interesting is if you look at people

00:58:57.480 | that are getting a total knee operation,

00:58:58.880 | very painful operation, total knee replacement,

00:59:03.140 | and you age, sex, everything matched,

00:59:06.480 | the individuals that are going through that,

00:59:08.360 | but you have a group of people that don't have depression

00:59:11.020 | and a group of people that do have depression,

00:59:13.100 | the presence of depression triples the oral opioid dose

00:59:17.500 | by day four.

00:59:19.320 | - That's required.

00:59:20.520 | - That's required to cover the pain,

00:59:22.960 | but what may be happening

00:59:24.000 | is it's not just treating physical pain,

00:59:26.360 | maybe treating emotional pain as well, right?

00:59:28.500 | At least transiently, it seems to have a pro,

00:59:31.560 | an antidepressant effect.

00:59:32.800 | Chronically, it seems to have a very pro-depressant effect

00:59:35.520 | that can make people treatment resistant,

00:59:37.760 | but it's an interesting phenomenon,

00:59:40.400 | but yeah, the opioid system seems to be pretty involved,

00:59:43.880 | but what's interesting there with the ketamine trial

00:59:47.420 | is that we didn't see any effect on the dissociation,

00:59:50.960 | and so the dissociation was the same each time,

00:59:54.700 | so the psychological effect of what we call the TRIP

00:59:57.800 | or the kind of dissociative effect

01:00:00.100 | where people are having a psychological phenomenon

01:00:02.380 | from ketamine, that was identical both times,

01:00:06.140 | and so it also challenged this idea

01:00:10.380 | that the psychological experience of the psychedelic effect

01:00:14.620 | may be all that's necessary to produce an effect,

01:00:17.860 | and that the pharmacology doesn't matter

01:00:20.100 | as long as you can achieve that state,

01:00:22.500 | and so we think we pretty clearly debunked that idea

01:00:26.420 | that the underlying pharmacology and the state

01:00:29.540 | seem to be important.

01:00:33.460 | We don't know for sure if you can, and a lot of people

01:00:36.140 | are working on this, if you can take out

01:00:38.380 | essentially the psychological effect

01:00:39.940 | and still have a drug that works to treat the illness

01:00:44.180 | that you're trying to target,

01:00:45.260 | and there was a mouse study out this week

01:00:48.260 | where they had an LSD analog,

01:00:50.460 | and they were able to see some animal level data

01:00:54.900 | to suggest that could be true,

01:00:56.220 | but until we figure that out in humans,

01:00:58.500 | it's kind of to be determined, but it is curious, right,

01:01:02.760 | being able to kind of use experimental manipulations

01:01:06.360 | to try to separate some of these phenomenon apart

01:01:10.580 | and really understand what's doing what.

01:01:13.020 | - It's so critical, and it's so critical

01:01:14.740 | to the other conversation that we'll surely get to,

01:01:18.040 | which is the progression of psychedelics

01:01:20.900 | from illicit illegal drugs to clinically validated

01:01:25.640 | and presumably at some point,

01:01:27.080 | either decriminalized or legal drugs,

01:01:29.480 | which has not yet happened, at least not in the US,

01:01:33.260 | but just to make sure that people are getting this

01:01:36.020 | and how crucial this is.

01:01:38.760 | What we're really talking about here is the fact that,

01:01:42.340 | you know, somebody takes a multigram dose of psilocybin,

01:01:46.400 | or somebody takes MDMA, or they take ketamine,

01:01:50.140 | and they experience relief from their trauma,

01:01:51.980 | their depression, their addiction,

01:01:53.400 | or any number of the other things that indeed

01:01:55.300 | those compounds have been shown to be useful for

01:01:56.980 | in certain contexts, clinically supported, et cetera.

01:02:00.860 | There's this gravitational pull to the idea that,

01:02:04.040 | oh, it was the hallucinations.

01:02:06.040 | It was the dissociative state.

01:02:07.980 | It was the feeling of connectedness.

01:02:10.240 | And what we're really saying is that

01:02:11.700 | while that certainly could be true,

01:02:14.280 | it may be the case that a major source

01:02:16.900 | of the positive shift that occurs

01:02:18.700 | after the effect of the drug is some underlying biology

01:02:23.060 | like shifts in the mu opioid receptor,

01:02:25.460 | a lot of your experiments with naltrexone,

01:02:27.780 | or a change in the underlying neuromodulation

01:02:30.220 | that had anywhere from nothing

01:02:33.700 | to something to do with the real shift.

01:02:36.620 | And I know there's a group up at UC Davis

01:02:38.900 | that published a paper in "Nature" about a year ago,

01:02:42.340 | also looking at, these are,

01:02:45.020 | is a chemistry lab essentially modifying psychedelics

01:02:48.060 | to remove the hallucinogenic properties,

01:02:51.160 | the mood-altering properties,

01:02:52.420 | and actually seeing some pretty impressive effects

01:02:54.500 | and shifts in mood after the drug wears off.

01:02:57.680 | And I know this gets people upset when they hear it.

01:03:00.800 | A lot of people, this gets a lot of people upset really

01:03:03.540 | because people think,

01:03:04.380 | oh no, it's the intense experience that matters.

01:03:07.460 | But in fact, that may not be the case at all.

01:03:12.460 | In fact, it's so powerful for people

01:03:14.740 | that sometimes I liken it in my mind to,

01:03:17.040 | you know, it's like somebody,

01:03:17.880 | it's like the birth of a new child

01:03:19.380 | and it's such an incredible experience.

01:03:21.300 | And then people feel so much connection

01:03:22.820 | and then they sort of connect the experience

01:03:25.060 | of the actual birth to the connection

01:03:26.840 | when in fact that's true, it turns out,

01:03:28.900 | but there are a bunch of other things happening too

01:03:31.060 | that's simply the reflection of the fact

01:03:33.160 | that you're holding a child

01:03:34.180 | and the pheromonal effects, et cetera.

01:03:35.780 | So anyway, I think it's very important

01:03:38.780 | that these different variables be figured out.

01:03:43.780 | Along those lines, I want to make sure

01:03:46.140 | that before we dive a bit deeper into ketamine and psilocybin

01:03:50.540 | that we do touch on a really important topic

01:03:53.740 | that has been in the press a lot lately,

01:03:56.100 | which is SSRI, selective serotonin reuptake inhibitors,

01:03:59.060 | 'cause we can't really have a discussion about depression

01:04:01.140 | without talking about SSRI's.

01:04:02.660 | And then I want to circle back to ketamine and psilocybin.

01:04:05.600 | It seems that there are now data

01:04:10.100 | that essentially state that there's no direct link

01:04:14.740 | between serotonin levels and depression.

01:04:18.460 | Although my understanding is that the SSRI's

01:04:22.380 | are powerfully effective for certain forms

01:04:24.500 | of obsessive compulsive disorder

01:04:26.760 | and may also be effective for treatment of depression,

01:04:29.380 | but it may again be through some effect

01:04:31.660 | unrelated to serotonin itself.

01:04:33.540 | Is that right?

01:04:34.360 | And how should we think about SSRI's?

01:04:35.820 | Are they useful?

01:04:36.660 | Are they not useful?

01:04:37.540 | What's going on with SSRI's in your patients

01:04:41.820 | and in other people as well?

01:04:44.180 | - Yeah, the experiment that I described a bit ago

01:04:48.020 | around the naltrexone and ketamine

01:04:51.220 | is the first time I'm aware of where we were able

01:04:54.020 | to essentially eliminate an antidepressants effect

01:04:58.120 | by using a second drug as kind of a blockade.

01:05:01.740 | And it highlights a bigger issue, right?

01:05:03.900 | The issue that we haven't had a good way

01:05:07.240 | of really understanding how these drugs work.

01:05:10.760 | And so it's the difference,

01:05:12.300 | I think a lot of the controversy there

01:05:14.540 | is that it's been difficult I think for folks

01:05:19.420 | to see that something can in one hand work

01:05:24.340 | and in the other hand we don't know how it works, right?

01:05:27.380 | And so SSRI's clearly work.

01:05:31.100 | Many, many meta-analyses kind of proving that out, right?

01:05:36.420 | That in a sub-population of individuals

01:05:39.140 | they achieve great benefit.

01:05:41.200 | From depression, for depression, for obsessive compulsive

01:05:45.560 | disorder, for generalized anxiety disorder, panic,

01:05:48.760 | all these things you can see an improvement

01:05:51.400 | in those symptoms with what we call SSRI's

01:05:54.920 | or selective serotonin reuptake inhibitors.

01:05:57.000 | The issue there is that these selective serotonin

01:06:00.600 | reuptake inhibitors end up blocking the reuptake

01:06:05.120 | of serotonin and leaving the serotonin

01:06:08.240 | in this kind of in between two neurons for a while

01:06:13.240 | and allowing for more serotonin to kind of be there.

01:06:17.440 | The issue is that they don't work immediately, right?

01:06:21.940 | So they don't work like the same day you start taking them.

01:06:25.640 | And that suggests that probably it's not exactly

01:06:29.480 | the serotonin being in there that's directly driving it,

01:06:33.020 | that it's much more likely that it may have

01:06:35.440 | some say brain plasticity effects, right?

01:06:38.780 | We know that things like brain derived neurotrophic factor

01:06:43.260 | get upregulated with chronic oral anti-depressant use.

01:06:47.560 | And so that's kind of the idea is that these things work

01:06:52.560 | but what's powerful, and I think with the authors

01:06:56.400 | of this paper, it was extremely controversial paper,

01:07:00.160 | we're in part trying to say was that there's not a,

01:07:05.280 | there's not a deficit of serotonin.

01:07:07.600 | You're not born with what people call a chemical imbalance.

01:07:12.040 | And psychiatry has known this.

01:07:13.240 | This is not actually new information to anybody.

01:07:15.920 | It's kind of a rehashing of a bunch of information

01:07:19.100 | we've known for a while now but in the lay press

01:07:21.920 | it's kind of hit in a way that it didn't seem

01:07:24.320 | to grab attention before with previous publications

01:07:29.240 | but this idea that this chemical imbalance idea is wrong.

01:07:34.140 | I really think that part's important

01:07:36.900 | because I think that for a while I think psychiatry,

01:07:41.900 | what I'll call psychiatry 1.0, this kind of idea of Freud

01:07:47.880 | and psychotherapy and its origins,

01:07:50.460 | it was a lot around your family and those experiences

01:07:55.800 | and psychotherapy kind of going in and correcting

01:07:58.620 | or helping you to figure out or show you being able to see

01:08:03.720 | or people hear you so that you can eventually come

01:08:06.080 | to the conclusion of certain cognitions

01:08:09.700 | that aren't helping you.

01:08:11.220 | And there's a huge importance there but there's a history

01:08:15.220 | where things like the schizophrenogenic mother

01:08:18.300 | and all of that, that was a concept at some point.

01:08:21.240 | And so we've transitioned from that to for a long time

01:08:25.440 | the chemical imbalance which I'll call psychiatry 2.0,

01:08:30.240 | this idea that there's something chemically missing.

01:08:34.280 | And I think that the trouble there for a patient

01:08:40.840 | who's not a physician, who's not someone

01:08:44.620 | who's steeped in these sorts of ideas,

01:08:49.620 | who's more of a kind of average American out there

01:08:56.800 | is that it's sending a message of there's something missing

01:09:01.100 | with me, whether it be my experiences I had no control of

01:09:04.560 | over when I was a child or a chemical in my brain.

01:09:08.620 | What I think is really powerful with TMS,

01:09:11.860 | really powerful TMS and a lovely even powerful

01:09:16.700 | the psychedelic story is it's saying something different.

01:09:20.700 | You know, TMS works and there's no serotonin coming in

01:09:24.460 | or out of the brain, right, and we're doing a rapid form

01:09:27.480 | of TMS that works in one to five days.

01:09:29.860 | There's no, it's very unlikely that there's some long-term

01:09:33.960 | kind of upregulation of serotonin that's driving that.

01:09:36.720 | So our work actually kind of pushes back

01:09:39.200 | on this serotonin hypothesis as being kind of the center

01:09:42.780 | of depression because it says, look, we're not giving

01:09:45.440 | anybody any serotonin, we're simply turning

01:09:48.120 | these brain regions on and we're focused on the circuitry.

01:09:51.940 | And that's psychiatry 3.0, it's not just like

01:09:54.000 | neuromodulation, neuromodulation's a really nice use case

01:09:57.800 | for psychiatry 3.0 'cause it's a way to focally

01:10:00.700 | and directly perturb brain regions

01:10:03.000 | in whatever modality you're using.

01:10:05.500 | But there are a lot of groups that are actually doing

01:10:08.700 | neuroimaging before and after and they're able to see

01:10:11.220 | circuit level changes for something like psilocybin

01:10:14.440 | or ketamine long after the drug is gone, right,

01:10:18.500 | suggesting in those same brain regions converge

01:10:22.260 | so the subgenual default mode network connection

01:10:24.500 | that we see is changing with our Stanford neuromodulation

01:10:29.020 | therapy technique, it's that same set of brain regions

01:10:32.860 | that ketamine and psilocybin seem to act on,

01:10:36.900 | act on these connections between brain networks

01:10:40.260 | that seem to shift.

01:10:41.780 | And so it refocuses the story on something

01:10:45.940 | that's highly correctable and it's basically

01:10:49.740 | electrophysiology and it's basically

01:10:53.100 | kind of recalibrating a circuit that is recalibratable

01:10:58.100 | instead of I have something missing

01:11:00.860 | or I have some set of experiences early in life

01:11:04.980 | that are gonna forever trap me

01:11:08.060 | in these psychiatric diagnoses.

01:11:10.300 | And so it kind of challenges that idea

01:11:12.060 | and I think that's what's so powerful about psychiatry 3.0,

01:11:16.500 | this idea of focusing on the circuit

01:11:18.300 | because it gets us into thinking about psychiatry

01:11:21.620 | and psychiatric illnesses as something that are recoverable.

01:11:25.420 | People can get better, we've seen with our TMS techniques,

01:11:29.060 | we've seen it with some of the psychedelic work

01:11:30.740 | that we've done where people are actually in normal levels

01:11:34.780 | of mood for sustained periods of time or--

01:11:37.300 | - Within five days.

01:11:38.260 | - Within five or less days and in the case of the

01:11:41.220 | psychedelics within a few days, right?

01:11:42.980 | So we can get people out of these states,

01:11:46.140 | they're totally well, there's no drug in their system

01:11:48.820 | at that point, in the case of psychedelics,

01:11:50.500 | it was never a drug in their system in the case of TMS

01:11:54.300 | and it just tells us that it's fixable,

01:11:57.980 | it's just like the heart, it's just like an arrhythmia

01:12:01.020 | in the heart, it's just like these other illnesses

01:12:03.740 | that it's like a broken leg, we can go in and do something

01:12:06.820 | and we can get somebody better.

01:12:08.460 | Then I think what's empowering and what a lot of patients

01:12:11.740 | have told me is they say, I've gotten to,

01:12:14.540 | some people will relapse and need more stimulation

01:12:17.580 | or need more psychedelics or whatever it is

01:12:19.820 | but they'll tell me, I've relapsed and I'm depressed again

01:12:24.300 | but I'll never think about killing myself again

01:12:26.680 | because I know that if I go get stimulated again,

01:12:31.460 | it improves, it gets better, I will be able to re-achieve it

01:12:35.500 | and I can't, and I don't fear that I'm chronically broken,

01:12:39.460 | I don't fear that the chemical imbalance

01:12:42.380 | is still imbalanced, I don't fear that these things

01:12:45.320 | that I couldn't control in my childhood

01:12:47.820 | are gonna be there and drive this problem forever

01:12:50.580 | and I think that's what's so powerful about this.

01:12:53.740 | - The sense of control.

01:12:54.760 | - The sense of control, the sense of,

01:12:56.540 | they're not doing the stimulation themselves,

01:12:58.700 | they're not administering the drug in these trials themselves

01:13:01.460 | and they probably never will,

01:13:02.460 | these will probably be medical treatments

01:13:04.500 | but they are choosing to do it

01:13:06.420 | and in that sense, they are in control.

01:13:08.700 | - Yeah, I have a good friend, I won't out him for reasons,

01:13:12.180 | they'll become clear in a moment,

01:13:13.140 | who was quite obese and lost a lot of weight

01:13:18.140 | and was really proud of himself

01:13:20.100 | and then I guess we could say he sort of relapsed in a sense,

01:13:22.900 | not all the way but far along

01:13:26.420 | but his tone around it was very different.

01:13:28.660 | He knew he had accomplished his goal once before,

01:13:32.300 | he was disappointed in himself

01:13:33.700 | but he knew exactly why he had relapsed, it was very clear,

01:13:37.500 | he had essentially relapsed to the previous set

01:13:39.740 | of eating behaviors and lack of exercise behaviors

01:13:42.820 | and has now brought himself back again

01:13:44.740 | and it just resonates with your story

01:13:49.420 | that once somebody understands they can do it

01:13:51.580 | because they've been there before,

01:13:52.860 | this idea again of considering new rules.

01:13:56.200 | And that brings me to this question about psychedelics

01:14:01.180 | and frankly, the altered thinking and perception

01:14:04.420 | that occurs in high dose psilocybin clinical sessions

01:14:10.380 | it seems that the disordered thinking

01:14:12.800 | even though it could be random, right?

01:14:16.040 | Hearing colors and seeing sounds is always

01:14:19.240 | the kind of cliche statement of the Timothy Leary area.

01:14:22.540 | Also, right there, that's a Stroop task of sorts.

01:14:26.900 | It's a synesthesia, it's a combining of perceptions

01:14:29.740 | but it's sort of Stroop task-ish

01:14:32.260 | in that it's a new set of rules for the same stuff, right?

01:14:36.860 | And people do, many people do report improvements

01:14:41.820 | in trauma-related symptomology and depression

01:14:45.180 | as I understand it from my read of the clinical trials

01:14:47.720 | after taking psilocybin because during those sessions

01:14:50.020 | something comes to mind spontaneously

01:14:53.420 | as you and I were talking about earlier,

01:14:56.220 | they will report for instance a new way

01:14:59.100 | of seeing the old problem and the old problem

01:15:01.760 | could be the voice that they're no good,

01:15:03.140 | they'll never, nothing will ever work out

01:15:04.900 | or could be even more subtle than that.

01:15:06.960 | So that raises two questions.

01:15:09.620 | One is about the basic functioning of the human brain

01:15:13.420 | which is why do you think the brain would ever hold on

01:15:18.420 | to rules that don't serve us well?

01:15:22.620 | That's one question.

01:15:23.820 | And then the second question is what is it

01:15:27.940 | about psilocybin and related molecules

01:15:30.620 | in terms of their neurochemistry,

01:15:32.060 | in terms of the ways they disrupt thinking and feeling,

01:15:35.060 | et cetera, during the session

01:15:37.540 | that allow this novel rule consideration phenomenon?

01:15:42.540 | - Yeah, so the first question,

01:15:45.980 | I think it's an evolutionary neurobiology answer, right?

01:15:50.980 | I think that at the individual person level,

01:15:55.220 | you know, it doesn't make a whole lot of sense

01:15:56.840 | that when we're really stressed out

01:15:58.100 | some of us want to eat more, right,

01:15:59.840 | at the individual person level

01:16:01.580 | 'cause it's like that's not particularly that good

01:16:03.760 | for my health in the long term.

01:16:06.300 | But if you think about it like, you know,

01:16:08.820 | in some 500 years ago, 1,000 years ago,

01:16:12.100 | if I'm highly stressed out, it's most likely

01:16:14.400 | that I'm about to not have food at some point

01:16:16.940 | and I should eat a bunch of food that is high fat,

01:16:19.100 | high sugar, high carb food to put on weight

01:16:21.940 | for that next phase where in this stress,

01:16:25.620 | I may be in battle and I don't have food

01:16:27.900 | and I have enough fuel on board, right?

01:16:30.220 | And so we end up being a, you know,

01:16:33.460 | we end up being a result of probably a lot of biology

01:16:36.740 | that's not that useful in the modern era

01:16:39.140 | and I think in the brain for, let's say, PTSD, right?

01:16:42.900 | A lot of veterans come back

01:16:44.700 | and they experience these PTSD symptoms

01:16:46.460 | and they're not at all useful back home, right?

01:16:50.260 | You know, they hear some loud noise

01:16:53.020 | and all of a sudden they're behind a car

01:16:54.660 | or they're behind a, you know, I've heard of folks,

01:16:57.420 | jump and run behind a trash can or whatever

01:16:59.520 | in the middle of San Francisco when they hear a loud noise

01:17:02.960 | but if you put them back in the battlefield--

01:17:05.800 | - Highly adaptive.

01:17:07.920 | - That's highly adaptive, right?

01:17:09.180 | And so I think what's interesting is that we,

01:17:14.180 | in the absence of using substances like psychedelics,

01:17:22.080 | end up having these very persistent memories

01:17:26.540 | that are attached to negatively balanced emotion

01:17:29.100 | predominantly, as you were saying earlier,

01:17:31.720 | the jacket in elementary school, you know,

01:17:34.560 | I had various things like that for me too, right?

01:17:36.620 | You remember these things and we hold onto those things

01:17:41.620 | from I think an evolutionary neurobiology standpoint

01:17:46.320 | but what seems to, for whatever reason,

01:17:50.060 | kind of alleviate that are these substances,

01:17:55.060 | some new like MDMA, some that have been around

01:17:58.660 | for thousands of years like psilocybin

01:18:00.980 | and used as a sacrament in traditions

01:18:05.980 | seem to have a therapeutic effect

01:18:12.600 | that seems to be pretty long lasting for these phenomenon

01:18:15.220 | and so it's just curious, right?

01:18:17.560 | It's curious that in the absence of that,

01:18:22.560 | these things will keep going on and on

01:18:24.660 | but in the presence of that exposure,

01:18:28.320 | then all of a sudden you see a resolution of the problem

01:18:31.540 | and we have some work now.

01:18:32.660 | We're treating folks with Navy Seals

01:18:34.980 | and the data's still being, you know, being analyzed

01:18:37.620 | but the anecdotes that we're getting, right,

01:18:39.900 | are folks are coming back

01:18:41.060 | and they're saying it's finally gone, right?

01:18:44.200 | This kind of, these set of PTSD symptoms are finally gone

01:18:48.320 | and so this idea that for whatever reason,

01:18:51.340 | going into what's probably a highly plastic state

01:18:54.020 | like we were talking about earlier,

01:18:54.980 | upregulation of brain-derived neurotrophic factor

01:18:57.220 | in the case of Ibogaine, glial-derived neurotrophic factor,

01:19:01.260 | this highly plastic state and the ability

01:19:04.180 | to kind of re-experience memories

01:19:07.760 | and then, as you know, we always re-consolidate a memory.

01:19:12.620 | When we bring it back up, we always re-consolidate,

01:19:14.660 | but re-consolidating it in that state,

01:19:17.340 | for whatever reason, may drive a therapeutic effect.

01:19:22.340 | And, you know, the jury's still out.

01:19:27.040 | I'm a, I would say that I'm kind of a,

01:19:30.660 | I'm an agnostic to what tool I'm using kind of guy.

01:19:35.140 | Like, I'm, my business is to find treatments

01:19:38.760 | that help people and so I'm much more, like,

01:19:41.940 | pragmatic about it, you know?

01:19:43.440 | If this sort of thing, which has a lot of cultural baggage,

01:19:48.440 | but if this sort of thing ultimately ends up

01:19:51.760 | being therapeutic, if we can design trials

01:19:53.660 | that convince me and others that it is,

01:19:56.400 | then we should absolutely use it, you know?

01:19:58.600 | And if it doesn't, then we clearly shouldn't use it, right?

01:20:03.600 | And I think that's a big, that's a big question

01:20:06.860 | the field's going to have to work out.

01:20:08.040 | We have a hard time blinding these trials

01:20:10.100 | because the placebo condition is not easy to pull off,

01:20:14.740 | obviously. - Right, a placebo

01:20:16.020 | for a psilocybin journey is hard to imagine.

01:20:18.960 | - We've got, you know, we've been thinking about this

01:20:22.060 | and maybe that ketamine study

01:20:24.500 | that I was talking about earlier,

01:20:25.460 | if we could give people naltrexone and ketamine,

01:20:28.260 | maybe that's a good, you know,

01:20:30.000 | a good sort of placebo condition, right?

01:20:33.220 | 'Cause we know that we can block

01:20:34.600 | any of the actual antidepressant effects of ketamine,

01:20:36.820 | they can still have an experience, you know?

01:20:38.700 | So that's one way of doing it,

01:20:40.460 | but thinking about ways to do that

01:20:42.140 | and really kind of proving this out

01:20:43.860 | and that's been, yeah, I think that's been kind of central

01:20:48.020 | to the way I've been thinking about this.

01:20:50.400 | But yeah, I think there's the work that's been done so far,

01:20:53.220 | the first psilocybin trial, the first MDMA trial

01:20:57.300 | is published in "Azure Medicine" recently.

01:20:59.760 | - And what do those generally say?

01:21:01.220 | I mean, that they are effective for a number of people

01:21:04.260 | after one session, two sessions,

01:21:06.340 | but what's sort of the general contour?

01:21:08.340 | Let's start with psilocybin and MDMA.

01:21:11.300 | - Yeah, so MDMA appears to in, you know,

01:21:14.900 | one to a few MDMA sessions have an anti-PTSD effect

01:21:18.880 | that seems to be, you know, outside of the kind of standard

01:21:23.880 | assumed levels of PTSD improvement that you can observe

01:21:28.020 | in individuals with this level of PTSD, right?

01:21:31.280 | So what we call the effect size,

01:21:33.120 | which is essentially like a measure,

01:21:37.320 | a co-intensity effect size,

01:21:38.620 | a measure that allows for you to compare

01:21:41.360 | different treatments to each other

01:21:42.480 | for different conditions that are, you know,

01:21:44.000 | agnostic to what the actual illness is, you know?

01:21:47.440 | The effect sizes there, you know, approach effect sizes,

01:21:51.200 | the things that are pretty effective,

01:21:52.740 | like antacids for heartburn, right?

01:21:55.760 | And you see that with MDMA treatment.

01:21:59.040 | - So does that mean that for people that have trauma

01:22:02.320 | who do a, and again, we're talking about

01:22:04.220 | in a clinical setting, they take one or two doses of MDMA,

01:22:08.400 | I think the standard MAPS dose is 150 to 75 milligrams,

01:22:12.360 | again, doing this with a physician, et cetera,

01:22:14.240 | controlled clinical trial, legal.

01:22:17.200 | - Yep, exactly.

01:22:18.160 | - They do it once or twice.

01:22:20.220 | And broadly speaking, what percentage of people

01:22:23.240 | who had trauma report feeling significant relief

01:22:26.120 | from their trauma afterward?

01:22:28.720 | - It's about two thirds of people

01:22:29.980 | had a clinically significant change in their PTSD.

01:22:34.980 | - That's impressive.

01:22:36.440 | - Which is impressive, right?

01:22:37.360 | - And how long lasting was that?

01:22:39.020 | I mean, these trials were ended pretty recently, so.

01:22:41.800 | - It appears to last for a while.

01:22:43.120 | In the earlier trials where they followed people out,

01:22:45.040 | it seemed to last for kind of in the years range

01:22:47.280 | for some people.

01:22:48.120 | And so it's pretty compelling.

01:22:52.080 | Psilocybin, in contrast to it with ketamine,

01:22:55.680 | which only on average lasts about a week and a half

01:22:58.200 | for a single infusion.

01:23:00.180 | So it's a much shorter.

01:23:01.760 | - So they have to get repeated infusions of ketamine

01:23:03.800 | every 10 days or so?

01:23:05.960 | - Yeah. - Forever?

01:23:07.780 | - For some people, where they end up getting

01:23:09.520 | like a bunch of doses for a couple of weeks.

01:23:12.960 | And then for some people, that seems to last a while.

01:23:15.840 | You know, that's where I think the psilocybin story

01:23:19.600 | for depression and the MDMA story for PTSD

01:23:22.760 | seem more interesting to me.

01:23:24.160 | - So for psilocybin, what is the rough percentages on,

01:23:28.020 | and this would be relief not from trauma,

01:23:29.580 | but from depression.

01:23:31.440 | - Yeah, yeah, exactly.

01:23:32.720 | So it's, you know, in open label studies,

01:23:34.640 | it's closer to like half to two thirds of people

01:23:36.860 | end up getting better depending upon their level

01:23:38.560 | of treatment resistance.

01:23:39.520 | In the blinded trials, it was more like a third or so

01:23:42.960 | of people, you know, experienced relief.

01:23:45.840 | And this is a press release of the data.

01:23:49.760 | And so it hasn't, to my knowledge,

01:23:51.740 | it hasn't been published yet.

01:23:53.080 | And so I'm looking forward to seeing the full paper

01:23:55.400 | on that one.

01:23:56.240 | But it, you know, separated from placebo

01:23:59.760 | and looks, you know, looks pretty good as well.

01:24:02.000 | It looks like it's, you know, the first of two trials

01:24:04.800 | that need to be done to get this thing approved

01:24:07.000 | for treatment resistant depression.

01:24:08.440 | And so that stuff looks good.

01:24:11.780 | - In terms of MDMA, for many years,

01:24:15.480 | it was reported in the popular press

01:24:18.080 | and there was a paper published in Science

01:24:19.700 | that MDMA was neurotoxic,

01:24:21.580 | that it would kill serotonin neurons.

01:24:23.700 | This was what was always said.

01:24:25.600 | Then I saw another paper published in Science

01:24:29.040 | that wasn't a retraction of the previous paper,

01:24:31.400 | but rather was a second paper on the same group

01:24:33.640 | that essentially admitted that the first time around

01:24:37.000 | they had injected these monkeys

01:24:40.280 | 'cause of the, with not MDMA, but with methamphetamine,

01:24:44.240 | which is known to be neurotoxic.

01:24:45.900 | So it was kind of a public admittance of oops

01:24:49.400 | or big, like really big screw up.

01:24:52.320 | So oops, but never a retraction.

01:24:55.360 | And then never really a publicly acknowledged correction

01:24:59.180 | in the popular press.

01:25:01.300 | So it seems that in the appropriate dosage range

01:25:04.680 | and with these one or two sessions,

01:25:07.760 | my assumption, and this again is an assumption,

01:25:11.120 | tell me if I'm right or wrong here,

01:25:12.920 | is that MDMA is not neurotoxic for serotonergic neurons

01:25:17.600 | at appropriate doses and with appropriate sourcing, et cetera.

01:25:20.320 | - So it was an interesting study that,

01:25:23.560 | I think the guy's name is Halpern.

01:25:25.280 | Last name's Halpern.

01:25:26.760 | - Not Casey Halpern.

01:25:27.760 | - Not Casey, different now.

01:25:29.160 | I think Joshua Halpern, I'm blanking on his first name,

01:25:31.400 | but he- - Casey Halpern was a guest on this podcast

01:25:34.640 | and is a former colleague of ours at Stanford,

01:25:36.800 | who unfortunately we lost to University of Pennsylvania

01:25:39.600 | and maybe someday we'll bring him back.

01:25:42.240 | - Yeah, that's right.

01:25:43.080 | So this individual received some NIH funding

01:25:46.540 | to actually NIDA, National Institute for Drug Abuse funding

01:25:50.080 | to explore individuals of the Mormon faith in Utah

01:25:57.960 | who partake in only MDMA.

01:26:02.800 | So the way this works is that MDMA happened

01:26:07.800 | kind of after a lot of the religious documents

01:26:14.080 | were developed and so MDMA

01:26:16.640 | isn't on the prohibited drug list.

01:26:19.520 | - The banned substance list.

01:26:20.360 | - Above the banned substance list.

01:26:21.680 | - I have some good friends who are LDS.

01:26:23.240 | - Yeah, great people.

01:26:25.440 | - I do as well, just to kind of set a facts.

01:26:28.820 | And so these folks only use MDMA,

01:26:33.820 | but they're not, the problem with some people using drugs

01:26:37.900 | is they're polysubstance users, right?

01:26:39.920 | So you can't say it's the MDMA

01:26:42.280 | if they've also taken other psychedelics

01:26:44.120 | and they've taken opiates and they've taken cocaine.

01:26:45.920 | And you have this picture

01:26:47.240 | where you can't really tease out that problem.

01:26:50.520 | But with this, it was just individuals

01:26:53.800 | that were part of the Mormon faith

01:26:55.320 | and so they were kind of purists

01:26:58.240 | in the sense they only used MDMA

01:27:00.040 | and he confirmed all of that.

01:27:01.880 | And it was a brilliant study, right?

01:27:04.620 | Because then he was able to go in

01:27:06.200 | and look at their cognitive profiles

01:27:08.200 | versus individuals of the same geography, the same faith,

01:27:12.160 | all of that that happened to not take MDMA

01:27:15.720 | and found there were no neurocognitive differences.

01:27:19.440 | - So does that mean that it was not damaging?

01:27:22.760 | - It was not damaging.

01:27:24.680 | It's hard to know because to really do this study well,

01:27:27.760 | you'd have to track these folks down

01:27:29.400 | before they ever took MDMA and do a pre-post

01:27:32.780 | and compare it to people that didn't.

01:27:34.680 | But this is about as good of a study as you can do

01:27:37.800 | given the situation to be able to check this out.

01:27:43.000 | Additionally, when I was back in Charleston

01:27:46.000 | and working at the medical university of South Carolina,

01:27:48.740 | one of my mentors there, Dr. Wagner,

01:27:53.680 | was a neuropsychologist at MUSC

01:27:55.760 | and he was also the neuropsychologist

01:27:58.280 | for the early MDMA trials.

01:28:00.480 | And so he did all the neurocognitive batteries

01:28:03.140 | for individuals pre-post and similarly did not see

01:28:07.260 | any changes in neurocognitive profiles in a negative way.

01:28:11.300 | And so there's data from experimental patients

01:28:15.040 | receiving this, there's data from people

01:28:16.640 | that are chronic users who only take MDMA

01:28:21.680 | and that combination of data suggests

01:28:26.480 | that there's certainly no apparent risk

01:28:30.160 | in the kind of one to two to three dose range.

01:28:34.120 | It's probably unlikely that at least modest dose exposure

01:28:39.120 | over a lifetime doesn't appear to have a profound

01:28:43.200 | neurocognitive damaging effect.

01:28:46.640 | - Interesting.

01:28:47.480 | Yeah, I know that sourcing is key

01:28:50.080 | and here we're talking about clinical trials

01:28:51.720 | where purity is assured.

01:28:53.280 | And years ago when so-called raves were really popular,

01:28:58.080 | maybe they're still popular,

01:28:58.920 | never been to one so I wouldn't know

01:29:02.040 | if they're happening or not.

01:29:03.040 | That's how in the know I am.

01:29:05.120 | But it was clear that testing for purity was important

01:29:09.040 | because sometimes the drugs are made such that

01:29:14.040 | there are contaminants like methamphetamine,

01:29:17.520 | which we know is highly neurotoxic.

01:29:20.080 | I think that one reason why people think that MDMA

01:29:23.120 | might be neurotoxic is the reported drop in energy

01:29:27.640 | or sort of feeling fatigued for a few days afterward.

01:29:30.280 | I spoke to a physician colleague of ours

01:29:32.200 | who said that very likely has something to do

01:29:35.760 | with the surgeon prolactin that arrives subsequent

01:29:40.080 | to the big dopamine surge that occurs in MDMA.

01:29:43.520 | And I mentioned that because I know a number of people

01:29:46.520 | talk about serotonin depletion after taking MDMA.

01:29:50.280 | He has it in mind that while that could be true,

01:29:52.740 | it's likely that anytime somebody takes something

01:29:54.960 | or does something where there's a huge lift in dopamine,

01:29:57.920 | that there's very likely a huge compensatory increase

01:30:00.760 | in prolactin that follows and prolactin

01:30:02.440 | has a kind of sedative effect, numbing effect on mood

01:30:05.820 | and libido, et cetera, that eventually also wears off.

01:30:08.760 | Does that make sense to you as a physician?

01:30:10.700 | - Yeah, it makes sense.

01:30:11.540 | I mean, the difference between say MDMA and psilocybin

01:30:15.420 | is that MDMA is kind of an amphetamine of sorts, right?

01:30:17.800 | So it has effects in dopamine and psilocybin's

01:30:22.800 | pretty neutral and maybe a little bit of dopamine effects,

01:30:26.720 | but kind of much more of a serotonergic focused drug.

01:30:30.380 | And so, yeah, I think you're going to see

01:30:32.480 | kind of a different profile after.

01:30:34.120 | And that makes, I haven't heard that story,

01:30:35.720 | but that makes sense to me too.

01:30:37.220 | - Since you mentioned psilocybin,

01:30:39.420 | let's talk a little bit about the neurochemistry

01:30:40.860 | of psilocybin.

01:30:41.700 | As a serotonergic agent, my understanding is it operates

01:30:45.180 | on these, is it the 5-HT serotonin 2C receptor?

01:30:49.980 | - 2A. - 2A, excuse me, 2A receptors.

01:30:53.340 | And that I've seen a bunch of different reports

01:30:55.600 | in terms of what it's actually doing to the brain

01:30:57.360 | while people are under the effects of the drug.

01:30:59.560 | And this is important for us to segment out

01:31:01.580 | because there are the effects that happen

01:31:03.200 | while people are under the influence

01:31:04.600 | and then the more long lasting effects.

01:31:06.860 | But some of the effects that I've heard about are,

01:31:08.540 | for instance, and tell me again if these are right or wrong,

01:31:12.980 | that there is increased activation of lateral connection,

01:31:17.980 | sort of broader areas of the brain being co-active

01:31:21.000 | than would normally occur.

01:31:23.020 | Maybe that explains some of the synesthesia,

01:31:25.460 | seeing sounds and hearing colors as the trivial example,

01:31:29.520 | but rule-breaking within the mind.

01:31:34.260 | But then I've also heard that perhaps it's lack of gating

01:31:38.720 | of sensory input.

01:31:39.620 | So normally if I'm looking at something,

01:31:41.220 | I'm not thinking about the sensation in my right toe

01:31:43.820 | unless it's relevant.

01:31:46.040 | But if I'm thinking about the sensation in my right toe,

01:31:47.980 | I'm generally not thinking about the truck

01:31:49.300 | around the corner.

01:31:50.140 | So we have these attentional spotlights,

01:31:51.760 | but that somehow it creates a more, it adds spotlights.

01:31:56.000 | - Yeah, de-gates the thalamus.

01:31:57.540 | - De-gates the thalamus, right,

01:31:58.900 | through the reticular thalamic structure.

01:32:01.520 | So what is the evidence that any of that is true?

01:32:05.580 | And are there other phenomena?

01:32:07.520 | Is there involvement of dorsolateral prefrontal cortex

01:32:09.700 | that we are aware of?

01:32:10.780 | And where I'm really headed here in a few minutes is,

01:32:13.720 | is there a place for combining directed stimulation

01:32:18.700 | of the brain with psychedelics so that the effects

01:32:21.580 | of serotonin could be primarily within the structures

01:32:26.220 | that you know from your work to be relevant to depression?

01:32:28.980 | So, but to simplify it first,

01:32:30.940 | what's going on when one takes psilocybin

01:32:33.260 | and why is it interesting in light of depression?

01:32:36.740 | - Yeah, definitely.

01:32:37.580 | So David Nutt and Robin Carr and Harris' work

01:32:42.580 | around neuroimaging psychedelics are kind of some

01:32:45.700 | of the first folks to do that work.

01:32:47.520 | And to their great surprise,

01:32:50.100 | they thought there was gonna be an increase in activity

01:32:52.820 | on psychedelics and what they found is the opposite, right?

01:32:54.960 | There's kind of an overall decrease in the level of activity

01:32:58.180 | in the brain with psychedelics.

01:33:00.900 | But they've also looked at connectivity

01:33:03.660 | and there's this kind of small world,

01:33:05.700 | you know, large world connectivity that you think about.

01:33:08.900 | And so, you know, small world meaning there's a lot,

01:33:11.460 | there's kind of a much more kind of focused

01:33:13.860 | kind of cortical function or, you know,

01:33:15.540 | subcortical function or whatever it is.

01:33:17.660 | And what you see is a difference in that,

01:33:21.780 | in that level of engagement and of brain regions.

01:33:24.980 | So the connectivity, kind of global connectivity

01:33:27.220 | to your point kind of increases.

01:33:29.380 | And so, you know, it's interesting, you know,

01:33:32.020 | I think to kind of have a convergent theory on this,

01:33:36.100 | it's still, you know, to be determined,

01:33:38.700 | there's still a lot of work I think that needs to be done.

01:33:41.440 | But it's certainly suggestive

01:33:44.820 | that there's pretty profound changes in brain activity

01:33:49.260 | and brain connectivity after.

01:33:51.400 | And what we've found to be really interesting

01:33:54.020 | is the antidepressant effects of psilocybin

01:33:58.480 | have a particular connectivity change

01:34:02.400 | that we also see with our TMS approaches, right?

01:34:05.960 | And it's this connectivity

01:34:07.760 | between the subgenual anterior cingulate

01:34:10.080 | and the default mode network.

01:34:11.920 | And so when we do this effective

01:34:14.060 | Stanford neuromodulation therapy stimulation,

01:34:16.800 | we see a down regulation,

01:34:19.000 | the connectivity between the negatively valenced mood state

01:34:22.180 | in the case of depressed individuals

01:34:23.900 | and the self-representation of the brain.

01:34:26.320 | And you see that same connectivity change

01:34:29.040 | occur post psilocybin, you know,

01:34:31.840 | suggesting there's a convergent mechanism.

01:34:33.920 | And it makes sense, right?

01:34:34.840 | You've kind of got an over-connected,

01:34:36.860 | negatively valenced system, conflict system

01:34:40.320 | that's kind of, you know,

01:34:42.280 | kind of attached onto the self-representation

01:34:45.220 | and people feel stuck, right?

01:34:47.220 | And then when you do whatever you do that's effective,

01:34:49.940 | it unpairs those two systems.

01:34:53.200 | - I want to ask you about this phenomenon

01:34:56.480 | I've heard about during psilocybin journeys.

01:34:58.440 | I heard about this from Dr. Matthew Johnson,

01:35:00.840 | who's running a lot of the clinical trials

01:35:02.380 | at Johns Hopkins and has been a guest on this podcast.

01:35:07.160 | He said that there's something seems to be important

01:35:11.240 | about the patient who's depressed

01:35:13.700 | or who's and is under the influence of psilocybin

01:35:16.900 | or the patient who's trying to get a over smoking

01:35:19.160 | or an eating disorder who's taking psilocybin

01:35:21.400 | and is in the clinic, that there's something important

01:35:24.680 | to this notion of letting go,

01:35:27.400 | that people will feel as if their thoughts

01:35:30.560 | and their feelings and maybe even their body

01:35:32.320 | aren't under their control

01:35:33.480 | and that the clinician's job under those circumstances

01:35:36.640 | is of course to make sure that they're physically safe,

01:35:38.360 | so they don't jump out a window

01:35:39.520 | or try to actually give an example of a patient

01:35:41.560 | who thought that, I think it was a she,

01:35:43.640 | could move into the painting in the wall.

01:35:45.980 | And obviously that wasn't true in the real world,

01:35:48.580 | although it was true in her mind.

01:35:49.860 | So they prevented her from doing that.

01:35:51.840 | But that letting go, that somehow untethering

01:35:56.080 | from the autonomic arousal that's occurring is important,

01:35:59.800 | which brings us back to this idea

01:36:02.720 | or me back to this idea of like a seesaw

01:36:04.960 | where you're sort of letting go of the hinge

01:36:07.440 | and just sort of your heart rate's going up,

01:36:09.520 | like just go with it and trust.

01:36:11.860 | Your heart rate's going down, just go with it and trust.

01:36:13.860 | You're thinking about something very powerful

01:36:16.920 | and depressing related to your childhood.

01:36:19.180 | You're just supposed to go there without fear.

01:36:21.520 | You're thinking about what's possible

01:36:23.120 | in terms of what could happen.

01:36:24.400 | So anyway, you get the picture.

01:36:27.000 | Can we think of that as just the willingness

01:36:31.480 | to do a million different variations

01:36:35.080 | on the emotional Stroop task?

01:36:37.720 | You will entertain the full array of rules within your head

01:36:42.160 | and consider them.

01:36:43.320 | Or is there something more to it?

01:36:45.440 | And again, we're in the outer margins of understanding here,

01:36:50.100 | but what are your thoughts on this notion of letting go

01:36:53.540 | as such a key variable for relief from depression

01:36:57.220 | during the psychedelic journey?

01:36:58.420 | - Yeah, so I'll talk a little bit about something

01:37:00.580 | called exposure and response prevention therapy.

01:37:03.060 | That's a typical kind of gold standard treatment for OCD.

01:37:06.420 | And I'll help to kind of help this a little bit conceptually.

01:37:10.300 | And so what that really is, it's a letting go therapy.

01:37:14.220 | And so exposure response prevention,

01:37:18.060 | the idea is that you have to expose the individual

01:37:22.280 | to something that triggers an obsession

01:37:26.940 | that they then want to do whatever the compulsion is.

01:37:30.600 | And so I'll give you my first exposure

01:37:33.740 | and response prevention patient when I was a resident.

01:37:36.660 | He was very concerned about leaving the lights on this car.

01:37:42.280 | And so what we did is we went out

01:37:45.180 | and we turned the lights on in his car and locked his door.

01:37:50.540 | So his lights were on and he was super worried

01:37:53.020 | this is gonna kill his battery.

01:37:54.920 | And we went and we spent an hour talking about things

01:37:58.280 | and we went back out to his car and his battery was fine

01:38:02.000 | and his lights were on and he cranked the car

01:38:05.440 | and we did it maybe one other time.

01:38:07.980 | And then all of a sudden that was gone, right?

01:38:10.920 | And that's the idea is that you're essentially exposing

01:38:14.660 | and you wanna do it at levels that are

01:38:17.020 | from an anxiety standpoint, tolerable,

01:38:20.100 | but exposing the person to something

01:38:22.100 | and then letting them see that that exposure

01:38:25.740 | ends up being fine, right?

01:38:27.580 | It ends up not causing the thing

01:38:29.220 | that they end up being worried about.

01:38:31.400 | And so in some sense, being in the psychedelic state

01:38:36.860 | and we're all taught at a level to retain

01:38:41.320 | some level of control.

01:38:43.640 | People have more or less of that,

01:38:46.760 | but we're all effectively retaining some level of control.

01:38:50.600 | We all wake up in the morning and put clothes on

01:38:52.720 | to go into society.

01:38:53.780 | We all try to say, most people try to say the right things.

01:38:58.680 | They don't try to do things that are outside

01:39:00.540 | of cultural norms when they're in conversation.

01:39:03.680 | And so we're constantly at some level controlling

01:39:07.520 | the situation that we're in.

01:39:08.820 | And so it makes a lot of sense that in that state,

01:39:13.820 | part of the therapeutic effect that may be linked

01:39:16.900 | to the neural circuitry is this idea of letting go

01:39:21.360 | and essentially letting the system,

01:39:24.480 | the network configuration maybe, whatever it is,

01:39:27.320 | assume a state that you've essentially been fighting

01:39:32.480 | the whole time, the same way that my OCD patient

01:39:36.240 | was fighting this need to click the off button

01:39:41.240 | on the lights of his car 50 times before he would go

01:39:46.240 | and do whatever he needed to do.

01:39:48.320 | And in some level, letting go there,

01:39:50.080 | meaning letting us just turn the lights on

01:39:52.240 | and him not do anything, or letting go,

01:39:54.920 | meaning in the psychedelic state,

01:39:56.280 | you're just letting go of whatever it is

01:39:58.640 | you're holding onto.

01:39:59.960 | Negatively balanced thoughts about yourself

01:40:02.800 | in the setting of having depression

01:40:05.880 | or re-experiencing a trauma,

01:40:09.160 | memory and allowing that to just happen

01:40:13.160 | and re-seeing it again through a different light,

01:40:16.100 | it feels the same in the sense that that's allowing

01:40:20.120 | for whatever's going on with these psychedelic states

01:40:23.040 | to do whatever they do.

01:40:24.920 | - It's fascinating.

01:40:26.040 | You said exposure response therapy is the traditional name?

01:40:29.000 | - Closure response prevention.

01:40:30.400 | - Prevention therapy done outside of the psychedelic journey.

01:40:34.680 | - It's done outside the psychedelic journey,

01:40:36.320 | but that idea of letting go is present in both of those.

01:40:41.320 | Psychotherapy kind of straight up, totally sober,

01:40:45.240 | non-psychedelic, non anything,

01:40:48.120 | manualized that psychotherapy that we know

01:40:50.280 | works really well for OCD.

01:40:52.400 | And then in that psychedelic state.

01:40:54.840 | And so people have done studies with psilocybin

01:40:58.560 | and now there's some studies with MDMA

01:41:00.240 | trying to look at treating OCD

01:41:03.480 | with the same sort of idea of letting go, right?

01:41:08.080 | And how do you have an OCD patient kind of let go,

01:41:11.320 | maybe even letting go of not washing their hands anymore,

01:41:14.920 | kind of accepting the idea they're not going to get germs

01:41:18.160 | in their hands or whatever it is.

01:41:19.960 | And so it's kind of part and parcel

01:41:21.720 | that same sort of thinking.

01:41:23.760 | - When I was in college,

01:41:24.600 | I developed a compulsive superstition.

01:41:26.960 | I'm not afraid to admit this.

01:41:28.080 | I somehow developed a knock on wood superstition

01:41:31.960 | and I was actually kind of ashamed of it

01:41:35.640 | because it rationally made no sense.

01:41:38.400 | I don't consider myself a superstitious person,

01:41:40.540 | never was a superstitious kid.

01:41:42.820 | I'd step on the sidewalk cracks, I'd walk under ladders.

01:41:46.160 | You know, I'd probably even try to walk under a ladder

01:41:49.680 | even though I don't suggest it.

01:41:52.040 | But somehow I picked this thing up

01:41:53.880 | and I used to sneak it at times.

01:41:57.080 | I told my girlfriend at the time that I had it

01:41:58.580 | in hopes that that would prevent me from doing it.

01:42:01.520 | And it's tricky.

01:42:02.580 | Sometimes it actually comes back where I think,

01:42:04.280 | gosh, I didn't say, you know, knock on wood.

01:42:06.120 | I didn't knock on wood.

01:42:06.960 | I hope that doesn't actually happen.

01:42:08.520 | And it's quote unquote crazy, right?

01:42:11.360 | But crazy in the sense that it makes no sense rationally

01:42:14.400 | why the events would be linked.

01:42:16.240 | And yet I think a lot of people out there

01:42:17.640 | do have internal superstitions.

01:42:21.000 | Maybe by talking about it now, it'll go away.

01:42:23.800 | Clearly I just need to challenge it.

01:42:25.960 | You know, it's, anyway, I mentioned it

01:42:27.600 | because I concern myself, you know,

01:42:29.720 | generally rational person,

01:42:31.040 | but it's interesting how these motor patterns get activated

01:42:35.920 | and this notion of letting go

01:42:37.600 | because I don't actually know what consequence I fear.

01:42:41.360 | And the fear, as I was hearing the example you gave,

01:42:43.400 | you know, the fear of the car running,

01:42:44.600 | battery running down, I was about to say,

01:42:46.020 | well, what if the battery actually did run out?

01:42:47.960 | Then the therapy would be undermined.

01:42:49.740 | And yet that could also be interesting too

01:42:51.800 | because it's not that big of a deal.

01:42:53.040 | You jumped the car.

01:42:54.400 | But in my case, I need to think about

01:42:56.120 | what the ultimate fear is.

01:42:58.520 | - Yeah, and I, you know, I think a lot of people,

01:43:01.160 | so there's, it's interesting if you look at,

01:43:03.200 | say the OCD scale or the depression scale or whatever,

01:43:06.480 | we don't define normal as zero.

01:43:08.960 | We define normal as some number range above,

01:43:13.960 | so zero to, in the case of the Montgomery-Asburg

01:43:18.200 | Depression Rating Scale,

01:43:19.560 | one of the depression scales we use, 10, right?

01:43:22.400 | That's the normal range.

01:43:23.620 | And so people can have some sadness

01:43:26.240 | and still be considered normal.

01:43:27.720 | In the case of the OCD scale, it's about the same 10, right?

01:43:30.320 | Where we say it's kind of starts to be, you know,

01:43:33.940 | mildly abnormal or something.

01:43:36.040 | And I always, you know,

01:43:36.880 | I'd always tell the medical students,

01:43:38.180 | look, my friends that are surf instructors,

01:43:40.800 | they're more like a zero on the YBOC.

01:43:42.780 | People that are professionals, you know, they're non-zero,

01:43:46.240 | but it's still within the normal range.

01:43:48.800 | And especially, you know,

01:43:49.960 | in the case that you're talking about,

01:43:51.980 | it doesn't sound like it got in your way.

01:43:53.560 | It doesn't sound, I mean,

01:43:54.400 | you're obviously highly successful tenured professor

01:43:57.560 | at Stanford and do all the great things that you do.

01:44:01.800 | And so it's very much kind of within the normal range.

01:44:05.220 | And I think totally assumed that a lot of people

01:44:10.220 | have these sorts of things.

01:44:12.160 | And as long, I think something as a psychiatric diagnosis,

01:44:15.880 | when it severely impairs your ability to function,

01:44:19.440 | and that's when we kind of cross that threshold.

01:44:22.680 | But, you know, I think that a lot of people,

01:44:25.680 | and it's great that you're bringing this up.

01:44:27.000 | I mean, it's very anti-stigmatizing

01:44:28.720 | that you're bringing it up, right?

01:44:29.560 | Because I think a lot of people hold that stuff in

01:44:32.280 | and they don't want to talk about it

01:44:33.620 | because they're worried

01:44:35.320 | that somebody else may think something.

01:44:36.960 | But the reality is as a psychiatrist,

01:44:39.400 | I talk to a lot of patients,

01:44:41.400 | a lot of people that are, you know, family members,

01:44:43.840 | you know, folks that are just going through a death

01:44:46.920 | in the family, whatever it is.

01:44:48.480 | And what you figure out is like,

01:44:49.720 | everybody's got a little something here and there.

01:44:52.360 | Everybody has the knock in some way, if that makes sense.

01:44:55.180 | And it's just, and we're just all,

01:44:58.160 | we're all just kind of more predisposed

01:44:59.640 | not to talk about it.

01:45:00.600 | But I think it's important to talk about it

01:45:02.780 | because I think that when we start all talking about it,

01:45:05.320 | then we realize that we're all

01:45:07.100 | kind of in this together in a way.

01:45:09.120 | And that we're, and then some folks that, you know,

01:45:11.760 | have, you know, have to knock a hundred times,

01:45:14.880 | we call that OCD, you know, and they have all, you know,

01:45:18.520 | germ, they're worried about germs

01:45:19.760 | and all these other things, we call that OCD.

01:45:22.000 | And then in that circumstance, you know,

01:45:24.420 | they need treatment, right?

01:45:25.640 | But it is really on just like blood sugar,

01:45:28.360 | just like blood pressure, it's on a range, you know,

01:45:30.960 | and it's not just these discrete diagnoses,

01:45:33.040 | you have them or you don't.

01:45:34.740 | - It's good to know.

01:45:35.580 | I actually feel some relief just hearing this

01:45:37.920 | because I am slightly, I wouldn't say ashamed

01:45:40.720 | or sort of embarrassed by it, but I offer it as a,

01:45:43.640 | you know, that, you know, it is what it is, as they say.

01:45:48.140 | And it certainly doesn't seem to hinder my life

01:45:51.840 | much, knock on wood.

01:45:53.260 | So if we could talk a bit about ibogaine.

01:45:58.600 | I don't know much about ibogaine,

01:46:00.480 | although anytime I hear the, you know, A-I-N-E, you know,

01:46:03.240 | lidocaine, ibogaine, I think of an anesthetic

01:46:05.600 | and going to the dentist,

01:46:08.460 | which is an unpleasant experience for me, generally.

01:46:11.100 | What's, what is ibogaine?

01:46:14.640 | Does this have anything to do with the so-called toad?

01:46:19.360 | You know, people talk about smoking frog skin, toad skin.

01:46:22.400 | What is it used for clinically?

01:46:26.120 | Is it legal in the U.S. as a clinical tool?

01:46:29.560 | Who's using it and for what purposes?

01:46:33.380 | If you could educate me on ibogaine,

01:46:35.680 | I truly know nothing about it,

01:46:37.200 | except I think I know how to spell it correctly.

01:46:39.200 | - Yeah, that's fair.

01:46:40.520 | So ibogaine is one of the alkaloids

01:46:46.320 | that you can extract from a iboga tree root bark

01:46:51.320 | that's typically growing in the country of Gabon, Africa.

01:46:57.120 | So Gabon is one of the West African countries,

01:47:04.760 | kind of middle of Africa on the West coast.

01:47:09.120 | And Gabon is,

01:47:13.920 | has a group of folks called the Bawiti.

01:47:18.920 | It's a religious kind of sacramental group

01:47:23.480 | that sacramentally uses iboga root bark

01:47:28.480 | as part of that, this sacrament.

01:47:32.340 | And they've been using iboga root bark

01:47:36.160 | for a very long time and it's part of the tradition.

01:47:41.280 | There's a whole set of kind of ceremony around it.

01:47:46.120 | If you're interested in this,

01:47:47.140 | there's a book called Breaking Open the Head

01:47:49.100 | by Daniel Pinchbeck that goes through

01:47:51.800 | and talks about this whole process.

01:47:54.740 | But essentially, the Gabonese have been using this

01:47:58.080 | for a long time.

01:47:59.560 | And it's a kind of an atypical psychedelic.

01:48:03.860 | It's not a psychedelic that we normally think about

01:48:09.440 | with psilocybin and LSD where there are visual

01:48:11.680 | perceptual changes.

01:48:13.320 | So if you take psilocybin or LSD,

01:48:16.520 | what you experience is you experience

01:48:19.580 | these kind of visual perceptual differences

01:48:22.680 | in the external world.

01:48:24.440 | On enough LSD or psilocybin,

01:48:26.520 | an individual can actually perceive something

01:48:29.600 | visually in the external world that isn't there,

01:48:32.480 | as we talked about earlier.

01:48:33.840 | Ibogaine doesn't do that.

01:48:36.520 | Ibogaine does something different.

01:48:37.920 | It's kind of like, have you ever seen Minority Report

01:48:40.420 | with the movie with Tom Cruise,

01:48:41.980 | I think 15 or 20 years ago or something,

01:48:44.680 | so it dates us a little bit.

01:48:45.560 | But it was this movie where he would be able to go

01:48:49.640 | and see these kind of pre-crimes

01:48:51.380 | and he had this big screen where he could look at scenes

01:48:56.120 | from time and kind of go through that scene and see it.

01:49:00.160 | And so what individuals taking Ibogaine will say

01:49:03.600 | is that open eyes, they don't see anything,

01:49:06.200 | but closed eyes, they'll go back through

01:49:08.760 | and re-experience earlier life memories

01:49:13.120 | and they will be able to experience it

01:49:15.680 | from a place of empathy, not only for themselves,

01:49:20.680 | but from others and kind of a detached empathy

01:49:24.800 | and being able to see this as almost a third party,

01:49:28.240 | even though they were there,

01:49:30.240 | but they're able to see it as a third party.

01:49:32.640 | So Claudio Naranjo, a psychiatrist from Argentina,

01:49:36.080 | described this with a lot of books that he wrote

01:49:38.280 | in I think the '80s and '90s around this.

01:49:41.100 | And so Ibogaine's been around for a long time.

01:49:44.880 | Howard Lotsoff, American guy that brought it over

01:49:48.000 | from Africa, he was a polysubstance user,

01:49:50.760 | used every drug that he had his hands on,

01:49:54.560 | took Ibogaine, and including a lot of other psychedelics

01:49:57.400 | by the way, took Ibogaine and then never did another drug

01:49:59.560 | again supposedly because he had such a profound

01:50:02.560 | Ibogaine experience.

01:50:04.480 | Ibogaine is in no way a recreational substance.

01:50:07.600 | It's not a recreational substance

01:50:09.160 | if you want it to be a recreational substance

01:50:11.080 | because you're essentially having this

01:50:13.380 | what they call life review.

01:50:14.960 | They also call it 10 years of psychotherapy in a night.

01:50:17.600 | So these are the terminology that people talk about.

01:50:21.460 | The issue-- - How long does it last?

01:50:22.700 | Is it truly one night?

01:50:24.040 | - It's usually, you know, it can go,

01:50:26.340 | depending upon if you get re-dosed or anything go,

01:50:28.560 | sometimes depending upon how fast you metabolize it,

01:50:31.360 | sometimes 24, sometimes 36 hours,

01:50:33.680 | sometimes it can be shorter, but it is a long time.

01:50:37.120 | It's a very long time.

01:50:38.000 | So it's definitely the longest acting

01:50:40.920 | psychedelic substance I know of.

01:50:43.300 | And so people, you know, will take this

01:50:48.300 | and they'll have this reevaluation of a given memory

01:50:52.640 | and then as we were talking earlier,

01:50:54.140 | reconsolidate that memory again

01:50:56.280 | and then it seems to have, you know,

01:50:57.960 | an effect of that reconsolidation process.

01:51:00.500 | And so, you know, about four or five years ago,

01:51:04.720 | I was tapped by Robert Malinka,

01:51:06.860 | one of the, you know, senior neuroscientists

01:51:09.380 | we both know in the university.

01:51:10.820 | He says, well, there's an unnamed donor

01:51:13.680 | that's very interested in funding a group,

01:51:17.660 | you know, a scientific kind of open label study

01:51:21.460 | of these Navy SEALs that have been going down to Mexico

01:51:25.340 | and taking Ibogaine and also, and I'm five MEO DMT,

01:51:29.720 | which I'll talk about in a second, to treat PTSD.

01:51:33.500 | You know, they claimed to have traumatic brain injury,

01:51:36.920 | depression, you know, that whole constellation of symptoms.

01:51:40.320 | You know, and as it was described to me

01:51:42.860 | by various people that had done this,

01:51:45.280 | by their spouses and whatnot, you know, John,

01:51:49.440 | we'll just say John.

01:51:50.280 | John couldn't screw a light into a light bulb

01:51:53.900 | into a light fixture, right?

01:51:55.500 | They just, they were just so debilitated,

01:51:58.100 | they couldn't do, you know, simple tasks,

01:52:00.640 | what we call activities of daily living.

01:52:02.940 | And they were coming back and having these

01:52:04.620 | really dramatic improvements in, you know,

01:52:08.360 | all aspects of life.

01:52:10.800 | And so, you know, we have over the last couple of years

01:52:14.540 | been able to do this first in human

01:52:19.400 | kind of full neurobiological, clinical,

01:52:22.160 | neurocognitive evaluation of what Ibogaine is doing.

01:52:26.780 | In this case, in special operations, special forces,

01:52:30.800 | individuals, former Navy Seals, former Army Rangers,

01:52:33.640 | that kind of crew of folks,

01:52:35.500 | and look at the pre-post changes that we,

01:52:38.320 | that their experience to be able to totally

01:52:40.120 | quantitate all of that.

01:52:41.120 | And so we've been able to capture all the clinical scales,

01:52:44.480 | you know, depression scales, PTSD scales,

01:52:46.540 | all that standard stuff, neurocognitive batteries.

01:52:48.560 | So how does your executive function work specifically?

01:52:51.160 | How does your verbal memory, all of that?

01:52:53.640 | And then neuroimaging and EEG.

01:52:55.800 | So this will be the first human study of Ibogaine for those.

01:52:59.880 | And the reason why is because Ibogaine is kind of the,

01:53:03.700 | both seemingly the most potent and most,

01:53:06.740 | seemingly to me at least most powerful psychedelic,

01:53:13.080 | but the one that has the most risk too,

01:53:15.520 | because it has a cardiac effect.

01:53:17.400 | It seems to be that you can screen people out

01:53:19.480 | that have risk off of their electrocardiogram

01:53:22.180 | and reduce the risk quite a bit.

01:53:23.980 | And that's what we all did.

01:53:25.380 | But that's why people haven't really studied it as much.

01:53:29.260 | And it isn't as, in addition, there's no, right.

01:53:33.060 | Nobody goes to rave on Ibogaine.

01:53:34.480 | There's no recreation at all with it.

01:53:36.360 | - It's not fun.

01:53:37.700 | - It's, people say that it's relieving,

01:53:40.500 | but it's hard work, right?

01:53:42.540 | Because yeah, you're re-examining things.

01:53:45.800 | And, you know, and so then we see these folks after,

01:53:50.800 | and I'll tell you, you know,

01:53:52.040 | we haven't fully analyzed the data yet,

01:53:54.020 | but I'll tell you that, you know,

01:53:56.740 | from what my folks are telling me, it's pretty dramatic.

01:54:00.020 | You know, people come back and they're doing,

01:54:02.560 | they're doing a lot better.

01:54:03.740 | They're doing a lot better.

01:54:04.680 | And nobody, I'll knock on wood,

01:54:07.580 | nobody's had any sort of a cardiac issue at all in,

01:54:12.580 | you know, in the cohort that we've studied.

01:54:15.500 | And they look a lot better and they feel a lot better too.

01:54:20.340 | And they describe these experiences

01:54:22.600 | of being able to go back through.

01:54:24.000 | And, you know, soldiers experience

01:54:27.380 | something called moral injury, right?

01:54:28.960 | Where they, maybe they accidentally blew something up

01:54:32.240 | and it had a kid in it or something like that.

01:54:34.220 | You know, if they're in Afghanistan or Iraq,

01:54:36.960 | maybe a child died on accident,

01:54:39.100 | or maybe, you know, a civilian died or whatever it was,

01:54:42.480 | right, and they suffer these moral injuries

01:54:45.040 | as part of the job.

01:54:46.040 | And it's almost one of the kind of, you know,

01:54:47.940 | vocational risks.

01:54:49.400 | They come back and say that they've forgiven themselves,

01:54:53.460 | you know, which is huge, right?

01:54:55.500 | And part of that is being able to see themself

01:54:58.480 | in a different light and having empathy finally for themself

01:55:01.580 | and being able to kind of have that experience of forgiving.

01:55:05.240 | And so, very cool.

01:55:07.640 | The study, you know, what was happening

01:55:11.180 | was they were taking Ibogaine

01:55:12.320 | and then taking something called 5-MeO DMT,

01:55:14.480 | people call the toad.

01:55:15.460 | It's the Sonoran River toad, I think.

01:55:19.940 | It's like, you can find these in Mexico,

01:55:21.700 | find them in Arizona.

01:55:22.980 | In the back of the toad produces something called 5-MeO DMT,

01:55:28.900 | which is a, you know, flavor of DMT

01:55:32.980 | that produces a particular psychedelic effect,

01:55:35.940 | also used as a sacrament.

01:55:38.500 | - Is it a dimethyltryptamine?

01:55:40.540 | - It is a 5-MeO dimethyltryptamine.

01:55:44.420 | So it's a kind of dimethyltryptamine

01:55:46.140 | with a kind of addition to it.

01:55:47.740 | The deal there is that it lasts longer than traditional DMT.

01:55:52.740 | You know, it's like 20 minutes to five,

01:55:56.420 | three or whatever kind of thing.

01:55:58.540 | And so then, so these guys were taking Ibogaine

01:56:02.620 | and then they would take the 5-MeO DMT

01:56:04.660 | after we had to kind of divorce those two things,

01:56:07.780 | be able to do the study

01:56:08.600 | and just understand what Ibogaine was doing.

01:56:10.500 | And they go back down a month later

01:56:11.860 | and they'll do the 5-MeO DMT.

01:56:14.100 | - So two completely separate sessions.

01:56:16.300 | - Two completely separate sessions.

01:56:17.820 | - And then one quick question about Ibogaine

01:56:19.340 | before a bit more on 5-MeO DMT.

01:56:22.580 | Is the Ibogaine journey guided

01:56:25.080 | or the person just closes their eyes

01:56:26.700 | and they just start falling

01:56:27.940 | into the back catalog of memories?

01:56:30.060 | - They have a bunch of preparatory sessions

01:56:32.460 | and then they have a bunch of sessions after

01:56:34.260 | that they kind of, they're able to kind of rehash things.

01:56:37.500 | During, there's a sitter that sits there

01:56:39.700 | and kind of sits with them and helps them out,

01:56:43.300 | but it's not, it's pretty,

01:56:45.900 | the phenomenon of the drug seems

01:56:48.000 | to drive a lot of this, right?

01:56:49.860 | And so a lot of it ends up being

01:56:51.340 | what we call supportive psychotherapy,

01:56:52.820 | or just kind of being there and, you know,

01:56:55.180 | maybe you're holding the person's hand,

01:56:56.240 | maybe you're just saying I'm here or maybe whatever it is,

01:56:59.380 | but you're making sure they know you're around,

01:57:01.540 | but you're not really,

01:57:02.740 | there's not really an interaction per se.

01:57:05.180 | And then the whole kind of goal there is just to get,

01:57:08.100 | to get folks to kind of go back through

01:57:09.760 | and re-examine these memories

01:57:11.840 | and ultimately look like they reconsolidate them.

01:57:15.160 | And, you know, it's very interesting.

01:57:17.960 | I mean, there's this kind of, as you said earlier,

01:57:22.200 | Timothy Leary kind of socio-cultural construct

01:57:25.520 | that ends up being overlaid over psychedelics.

01:57:28.520 | And what I think is that if you rid yourself

01:57:33.520 | of all of those preconceived notions

01:57:36.000 | of what it is and isn't and the counterculture movement,

01:57:38.920 | all that stuff that neither of us were ever involved in,

01:57:41.280 | neither of us are ever partaken, you know,

01:57:43.800 | as kind of straight scientists looking at this, right?

01:57:46.240 | If you can kind of rid yourself

01:57:47.360 | of all those socio-cultural constructions

01:57:49.960 | and then re-examine this,

01:57:51.760 | these, if we just discovered these today,

01:57:54.720 | we would say that these sorts of drugs

01:57:58.000 | are a huge breakthrough in psychiatry

01:57:59.900 | because they allow for us to do

01:58:01.960 | a lot of the sorts of things we've been thinking about

01:58:04.520 | with SSRIs, with psychotherapy,

01:58:06.640 | but kind of combined, right?

01:58:09.080 | Psychotherapy plus drugs in a substance

01:58:13.680 | that kind of allows you to re-examine these things.

01:58:16.400 | And so it's interesting, you know,

01:58:18.860 | there's a lot to do to try to figure out if that's true,

01:58:22.080 | you know, and I can say that as it stands right now,

01:58:25.200 | we don't know if that statement is true, right?

01:58:28.520 | There's a lot more work that needs to happen

01:58:30.400 | for that statement to be proven to be true.

01:58:32.080 | But the hypothesis is if it is true,

01:58:35.880 | then it's very likely that this will be seen

01:58:39.520 | as a breakthrough because it allows you

01:58:41.920 | to do these sorts of things that you can't do

01:58:44.320 | with normal waking consciousness.

01:58:46.760 | But also why we have to really think about this

01:58:50.040 | and you know, these drugs can't be recreational drugs.

01:58:55.040 | They really shouldn't be recreational drugs, right?

01:58:58.580 | They're really too powerful to be used

01:59:01.760 | in the context of recreation

01:59:03.420 | because they can put you into these states.

01:59:06.380 | And this generation of psychedelic researchers

01:59:10.020 | are really clear about that.

01:59:11.900 | You know, I think the '60s folks were not clear about that

01:59:14.580 | and they felt like there was this whole kind of cultural

01:59:17.460 | thing that was going on there.

01:59:19.340 | But I think this cohort of individuals really understands

01:59:23.240 | that in order to really make this happen,

01:59:25.640 | we have to understand that if you need a prescription

01:59:29.020 | for an SSRI, which doesn't change your consciousness

01:59:32.640 | a whole lot and we're very worried about that

01:59:35.740 | and the doctor has to evaluate you for that every week,

01:59:38.620 | the idea that some of these substances would go outside

01:59:42.080 | of very strict medical supervision

01:59:44.540 | is kind of preposterous actually.

01:59:47.040 | It's kind of a dumb moment I think for all of medicine

01:59:51.220 | to say look, if we're gonna do this right,

01:59:53.860 | we've gotta do it in such a way that's so protected,

01:59:56.860 | that's so safe that we make sure people know

02:00:00.180 | these things are not recreational

02:00:02.060 | and they're really for the pure purposes

02:00:04.160 | of really powerfully changing cognition for a while

02:00:08.540 | and letting people have these,

02:00:10.440 | what seemed to be, you know, relatively therapeutic states.

02:00:14.020 | - I think it's great that you're doing this study

02:00:15.720 | and along the lines of the sort of the early iterations

02:00:19.260 | of psychedelics and the counterculture of the '60s and '70s,

02:00:22.360 | some of which took place like one flow of the cuckoo's nest

02:00:24.900 | I think is actually based on the Menlo Park VA,

02:00:28.900 | which is, you know, in our neighborhood of Stanford.

02:00:32.900 | And things are quite a bit different now.

02:00:34.700 | I know you and I have spent some time with the operators

02:00:38.180 | and former operators at an event and last Veterans Day.

02:00:41.080 | In fact, the so-called Veterans Solutions Group

02:00:43.820 | that's pioneering a lot of these psychedelic treatments

02:00:46.980 | for former special operators and current special operators.

02:00:49.340 | And what's interesting to me about that is in contrast

02:00:53.020 | to the counterculture movement of the '60s and '70s,

02:00:57.220 | that room was filled with people that are very much

02:00:59.520 | of a structure, the military, right?

02:01:01.720 | So it's no longer considered left-wing, right-wing,

02:01:05.460 | anti-military, pro-military.

02:01:06.940 | Here, this is just about one group of people

02:01:09.060 | who's exploring psychedelics as a treatment

02:01:10.900 | for trauma and PTSD and other things.

02:01:13.940 | And of course you also have other domains of society

02:01:16.380 | looking at this.

02:01:17.220 | And in fact, there were, it was really interesting

02:01:18.860 | because there were both far left and far right politicians

02:01:23.860 | at that event up on stage together

02:01:26.620 | talking about in kind of a lighter terms heart medicine,

02:01:30.260 | but also talking about neurobiology

02:01:31.940 | and it was just fascinating from the perspective

02:01:35.340 | of somebody who's trying to learn about this stuff

02:01:36.880 | that psychedelic therapies no longer sit

02:01:40.300 | within the anti-establishment realm.

02:01:43.300 | It's both, it's independent of all that.

02:01:47.620 | Certainly when people in the military are adopting it

02:01:49.580 | as a potential treatment.

02:01:51.100 | Again, still under exploration,

02:01:52.620 | but also under exploration at universities like Stanford

02:01:55.580 | and Johns Hopkins and UCSF and University College London

02:01:58.980 | and on and on.

02:02:00.580 | Along the lines of tree barks and toad skins,

02:02:03.140 | tell me about ayahuasca and as a plant, it's intriguing.

02:02:09.080 | And is it a pro-serotonergic drug like psilocybin?

02:02:14.600 | And is it useful for the same sorts of conditions

02:02:19.760 | that we've talked about thus far?

02:02:21.860 | And if you could perhaps tell me a little bit also

02:02:24.540 | about the Brazilian prisoner study.

02:02:26.700 | - Yeah, yeah, definitely.

02:02:28.580 | Ayahuasca is another psychedelic.

02:02:30.540 | It's used as a sacrament in Brazil and in Peru

02:02:35.540 | and Ecuador and Colombia.

02:02:38.160 | So a lot of the South American countries

02:02:41.020 | and what they do is they combine two plants together

02:02:46.020 | where one plant of the two plant combination

02:02:50.940 | would effectively do nothing,

02:02:53.220 | but the two plant combination together

02:02:55.900 | is capable of producing this very profound psychedelic effect

02:03:00.900 | and what's really kind of curious is that there are,

02:03:06.620 | as I understand it, 10 to 20,000 plant species in the Amazon

02:03:11.620 | and somehow somebody-- - Someone tried them all.

02:03:17.020 | - Combined these two plants together

02:03:19.440 | in certain proportionality and cooked this for five,

02:03:23.780 | 10 hours to the point where you cook out

02:03:26.660 | the dimethyltryptamine out of one of the plants

02:03:28.940 | and cook out the reversible monoamine oxidase inhibitor

02:03:32.900 | out of the other plant, it's such a way

02:03:35.500 | that the reversible monoamine oxidase inhibitor

02:03:38.900 | prevents the GI breakdown of the dimethyltryptamine

02:03:43.500 | in such a way that it's then allowed

02:03:45.260 | to cross the blood-brain barrier and get into the brain.

02:03:49.320 | And if you didn't add the reversible

02:03:51.540 | monoamine oxidase inhibitor plant-derived

02:03:54.580 | into this combination, then it would never cross the brain.

02:03:58.500 | If you put people on a standard psychiatry-prescribed

02:04:03.100 | monoamine oxidase inhibitor that wasn't reversible,

02:04:05.920 | you'd throw them into serotonin syndrome, right?

02:04:09.980 | So this kind of like sweet spot

02:04:13.340 | that somehow ayahuasca practitioners have found

02:04:17.020 | being able to get DMT into the brain from an oral source

02:04:21.440 | with this combination of a monoamine oxidase inhibitor

02:04:24.840 | is curious and so that substance has been explored

02:04:29.800 | as an antidepressant agent

02:04:31.540 | and some studies have looked at that.

02:04:33.860 | It also seems to be very safe.

02:04:35.900 | There was a psychiatrist down at UCLA Harbor

02:04:40.140 | who's done a lot of work with this

02:04:41.800 | where he's looked at children even that have been exposed

02:04:46.040 | to small doses of ayahuasca as a kind of a sacrament

02:04:49.660 | within Amazonian tribes and found no neurocognitive effects,

02:04:53.720 | no neurocognitive effects in adults.

02:04:56.160 | And so it appears to be safe.

02:04:59.240 | It's kind of part and brought into various religions,

02:05:05.000 | including kind of merged with Catholicism in South America,

02:05:08.480 | which is kind of very interesting.

02:05:10.220 | And so in some sects of Catholicism in Brazil,

02:05:15.220 | it's used as a sacrament during religious ceremonies.

02:05:20.220 | And so it became interesting to Brazilian researchers

02:05:25.300 | as to whether or not they could affect recidivism rates

02:05:28.440 | for prisoners in Brazilian prisons, right?

02:05:31.800 | So they gave half of the prisoners

02:05:34.340 | some sort of inert substance

02:05:37.680 | and half of the prisoners an ayahuasca session

02:05:41.940 | and the recidivism rate or the return to prison rate

02:05:45.820 | in the ayahuasca exposed individuals

02:05:47.920 | was statistically significantly lower

02:05:50.400 | than the recidivism rate in the control group,

02:05:53.560 | suggesting that whatever's going on there

02:05:58.040 | seems to have an effect on whatever drives criminal behavior

02:06:02.360 | or whatever criminal behavior that happened to be.

02:06:04.320 | And I don't have the details

02:06:06.060 | on the exact nature of the crime.

02:06:07.760 | I am also in no way saying

02:06:10.640 | that we should just be giving psychedelics

02:06:12.340 | to folks in prison and all of that.

02:06:15.000 | I think that that is a very edgy thing to do

02:06:18.740 | and probably not something that anybody should try,

02:06:21.320 | but it does kind of bring up this curious question

02:06:25.420 | of what is it about that that would drive people

02:06:28.520 | to change those behaviors

02:06:31.220 | and why do people make those behavioral decisions?

02:06:34.960 | And a lot of times,

02:06:36.780 | if you look at prisons in the United States,

02:06:40.360 | people say this,

02:06:41.200 | what's the biggest mental health facility

02:06:42.680 | in the United States?

02:06:44.000 | It's a prison.

02:06:44.820 | - Yeah, there's a lot to unpack there for sure.

02:06:49.460 | The homeless issue, the prison issue,

02:06:54.340 | it does lead to something that I heard recently,

02:06:58.040 | which is related to all this, which is cannabis.

02:07:01.860 | We hear a lot nowadays about people will say,

02:07:04.860 | well, it's safer than alcohol.

02:07:06.080 | And we did an episode on alcohol

02:07:07.440 | that at least by my read of the literature,

02:07:10.400 | indeed alcohol does seem to be quite bad for our health.

02:07:14.800 | I think it's pretty clear that not drinking

02:07:16.960 | is better for your health than drinking at all.

02:07:19.640 | And here, I'm not trying to tell people what to do,

02:07:21.280 | but those are what the data say

02:07:22.680 | and forget the studies on red wine.

02:07:24.400 | You'd have to drink so much red wine

02:07:25.680 | to get enough resveratrol.

02:07:26.880 | It's not even clear what resveratrol does anything useful

02:07:28.880 | anyway, et cetera, et cetera.

02:07:31.080 | Nonetheless, cannabis is now available

02:07:33.360 | in a lot of very high potency forms.

02:07:35.760 | People are vaping cannabis.

02:07:38.340 | People are smoking cannabis.

02:07:40.280 | I certainly am not saying that cannabis

02:07:42.120 | is bad for people necessarily,

02:07:43.840 | although I think children,

02:07:45.580 | I would like to hope that their brain development

02:07:47.640 | would be completed first, get to age 25.

02:07:50.200 | I know that sounds late for a lot of people,

02:07:52.840 | but the THC obviously taps into some endogenous systems

02:07:57.840 | and the cannabinoid systems and is powerful.

02:08:03.420 | And I've seen this report that was in Lancet Psychiatry

02:08:08.420 | this last year that said that early use of potent cannabis,

02:08:12.780 | meaning age 14 to 20 or so can potentially lead

02:08:17.320 | to an exacerbation of psychosis later in life.

02:08:20.620 | And I actually put this out on social media

02:08:22.840 | and it sort of exploded.

02:08:25.000 | I didn't expect it to.

02:08:26.720 | When people were saying, "Well, that's not causal."

02:08:28.240 | And obviously it's not causal because people say,

02:08:31.160 | "Well, maybe people with psychotic tendencies

02:08:33.940 | are seeking out cannabis."

02:08:35.140 | Although that's sort of a weak argument

02:08:36.740 | in the sense that there's at least a four times,

02:08:40.300 | four X increase in these psychotic episodes

02:08:44.380 | for people later in life.

02:08:45.560 | But what are your thoughts about cannabis?

02:08:46.760 | Because I do want to acknowledge

02:08:47.820 | that it does have medical benefits for certain things,

02:08:50.380 | pain, chemotherapy.

02:08:52.600 | So by no means trying to knock on cannabis

02:08:55.100 | and its appropriate medicinal use.

02:08:57.420 | But what should we think about cannabis

02:09:01.100 | in terms of this finding that can exacerbate a psychosis

02:09:05.380 | in certain individuals?

02:09:06.500 | - Yeah, so I think there's a couple of things, right?

02:09:10.860 | So cannabis is multiple cannabinoids, right?

02:09:14.400 | - THC, CBD, CBN, sativas, and indicas.

02:09:18.720 | Yeah, there's a lot there to unpack.

02:09:21.220 | - Yeah, there's a lot.

02:09:22.620 | But there are two main kind of chemicals you think about

02:09:26.840 | and kind of how things are essentially bred, right?

02:09:30.700 | And so there's a lot of cannabis

02:09:33.760 | that's really bred to be very high, very potent THC.

02:09:38.140 | And there's cannabis where the THC is bred completely out.

02:09:41.700 | So there's stories from Colorado, right,

02:09:46.340 | this strain of cannabis that's THC-free.

02:09:49.980 | There's no THC at all, and it's all CBD.

02:09:53.460 | And it's called Charlotte's Web.

02:09:56.040 | And a bunch of kids' parents, one kid,

02:09:59.940 | and then kind of a string of parents after that

02:10:01.820 | moved to Colorado when cannabis was legalized

02:10:05.460 | because CBD is anti-epileptic.

02:10:09.540 | So CBD is also antipsychotic.

02:10:13.580 | And so there've been a number of studies

02:10:15.180 | that if you give CBD at high doses,

02:10:18.400 | it's antipsychotic in schizophrenic,

02:10:21.500 | established schizophrenic patients.

02:10:24.580 | The issue is that we've bred CBD out of marijuana

02:10:28.220 | selectively over time.

02:10:29.500 | We've gotten very good at figuring out how to do that, right?

02:10:32.340 | Conversely, THC is propsychotic and pro-epileptic, right?

02:10:37.340 | And so when you talk about does cannabis cause psychosis

02:10:43.640 | or does cannabis treat psychosis,

02:10:46.340 | it appears to be more related to the proportions of CBD

02:10:50.900 | to THC than it does to the kind of idea of cannabis.

02:10:55.020 | So for me, there's a, and I have no stock in this

02:10:58.820 | or anything like that,

02:10:59.820 | but there's a company called GW Pharmaceuticals,

02:11:01.900 | and I haven't looked into them in a while,

02:11:03.380 | but they have a lot of clinical trials

02:11:07.360 | for something called Dravet syndrome,

02:11:09.260 | which is a seizure disorder where kids seize a whole lot.

02:11:12.020 | Lennox-Gastaut syndrome, which is a seizure disorder

02:11:15.220 | where kids are seizing 300 times a day.

02:11:16.860 | Both of these are like kids are seizing so much,

02:11:19.220 | they're basically in a seizure

02:11:20.820 | or in the post-ictal phase constantly.

02:11:23.940 | And they've failed everything.

02:11:25.700 | They've failed barbiturates, they've failed bromides,

02:11:28.660 | which we just don't use anymore except in these cases

02:11:32.700 | because of the side effects.

02:11:34.060 | And they'll give kids CBD.

02:11:35.520 | And I think CBD is a pretty safe drug

02:11:37.480 | compared to bromide, right?

02:11:39.140 | And so this idea that CBD in a kid is actually safe.

02:11:44.140 | It's a cannabinoid, but it's CBD and it's safe, right?

02:11:48.860 | And so that to me is totally fine.

02:11:52.400 | Also giving CBD as an adjunct of treatment

02:11:55.860 | for schizophrenia, there've been some positive trials

02:11:58.980 | and negative trials in that,

02:11:59.860 | but there seems to be no negative side effects.

02:12:01.780 | It seems to reduce some of the metabolic syndrome issues

02:12:04.880 | in folks with schizophrenia who are having side effects

02:12:08.080 | from the primary antipsychotic.

02:12:09.880 | The converse is there's clearly cases

02:12:13.380 | where people that are taking very high doses of THC

02:12:17.180 | become psychotic, they get put into the psychiatric unit,

02:12:21.040 | nothing happens other than they kind of get the THC

02:12:24.440 | out of their system and then they resolve their psychosis.

02:12:27.980 | And a handful of people who've had seizures related

02:12:34.720 | to high doses of THC and syncope and all sorts of things.

02:12:38.380 | And so this idea that THC, high doses of THC

02:12:43.260 | can be propsychotic is also not taking a shot at people

02:12:46.900 | that think that cannabis overall is a good thing.

02:12:49.860 | It just is what it is.

02:12:52.000 | And the kind of pure, I think if you zoom back

02:12:54.540 | and you say, you're a true naturalist,

02:12:56.860 | you're thinking about natural medicines in the world,

02:12:59.420 | you should think, well, probably marijuana was balanced

02:13:02.700 | THC, CBD at some point and then we humans messed with it.

02:13:06.860 | And that most likely that was probably okay at some level

02:13:11.860 | and then we pushed it one way or another.

02:13:16.100 | And what I mean by okay is in a 45 year old,

02:13:19.380 | it's okay kind of thing.

02:13:21.840 | Now, what I think is going on with the kids,

02:13:26.360 | with the teenagers is you've got prefrontal maturation,

02:13:29.500 | and then you're exposing them to a whole lot

02:13:31.880 | of high THC load.

02:13:35.340 | And while it's unclear if it's cause or effect,

02:13:40.340 | it's certainly in the picture.

02:13:42.120 | And if I were a parent,

02:13:43.660 | I wouldn't want my 16 year old smoking marijuana.

02:13:46.800 | If I were a parent in my 30 year old,

02:13:49.560 | otherwise healthy, totally fine, whatever,

02:13:54.560 | banker, lawyer, kid decided to try marijuana

02:13:58.860 | for the first time, I wouldn't scold them about it, right?

02:14:01.860 | So I think it's kind of a different thing, right?

02:14:03.860 | I would never want my up to 25 year old,

02:14:07.360 | just like you're saying before prefrontal maturation

02:14:09.780 | of never want my kid to be exposed at all.

02:14:13.340 | But it looks like except in susceptible individuals

02:14:17.980 | that are susceptible to drug induced psychosis,

02:14:19.940 | it looks like it's a relatively safe thing

02:14:24.940 | past prefrontal maturation.

02:14:27.040 | Again, I'm not gonna comment of cause and effect,

02:14:31.260 | but I would say that if you're a parent,

02:14:35.980 | it doesn't make much sense, right?

02:14:37.700 | You never know what's ultimately gonna hurt your kid.

02:14:40.700 | I mean, we were talking about this earlier,

02:14:42.580 | my wife's pregnant now, she kind of avoids everything,

02:14:45.800 | right, rightfully so, right, this idea that we just,

02:14:48.980 | we wanna be careful when our children's brains

02:14:51.180 | are developing and I think that's really

02:14:52.760 | what you were saying and I think actually important.

02:14:55.560 | The bigger question that you asked,

02:14:57.640 | which is relative risks of drugs is an interesting one.

02:15:01.220 | So David Nutt published in, I think it was in the Lancet,

02:15:04.100 | I'll have to look it up, but I think in the Lancet,

02:15:06.260 | an article about relative drug risks

02:15:09.500 | for the person and for society.

02:15:11.180 | And this was like, he was on the UK's like British

02:15:16.180 | drug policy group where essentially what he showed

02:15:21.920 | was if you look at societal risk plus personal risk

02:15:26.920 | and you combine those two, you know what drug

02:15:29.760 | is the most dangerous drug in the world?

02:15:32.440 | - I'm gonna guess it's alcohol.

02:15:33.680 | - It's alcohol, right behind heroin and cocaine

02:15:37.080 | and duh, duh, duh, duh, duh and somewhere in the middle

02:15:38.600 | is marijuana and right on the tail end on the other,

02:15:41.480 | on the exact other end of this, psilocybin.

02:15:45.880 | - Is caffeine, it usually doesn't make the list.

02:15:49.740 | - I may have been on the list, if it was,

02:15:52.140 | it was probably pretty close to psilocybin,

02:15:54.000 | but somewhere in the middle was ketamine,

02:15:56.020 | somewhere in the middle was amphetamine,

02:15:58.860 | somewhere in the, you know, a little closer to psilocybin,

02:16:01.180 | I think it was MDMA, you know, but it's this combined

02:16:06.040 | personal, you know, kind of world risk of these things

02:16:09.960 | and so alcohol makes it because there's a huge amount

02:16:13.720 | of personal risk and there's a huge amount of societal risk,

02:16:16.960 | right, drunk drivers kill X amount of kids,

02:16:19.600 | you know, people in the world.

02:16:20.880 | - Fight sexual assault.

02:16:22.680 | - All that. - All that.

02:16:23.800 | - Yeah and then all the cancer and all that stuff

02:16:27.080 | and so it beats out cocaine, it beats out heroin,

02:16:29.760 | it beats out all of these things and yet we don't,

02:16:34.960 | we don't as a culture, for whatever reason,

02:16:37.420 | we don't as a culture see it as a drug

02:16:41.400 | and that's the part that really baffles me, you know?

02:16:44.600 | - I mean, they serve it, I mean,

02:16:45.780 | this is no knock on Stanford at all,

02:16:48.240 | of course I wouldn't do that,

02:16:49.200 | this is at every institution I've been to,

02:16:50.920 | they serve alcohol at the graduate student events.

02:16:54.160 | - That's right.

02:16:55.440 | - They serve alcohol, they do a happy hour.

02:16:58.600 | I've never been a drinker, I can take it or leave it, so,

02:17:01.660 | and I realized that some people, they really enjoy alcohol,

02:17:05.020 | you know, my former partner, I mean,

02:17:06.860 | she just was in that, you know,

02:17:08.660 | 10% or so of people who have a glass of wine

02:17:11.120 | and just feel great and the second one feel great,

02:17:14.060 | I just want to take a nap after I have a bit of alcohol,

02:17:17.020 | so it never does much for me, I always feel poisoned,

02:17:19.460 | I feel lucky in that sense, but it's unbelievable

02:17:23.420 | that it is so prevalent and it's just,

02:17:26.320 | it's baked into the medical, even medical institutions,

02:17:29.460 | they'll pop a bottle of champagne to celebrate the opening

02:17:31.940 | of a hospital. - That's right, that's right.

02:17:34.300 | - It's pretty crazy.

02:17:35.340 | - Yeah, no, you're absolutely right, you know,

02:17:36.860 | I think what's gonna happen, but this is me, you know,

02:17:40.760 | looking at the crystal ball a little bit,

02:17:42.180 | but I think what's gonna happen

02:17:43.820 | is what happened with doctors and smoking,

02:17:45.420 | so if you look at the '50s and '60s, right,

02:17:47.020 | there are all these pictures of doctors smoking cigarettes,

02:17:49.780 | you know, with patients, there's, you know,

02:17:51.980 | psychiatrists doing psychotherapy and smoking a cigarette

02:17:54.340 | with the patients sitting on the couch, you know,

02:17:56.140 | surgeons smoking a cigarette in between cases,

02:17:58.860 | there are all these pictures of that, right,

02:18:00.500 | and now all of a sudden smoking's totally banned,

02:18:02.700 | I think it's totally banned from most of Stanford campus.

02:18:05.920 | My suspicion is, as you're suggesting, right,

02:18:09.120 | you know, this is everywhere and it's all kind of ubiquitous,

02:18:11.940 | it's some critical point, some tipping point,

02:18:14.580 | everybody's gonna realize that just like with smoking,

02:18:19.260 | we've got a rid, hospital systems and universities

02:18:22.940 | of alcohol, and at some point in 50 years,

02:18:27.820 | it's my view that we'll look back at these scenarios

02:18:31.420 | that you're talking about and be like, you know what,

02:18:34.820 | we were foolish about this, we can't believe

02:18:38.540 | that we gave people alcohol on the way, you know,

02:18:41.380 | when they graduated from whatever, you know,

02:18:43.540 | and I think we'll have a different take on it,

02:18:45.780 | but it's gonna take a longer time.

02:18:47.780 | I think people did a really good job

02:18:50.820 | tying smoking to lung cancer,

02:18:52.400 | and it's like a very simplistic story,

02:18:54.940 | smoking, lung cancer, you know.

02:18:57.860 | Now, as you know, alcohol increases the risk

02:19:01.340 | of a lot of different cancers, not so clear which one,

02:19:04.460 | I mean, there's like, you know, the kind of oral,

02:19:06.180 | like the throat, tongue cancer,

02:19:07.580 | that's one of-- - Breast cancer.

02:19:08.780 | - Yeah, breast cancer, you know, and so it's kind of,

02:19:12.220 | it's a harder story to tell, you know,

02:19:14.580 | and I think that's why, and everybody, you know,

02:19:17.620 | and then there's this whole, it's, you know,

02:19:19.100 | my mom says this, it's like, I drank my glass of wine

02:19:22.060 | because my doctor told me it was heart healthy,

02:19:24.980 | and we were talking about this, and I try to,

02:19:26.980 | no, no, no, but Dr. So-and-so said it's heart healthy,

02:19:30.340 | and so it ends up being this thing where, like,

02:19:32.820 | she's drinking alcohol because she thinks

02:19:34.780 | that it's good for her heart,

02:19:37.340 | and, you know, and it's hard,

02:19:39.460 | I've had those conversations with her,

02:19:40.940 | it's hard to untie that, and I think that, yeah,

02:19:44.500 | at some point, we're gonna hit some threshold moment,

02:19:48.340 | and it'll be interesting if we really look at the data

02:19:50.460 | and we really look at what's safe and not safe

02:19:52.420 | from purely from this analysis,

02:19:54.980 | it kind of, it kind of points to the right direction.

02:19:58.340 | - That's really interesting, and also saying nothing

02:19:59.940 | of poor judgment under the influence of alcohol.

02:20:02.900 | I mean, I would venture that if we were to remove alcohol

02:20:06.460 | from university campuses, watch the students

02:20:09.140 | are gonna lobby against me if I say this,

02:20:10.660 | but if you were to remove alcohol from campuses,

02:20:14.140 | I mean, just think about the,

02:20:16.100 | what I suspect would be the improvement

02:20:18.100 | in good decision-making and that would occur,

02:20:23.100 | or, you know, I've got stories from graduate school

02:20:26.340 | and it was very different, you know, 10 years ago,

02:20:30.300 | there was a lot more alcohol consumption,

02:20:32.360 | again, that was never my thing,

02:20:33.420 | but I know people who made really bad decisions.

02:20:36.180 | In any case, there's a whole landscape there emerging,

02:20:40.060 | I think you've got your finger right on the pulse of it.

02:20:42.580 | I want to touch on something slightly different

02:20:44.940 | than what we've been talking about,

02:20:45.900 | but definitely related to depression,

02:20:47.620 | and this is, again, is one of these intriguing

02:20:49.420 | but perplexing things, which is that sleep deprivation

02:20:53.380 | can improve symptoms of depression,

02:20:56.980 | and yet I'm personally very familiar with the fact

02:21:00.080 | that if I don't sleep well for one night,

02:21:02.380 | or don't sleep at all, in fact,

02:21:04.180 | I do have an ability to function pretty well the next day,

02:21:06.640 | I'll do this non-sleep deep rest practice

02:21:08.500 | that I blab a lot about on the Huberman Lab Podcast,

02:21:10.860 | which for me is tremendously restorative,

02:21:12.720 | but I like a good night's sleep,

02:21:15.020 | I think everybody understands now,

02:21:18.140 | thanks to the great work of Matthew Walker and others,

02:21:20.400 | they've really gotten out into the world saying,

02:21:22.500 | "Look, the foundation of mental health, physical health,

02:21:25.580 | and high performance, if that's your thing,

02:21:27.860 | being a functional human being,

02:21:28.980 | is to try and get enough quality deep sleep

02:21:32.620 | at least 80% of the nights of your life, if you can."

02:21:35.980 | That's something to focus on, just like good nutrition,

02:21:38.640 | just like exercise and social connection, et cetera.

02:21:42.100 | So sleep deprivation we know can in particular,

02:21:45.240 | I think rapid eye movement components of sleep deprivation

02:21:48.340 | can improve the symptoms of depression,

02:21:51.020 | and yet being sleep deprived

02:21:54.140 | can also really dysregulate our control

02:21:56.540 | of the autonomic system.

02:21:57.540 | I notice on night two or night three of poor sleep,

02:21:59.700 | if I'm going through a stressful phase and that's happening,

02:22:02.560 | all of a sudden my heart rate is chronically elevated,

02:22:05.380 | my thought patterns become really disrupted,

02:22:07.460 | I can't then exercise, my decision-making is thrown off,

02:22:11.260 | my emotionality is more labeled,

02:22:12.700 | the hinge as we were referring to it earlier,

02:22:14.980 | feels less in control, under my control,

02:22:18.180 | and maybe I wonder sometimes if I enter that state

02:22:21.360 | that you referred to earlier,

02:22:22.240 | where the dorsolateral prefrontal cortex

02:22:24.300 | is no longer leading the cingulate,

02:22:25.960 | but the cingulate is now in charge,

02:22:27.660 | the players are in charge of the coach.

02:22:30.180 | Not a good situation.

02:22:31.700 | So I know you've done some work on sleep deprivation

02:22:34.460 | and light and effects, please tell us about that,

02:22:38.120 | and please tell us about this triple therapy.

02:22:40.900 | - Yeah, yeah, so friend of mine, Greg Salem,

02:22:44.220 | another one of the professors at Stanford,

02:22:46.860 | is very interested in sleep.

02:22:49.180 | He did a bunch of training in sleep

02:22:51.980 | before he went to medical school

02:22:53.300 | and got very interested in this idea that,

02:22:57.100 | as you're saying, if you sleep deprive somebody one night

02:23:01.740 | in just kind of an isolated single night,

02:23:04.100 | at the end of that sleep deprivation

02:23:06.220 | they will have an antidepressant effect,

02:23:07.980 | but as soon as they fall asleep, they lose it.

02:23:10.480 | So if it's a depressed individual,

02:23:13.060 | you can get them to be less depressed acutely.

02:23:16.200 | Soon as they fall asleep, they wake up eight hours later,

02:23:19.040 | then they come back into the same level of depression.

02:23:22.420 | And so the idea was that you needed to do

02:23:24.740 | some sort of circadian reset,

02:23:26.580 | and part of what depression is

02:23:29.460 | is that it's a dysregulated circadian system.

02:23:32.140 | And so mentors of mine say,

02:23:33.960 | if you can just get the sleep better,

02:23:35.820 | that's half the battle of dealing with depression,

02:23:37.820 | 'cause so many people have insomnia around depression

02:23:41.080 | and have a whole host of types of insomnia,

02:23:43.400 | having a hard time falling asleep,

02:23:45.600 | waking up in the middle of the night and waking up earlier,

02:23:47.680 | all symptoms of depression.

02:23:50.180 | And so what this does is it sleep deprives the individual

02:23:55.160 | and then there's a certain calculation

02:23:57.100 | of shifting their phase

02:23:59.460 | and simultaneously exposing them to bright light.

02:24:02.680 | So that's the triple, the phase shift,

02:24:05.080 | the sleep deprivation and the bright light

02:24:07.280 | to try to get their circadian rhythm.

02:24:10.660 | Essentially, the theory is re-entrained.

02:24:14.080 | And so in the trials that we've done and other trials

02:24:19.080 | prior to ours and after,

02:24:22.400 | it looked like there was a pretty profound

02:24:24.640 | antidepressant effect from this triple therapy

02:24:29.120 | that seemed to be durable,

02:24:30.460 | meaning durability is this term we use to say

02:24:33.800 | that not only can you get kind of point relief,

02:24:36.280 | but that the relief ends up lasting.

02:24:39.440 | What's important to know about this is like,

02:24:41.680 | you shouldn't do this at home for sure.

02:24:44.000 | This is what you would need to do this with a professional

02:24:45.840 | 'cause it's complicated, it's not just one thing.

02:24:48.560 | And in sleep deprivation,

02:24:51.240 | while it seems to be antidepressant, it's pro-anxiety.

02:24:54.900 | So if you take a highly anxious person that's not depressed

02:24:56.960 | and you sleep deprive them, they get profoundly anxious.

02:24:59.920 | And so that's the other thing

02:25:01.120 | that you have to really realize is that this is,

02:25:04.000 | like everything else that I've talked about today,

02:25:06.040 | all things that you have to do under medical supervision,

02:25:09.560 | but curious, right?

02:25:11.240 | And I think the question that always comes up

02:25:14.280 | is why isn't this used more?

02:25:16.240 | And I think the reason is that there's not really

02:25:19.260 | a mechanism for,

02:25:21.480 | ultimately in medicine, as sad as it is,

02:25:23.920 | you have to have a code to do a thing.

02:25:26.060 | There has to be a code associated with a treatment

02:25:29.040 | and it's hard to figure out how to make a code for this.

02:25:32.040 | And so I think that's part of it.

02:25:33.680 | And so if there's a way,

02:25:36.560 | and somebody's gotta kinda take that baton on that,

02:25:39.580 | but if there's a way to make a code for this,

02:25:41.900 | I think you could actually turn it into something

02:25:45.960 | that was more widely utilized.

02:25:48.360 | And we probably dream up ways of how to integrate AI,

02:25:53.360 | passive sensing, all that stuff to really make that work.

02:25:57.640 | But I think that would be the idea,

02:26:00.320 | that would be the trajectory I'd see, so yeah.

02:26:02.480 | - Yeah, having a billable to insurance code is fundamental.

02:26:07.040 | And a lot of listeners to this podcast, I think,

02:26:09.760 | have a background in engineering science.

02:26:11.580 | And we will put a link to that manuscript

02:26:14.040 | that talks about the triple therapy,

02:26:15.180 | because here we're talking about

02:26:16.440 | one night sleep deprivation,

02:26:17.620 | some timed light exposure to the eyes,

02:26:20.280 | and then shifting in the circadian clock,

02:26:22.380 | things central to the themes of this podcast

02:26:24.880 | that come up often.

02:26:26.440 | I think for the typical person,

02:26:28.320 | can we say that trying to get a regular light-dark cycle

02:26:32.720 | and sleep rhythm would be beneficial

02:26:34.160 | for overall mood regulation?

02:26:36.000 | - Yeah, I think for the typical person,

02:26:38.680 | really kind of re-regulating your sleep

02:26:42.680 | and trying to get a good night's sleep

02:26:45.000 | in which you fall asleep, stay asleep, wake up,

02:26:48.060 | and a set time every morning is gonna be pretty crucial.

02:26:52.260 | In mild depression, I think that one has

02:26:56.380 | a lot of control over that.

02:26:57.600 | As we were talking about earlier,

02:26:58.600 | I think when you hit some threshold in depression

02:27:00.680 | where things become kind of semi-volitional,

02:27:02.520 | it's harder to kind of will yourself into that.

02:27:06.120 | There are therapies like,

02:27:07.540 | there's a CBT for insomnia, for instance,

02:27:11.160 | where you can do cognitive behavioral therapy

02:27:12.840 | to help with insomnia.

02:27:14.440 | Sometimes people, and I'm no sleep expert,

02:27:17.200 | that I'd kind of pass this to Greg to fully talk about this,

02:27:19.920 | but some of what goes on that people

02:27:24.280 | with kind of milder insomnia experience

02:27:26.960 | is like blue light out of their computer

02:27:29.340 | and things like that that they,

02:27:30.840 | so you can use like blue light blockers to,

02:27:33.680 | it tricks your brain, as you know better than me,

02:27:36.240 | it tricks your brain to think that it's still light outside

02:27:38.900 | and so people will, they'll have insomnia

02:27:41.560 | because their brain still thinks that it's light outside

02:27:44.520 | and then people will kind of strip CBT for sleep.

02:27:49.520 | Therapists will say there are only two things

02:27:54.840 | that you should do in your bed

02:27:56.520 | and if you're under a certain age and whatnot,

02:27:59.640 | it's really one thing that you should do in your bed,

02:28:01.800 | which is to sleep and be with your partner, right?

02:28:05.800 | And so those are kind of the two things

02:28:10.000 | that you should do in a bedroom

02:28:11.080 | and that's really the only things

02:28:12.440 | that you should do in a bedroom

02:28:13.380 | if you're having sleep problems.

02:28:14.920 | You shouldn't watch TV in a bedroom,

02:28:16.240 | you shouldn't eat in a bedroom,

02:28:17.160 | you shouldn't hang out.

02:28:18.280 | - Keep the phone out of the bedroom.

02:28:19.300 | - Keep the phone out of the bedroom, yeah.

02:28:21.080 | - Yeah, we should get Greg Salem on the podcast.

02:28:24.700 | I'll just mention for people

02:28:25.540 | that want to regulate their sleep,

02:28:26.580 | we have a sleep toolkit that's available

02:28:29.640 | as a downloadable PDF at hubermanlab.com.

02:28:31.860 | Just go to the menu and a lot of the things

02:28:33.380 | in that toolkit are based on work

02:28:35.500 | from Stanford sleep laboratories,

02:28:37.060 | including Jamie Zeitzers and others lab,

02:28:39.720 | not aimed at depression specifically.

02:28:41.640 | Listen, Nolan, Dr. Williams,

02:28:48.140 | this has been an amazing voyage

02:28:50.780 | through the circuitry of autonomic control.

02:28:53.620 | This landscape of the prefrontal cortex

02:28:55.460 | is I find incredibly fascinating

02:28:58.620 | and I just want to start off by saying,

02:29:01.020 | please do come back again

02:29:02.700 | and teach us more about that and your TMS work.

02:29:06.860 | Before we wrap, however,

02:29:08.760 | I do want to give you the opportunity

02:29:10.460 | to talk about the SAINT study.

02:29:12.620 | Is it SAINT or saints plural?

02:29:14.320 | - Yeah, it's SAINT.

02:29:15.500 | So SAINT or what we're calling it S-N-T now,

02:29:19.760 | SAINT has, you know, the intent was not

02:29:22.520 | to kind of connect it to religion,

02:29:24.760 | but we may have accidentally done so

02:29:28.320 | and so we abbreviated it to S-N-T for the subsequent trials,

02:29:33.000 | which was initially Stanford accelerated

02:29:35.820 | intelligent neuromodulation therapy

02:29:37.760 | or now what we're calling Stanford neuromodulation therapy,

02:29:39.980 | but the idea there, which is a cool idea,

02:29:43.760 | is that TMS is a device that delivers a treatment

02:29:48.760 | and the treatment is the protocol

02:29:54.520 | and the protocol is the stimulation parameter set

02:29:59.180 | in a specific brain region for a specific condition.

02:30:03.220 | And so what's cool about neuromodulation,

02:30:05.540 | whether it be transcranial magnetic stimulation

02:30:08.180 | or transcranial direct current stimulation

02:30:09.940 | or deep brain stimulation,

02:30:11.100 | like what Casey Halpern talked about, you know,

02:30:13.620 | on another podcast is this idea that in all of those cases,

02:30:18.620 | the device itself is a physical layer conduit

02:30:23.180 | of a stimulation protocol that's therapeutic

02:30:26.860 | for a given condition in a given brain region.

02:30:29.420 | And so in the case of depression,

02:30:31.060 | which we know the most about with TMS,

02:30:33.440 | we've been doing TMS studies for depression

02:30:35.980 | for, you know, since 1995, right,

02:30:39.180 | in the clearance in 2008, 2009.

02:30:43.340 | And in that timeframe, we were able to go

02:30:47.200 | from really knowing very little at all

02:30:50.340 | about how to do something like this

02:30:51.900 | to getting an FDA clearance.

02:30:53.740 | And the way that it went down was that

02:30:56.740 | there were two groups studying different components at NIH.

02:31:01.540 | The first group was studying mood neuroanatomy

02:31:05.520 | on functional imaging that was kind of the first generation

02:31:08.180 | of functional imaging back then.

02:31:09.460 | So PET scans, which are kind of metabolic scans

02:31:13.940 | and then SPECT scans.

02:31:16.340 | And the idea there was looking at activity

02:31:18.620 | and metabolism in prefrontal cortex.

02:31:21.020 | And what they found in these kind of more crude scans

02:31:24.220 | is a just general hypo activity, hypometabolism.

02:31:28.300 | The other group right upstairs at the National Institute

02:31:31.200 | for Neurological Diseases and Stroke, NINDS,

02:31:34.660 | they were looking at using TMS,

02:31:36.780 | which had been around for 10 years

02:31:38.180 | and repetitively stimulating in motor cortex.

02:31:41.860 | What they found was, gosh, we can get a readout

02:31:45.020 | in thumb muscle movement amplitude

02:31:49.200 | that's really reproducible across people.

02:31:51.500 | It's like universally reproducible.

02:31:54.780 | And if we do certain stimulation approaches,

02:31:57.480 | they are biologically active

02:31:59.100 | to either increase excitability, i.e. the thumb motion

02:32:02.740 | and a set intensity goes up,

02:32:05.140 | the amount of amplitude goes up,

02:32:06.820 | or inhibitory depotentiating goes down

02:32:09.900 | with other biological stimulation approaches.

02:32:12.480 | Then a third outcome, which is important,

02:32:14.540 | that it's inert, it doesn't do either.

02:32:16.140 | So you can have stimulation approaches that do one,

02:32:19.640 | increase activity, decrease activity, or are inert.

02:32:24.260 | And so what they found was,

02:32:25.760 | oh, we can excite certain brain regions.

02:32:28.000 | And my mentor, Mark George, had this kind of aha moment

02:32:31.480 | where he said, wow, there's underactivity

02:32:34.840 | in prefrontal cortex in depression,

02:32:37.440 | and we can increase activity using this thing

02:32:39.920 | that we know that we can increase activity in motor cortex.

02:32:41.980 | We just need to put it

02:32:43.160 | in the left-or-salateral prefrontal cortex.

02:32:45.800 | And then they combined the two

02:32:48.680 | and started stimulating once a day

02:32:51.140 | in this kind of very abbreviated fashion.

02:32:53.560 | And lo and behold, some of those depression patients

02:32:57.460 | resolved their depression.

02:32:58.540 | And back then, and still today,

02:33:00.380 | you can go and as a psychiatric patient,

02:33:02.140 | stay at the National Institute of Mental Health

02:33:04.640 | and go through clinical trials to try to get treated.

02:33:07.280 | And there were patients who'd been there for months

02:33:09.540 | and they were able to be discharged

02:33:11.360 | because their mood was better. - Incredible.

02:33:12.320 | - Yeah.

02:33:13.160 | And so it was just this very crude approach

02:33:15.520 | where they were using ruler measurements

02:33:17.200 | of where DLPFC was, and they were stimulating with devices

02:33:20.520 | that you needed to physically dunk the coil in an ice bath.

02:33:23.920 | And with that, they still were able to,

02:33:25.960 | the kind of genius of this, Mark and others,

02:33:27.800 | they'll still be able to create

02:33:30.780 | a purely engineered stimulation approach.

02:33:34.980 | What's cool about that is that they kind of

02:33:39.040 | found two things, right?

02:33:40.200 | They found this one stimulation protocol

02:33:42.320 | that does have some antidepressant effect.

02:33:44.040 | It's limited, it doesn't treat everybody.

02:33:46.240 | It does have some antidepressant effect.

02:33:48.180 | And this bigger concept that a neuromodulation device

02:33:52.200 | is kind of like a pharmaceutical company for you, right?

02:33:56.600 | That in a given individual, a TMS device

02:33:59.840 | or whatever neuromodulation device is able to generate,

02:34:03.600 | you can create a stimulation approach

02:34:06.240 | that is specific to a given condition

02:34:09.620 | and specific to an individual.

02:34:11.880 | And so the physical layer is just how you exert that.

02:34:16.020 | Similarly to how we make pharmaceutical drugs

02:34:18.760 | in a pharmaceutical company,

02:34:20.280 | but the actual therapy itself is what you do,

02:34:22.840 | where you do it.

02:34:24.280 | And so what we learned from another 20, 30 years of this

02:34:28.920 | is that you can modify the stimulation protocol

02:34:32.640 | in such a way where you can create a whole new treatment

02:34:35.640 | and put it through the same TMS device,

02:34:37.920 | or thank God, an evolved version of it

02:34:40.820 | where you don't have to dunk it in ice baths

02:34:42.460 | and they can actually really handle

02:34:44.660 | much more aggressive stimulation approaches.

02:34:47.540 | And so in 2005, a group published a neuron,

02:34:51.440 | a paper demonstrating that if you stimulate

02:34:55.080 | with the hippocampal rhythms through a TMS coil,

02:34:59.460 | you can excite the brain with memory rhythms

02:35:03.680 | and it'll last an hour.

02:35:05.800 | So you can change cortical excitability

02:35:07.580 | in this thumb twitch for an hour, sending three minutes

02:35:11.160 | of excitatory or 40 seconds in the case

02:35:13.660 | of inhibitory stimulation that mimics the hippocampal rhythms.

02:35:17.140 | So much more efficient than the original TMS approaches.

02:35:20.980 | And so after that, a group tried to do it

02:35:23.900 | in this kind of six-week schedule.

02:35:26.040 | And after that, and while they were doing that,

02:35:29.140 | we decided, gosh, this problem I talked about

02:35:31.940 | at the beginning of the show where you have this problem

02:35:35.040 | that we don't have a treatment for people

02:35:37.600 | who are in these high acuity psychiatric emergency states,

02:35:42.020 | this idea that we're gonna engineer a treatment

02:35:44.980 | where we can reorganize the stimulation approach in time

02:35:49.100 | to be much more efficient by utilizing something

02:35:52.520 | called space learning theory.

02:35:54.000 | And so you probably know about the space learning theory.

02:35:56.040 | So the idea for the viewers is it's a simple psychological

02:36:00.360 | thing, but we've also seen it in hippocampal slice

02:36:02.480 | sort of physiology too where if I'm cramming for a test,

02:36:07.480 | what I do is I write out 60 note cards

02:36:11.560 | and I read each one for a minute until I get

02:36:13.620 | to the first note card and again,

02:36:14.940 | and that's about an hour later, right?

02:36:16.880 | And we just intuitively do this.

02:36:18.980 | We all automatically do that.

02:36:22.620 | And we intuit that because we know that what doesn't work

02:36:26.420 | is writing out one note card and looking at it

02:36:28.480 | over and over again.

02:36:29.420 | Nobody ever does that, right?

02:36:31.500 | We've all been in graduate school, medical school,

02:36:33.980 | and we have these big stacks of note cards.

02:36:36.060 | That's space learning theory.

02:36:37.300 | It's this idea that you need to see it about every hour

02:36:39.620 | to an hour and a half and that optimizes learning.

02:36:42.440 | If you take the same stimulation approach

02:36:45.780 | that I'm talking about, this theta burst stimulation

02:36:47.500 | approach and you take a hippocampal slice of a mouse

02:36:50.400 | and you stimulate, you enlarge some dendritic spines

02:36:55.360 | and you prime some.

02:36:57.060 | And then if you stimulate right after that,

02:36:59.360 | you don't get any change.

02:37:00.340 | It's called in mass stimulation.

02:37:01.740 | But if you wait about an hour to an hour and a half,

02:37:04.860 | you get more dendritic spines enlarged and more primed,

02:37:08.380 | which by the way also is what ketamine does.

02:37:10.320 | It causes this dendritic spine enlargement.

02:37:13.840 | And so what we found was is that the old way of doing TMS,

02:37:18.300 | this idea of just doing it once a day, every day,

02:37:20.900 | five days a week for six weeks,

02:37:23.060 | didn't utilize the space learning theory.

02:37:24.980 | It's like studying for a month or two,

02:37:28.340 | just a little bit once a day.

02:37:29.740 | Like you remember some of that stuff,

02:37:31.260 | but it's like not as potent as that week

02:37:33.180 | where you're kind of cramming, right?

02:37:35.060 | And what we realized is that if we could reorganize

02:37:38.260 | the stimulation in times that we took the whole

02:37:40.440 | six week course, we actually figured out a way

02:37:42.240 | to do it in a day.

02:37:43.500 | And then what we also figured out is that people

02:37:46.500 | were underdosing TMS because if you just keep going

02:37:49.500 | after six weeks out to month three, four, five,

02:37:52.740 | more and more people got better.

02:37:53.980 | So we figured out it's not just one day,

02:37:55.780 | we're gonna get five times the normal dose.

02:37:57.460 | We have seven and a half months worth in five days

02:38:00.260 | using space learning theory.

02:38:02.440 | - So every hour?

02:38:03.640 | - Every hour for 10 hours.

02:38:05.140 | - For five days?

02:38:05.980 | - For five days.

02:38:06.820 | So it's a 50 hour block.

02:38:07.860 | It's 90 minutes of actual stimulation,

02:38:10.680 | but spread out through the day in the same way of learning,

02:38:13.740 | which is perfect for an inpatient psychiatric unit, right?

02:38:16.100 | - Five days is manageable.

02:38:17.340 | - Yeah, then you can get stimulation.

02:38:18.900 | Nobody's ever dropped out by the schedule.

02:38:21.320 | Folks that wanna do this wanna do it.

02:38:25.460 | So they'll do their nine minutes, they'll go get breakfast,

02:38:27.300 | they'll do their nine minutes,

02:38:28.460 | they'll go see their therapist or whatever it is.

02:38:31.120 | And so what we've found with this reorganization

02:38:34.380 | and time of the stimulation, dose,

02:38:38.020 | and then the third component is we do resting state

02:38:40.460 | functional connectivity scans on everybody.

02:38:42.580 | And we have ways now in the last five to 10 years

02:38:45.260 | of picking out that specific subgenual DLPFC subcircuit

02:38:50.260 | that I was talking about earlier, that cingulate DLPFC.

02:38:52.780 | We can pick that out in every single one.

02:38:54.220 | If you wanna come to the lab,

02:38:55.200 | we can find your DLPFC subgenual.

02:38:57.900 | It's even more robust and non-depressed.

02:38:58.960 | - And we can stimulate too just while we're in there.

02:39:00.940 | - Yeah, if you want to,

02:39:01.780 | we can move around your hypnotizability.

02:39:03.720 | And we can find that spot in each person.

02:39:09.820 | Instead of finding the same spot on the skull,

02:39:11.740 | we find the same spot on the brain and we can stimulate.

02:39:14.340 | We do that every hour on the hour.

02:39:15.580 | What we've found is that folks will,

02:39:20.460 | within one to five days, in more cases than not,

02:39:24.520 | depending upon if you're looking at this open label

02:39:26.460 | or in trials, somewhere between 60 and 90% of the time,

02:39:30.460 | they will go into full-on remission in the sense

02:39:33.060 | they're totally normal from a mood standpoint

02:39:36.260 | at the end of this.

02:39:37.400 | And like I said, with variable durability.

02:39:41.020 | So that's the part we have to figure out now

02:39:42.460 | about dosing and how to keep people well.

02:39:44.260 | But for some people, we've had four years of remission,

02:39:47.300 | a year of remission.

02:39:48.700 | And it's really that cramming of the test.

02:39:51.640 | It's really that idea that you're laying in that information

02:39:55.460 | in the exact right spot.

02:39:57.460 | And the signal is a simple signal,

02:39:59.360 | but it's a profound one, which is turn on, stay on,

02:40:04.140 | remember to stay on.

02:40:05.880 | You know, that idea that you're sending this memory signal

02:40:09.020 | into the brain and you're doing it in such a way

02:40:10.780 | that you're telling the system,

02:40:12.660 | you're kind of taking it out of the hippocampus,

02:40:15.180 | your own hippocampus's hand is you're sending

02:40:17.340 | the same signal the hippocampus normally signals out.

02:40:20.340 | Now you're sending that signal into the prefrontal cortex

02:40:24.160 | and kind of utilizing the brain's own communication style

02:40:28.960 | to get it to get out of the state.

02:40:31.360 | And what's very cool about this is that people,

02:40:35.440 | when they kind of exit out of that,

02:40:38.000 | they end up saying they don't have any side effects from it

02:40:43.720 | and they feel back to normal.

02:40:46.080 | Like some people, you know, not everybody,

02:40:47.880 | but there's a subsection of people with SSRIs

02:40:50.500 | where they'll say, I kind of feel numb

02:40:52.700 | or I have GI side effects or I can't,

02:40:54.740 | I can't, you know, I don't have the sexual interest

02:40:56.740 | that I used to have and that sort of thing.

02:40:58.940 | You know, not anything gets SSRIs, as I said earlier,

02:41:01.660 | life saving, you know, for a subsection of people,

02:41:03.740 | these things really work.

02:41:05.220 | But with this, what you see is that people don't talk

02:41:08.640 | about any of that stuff.

02:41:09.940 | And I think it's likely because you're tapping

02:41:13.500 | into that core circuitry and you're reversing it

02:41:15.860 | and you're doing it with a magnet

02:41:18.040 | that because it's a very profound electromagnet,

02:41:21.360 | it's the same field strength as an MRI scanner,

02:41:23.980 | it's able to induce a current in the brain

02:41:26.900 | in this focal targeted way

02:41:29.620 | without getting into the rest of the brain,

02:41:31.100 | without getting into the rest of the body at all,

02:41:32.860 | and just really kind of acting only

02:41:34.940 | on that circuitry that's involved.

02:41:37.460 | - Incredible.

02:41:38.440 | Is the SAINT study still ongoing?

02:41:40.460 | And if people are interested in potentially being patients

02:41:45.460 | or subjects in the study, can we provide them a portal link?

02:41:49.000 | - Absolutely, yeah.

02:41:49.840 | So we have, now the treatment,

02:41:53.480 | some of my students went over to a company

02:41:55.060 | called Magnus Medical and they've been working on this.

02:41:57.800 | They've gotten FDA clearance now.

02:41:59.820 | And now folks can get it through trials

02:42:04.820 | over the next couple of years,

02:42:06.360 | because it's going to take some time for that company

02:42:08.620 | to kind of get up and running and get a device

02:42:13.180 | and get the whole thing set up nationally.

02:42:15.660 | But while that's all going on,

02:42:18.020 | there's still about a thousand patients

02:42:19.940 | that need to be recruited

02:42:20.900 | across a bunch of different trials all over the country.

02:42:23.660 | We'll take people from anywhere in the country.

02:42:25.520 | We also have partners in New York and San Diego

02:42:28.540 | and in soon to be South Carolina and other places

02:42:32.720 | where we can actually kind of,

02:42:34.540 | my lab can help to kind of let people know where to go

02:42:38.180 | based off of where they're at in the US

02:42:40.340 | and get them access to being able to be in a trial

02:42:42.620 | and what we've tried to do is make it

02:42:44.620 | so that even if you get the 50/50 chance

02:42:47.780 | you're going to get the real deal

02:42:48.980 | or you're going to get the non-real deal,

02:42:51.500 | but what we have figured out is a way

02:42:53.940 | to let everyone have access.

02:42:56.660 | If they got the not real deal version,

02:43:00.060 | the kind of sham version or the fake version

02:43:02.300 | for the first part of the trial,

02:43:04.300 | there are other trials where they can have access

02:43:06.660 | to the real version.

02:43:07.560 | So essentially everybody eventually gets access

02:43:11.200 | to having the real version

02:43:12.880 | and so that's been a big thing for me

02:43:14.740 | is I want everybody that comes through one of our trials

02:43:17.800 | to be able to have access.

02:43:19.020 | I think it's important while the company's doing

02:43:22.760 | what they're doing and what the lab's doing

02:43:24.340 | and kind of nationally what other partner labs are doing.

02:43:28.240 | - Well, I can assure you you're going to get some interest.

02:43:30.640 | - Happy to have it, yeah.

02:43:31.920 | - Thank you and listen, thank you so much

02:43:36.920 | for taking us on this incredible voyage

02:43:40.080 | through the neurocircuitry underlying certain aspects

02:43:43.600 | of depression, the coverage of the different types

02:43:45.620 | of depression, the various therapeutic compounds,

02:43:48.540 | how they work.

02:43:49.380 | We've talked about a lot of things today

02:43:51.100 | and you've shared so much knowledge

02:43:53.060 | and even as I say that, I very much want to have you back

02:43:56.600 | to talk about many other things as well

02:43:58.620 | that we didn't have time to cover,

02:43:59.820 | but also just really want to thank you

02:44:01.900 | for the work that you do.

02:44:03.560 | I know we are colleagues,

02:44:04.560 | but you run an enormous laboratory.

02:44:07.340 | Enormous in my book, 40 people is a big group,

02:44:10.740 | very big group.

02:44:11.580 | Plus you're in the clinic.

02:44:12.880 | You also have a life of your own outside of work

02:44:16.420 | and to take the time to sit down with us

02:44:18.240 | and share all this knowledge that really is in service

02:44:20.920 | to mental health and human feeling better

02:44:25.300 | and in fact, avoiding often suicidal depression.

02:44:28.100 | It's just incredible work and an incredible generosity

02:44:30.900 | and just thank you so much.

02:44:32.620 | - Well, thank you, man.

02:44:34.460 | Similarly, I want to thank you for what you're doing.

02:44:36.900 | I mean, I think that I've got a lot of friends,

02:44:40.300 | folks that are not in the medical profession,

02:44:42.260 | friends of mine, one of my buddies

02:44:44.420 | who's a real estate agent who works with us,

02:44:47.060 | who's a big fan of your show

02:44:48.680 | and I told a couple people like that I was coming on

02:44:51.740 | and they were like super stoked.

02:44:54.900 | They're like, we watch every show

02:44:57.660 | and super excited to watch mine

02:45:01.980 | and they said something very important to me

02:45:03.740 | that you make this complicated neuroscience

02:45:08.740 | and kind of brain body science accessible

02:45:12.820 | in a way that few have a gift to do

02:45:17.240 | and I think that that's so important

02:45:19.900 | and this show is doing so much to help with science literacy

02:45:24.700 | and yeah, appreciate you.

02:45:27.620 | - Well, thank you.

02:45:28.740 | I'm gratified and honored by your statement

02:45:31.580 | and I look forward to more, thank you.

02:45:34.380 | - Absolutely, thank you.

02:45:35.700 | - Thank you for joining me today

02:45:36.740 | for my discussion with Dr. Nolan Williams.

02:45:39.060 | I hope you found our discussion about psychedelics

02:45:41.180 | and other compounds,

02:45:42.540 | about transcranial magnetic stimulation

02:45:45.400 | and about the treatments for depression in general

02:45:48.040 | to be as stimulating as I did.

02:45:50.260 | If you'd like to learn more about the work being done

02:45:51.980 | in Dr. Williams laboratory,

02:45:53.780 | you can go to the brain stimulation laboratory website,

02:45:56.320 | which is bsl.stanford.edu

02:45:59.620 | and there you have the opportunity to apply

02:46:01.660 | to be in one of the clinical trials for depression

02:46:04.140 | or other studies as well if you like

02:46:06.420 | to support the work being done in Dr. Williams laboratory

02:46:09.280 | for the treatment of depression

02:46:10.400 | and other psychiatric disorders.

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Dr. Nolan Williams: Psychedelics & Neurostimulation for Brain Rewiring | Huberman Lab Podcast #93

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