Essentials: Psychedelics & Neurostimulation for Brain Rewiring | Dr. Nolan Williams

1. 0:00 – 0:26

   Nolan Williams

   1. AHAndrew Huberman0:06

      Welcome to Huberman Lab Essentials, where we revisit past episodes for the most potent and actionable science-based tools for mental health, physical health, and performance. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. And now for my discussion with Dr. Nolan

2. 0:26 – 2:51

   Depression

   1. AHAndrew Huberman0:26

      Williams. Thanks for joining today. I'm really excited to have this conversation. I have a lot of questions about different compounds. Psychedelics in particular.

   2. NWDr. Nolan Williams0:35

      Yeah.

   3. AHAndrew Huberman0:36

      But before we get into that discussion, I want to ask you about depression, broadly speaking.

   4. NWDr. Nolan Williams0:41

      Sure.

   5. AHAndrew Huberman0:42

      I heard you say in a wonderful talk that you gave that depression is perhaps the most debilitating condition worldwide. Yet in contrast to other medical conditions like cancer, we actually have a fairly limited number of tools to approach depression, and yet the number of tools and the potency of those tools is growing.

   6. NWDr. Nolan Williams1:02

      Depression is, uh, the most disabling condition worldwide. Um, what's interesting about depression is it's both a risk factor, um, for other illnesses, and it makes other medical and psychiatric illnesses worse, right? So recently the American Heart Association added depression as the fourth, uh, major risk factor for coronary artery disease, right? So it... Alongside the, the risk factors that we know, hypertension, high blood pressure, hyperlipidemia, high cholesterol, and diabetes, you know, high blood sugar. Those three have been on the list for a long time, and depression end up, you know, being added to the list as the fourth one. A lot of what we're doing in the lab actually is, um, is measuring kind of brain-heart connections, and we can actually with transcranial magnetic stimulation, a form of brain stimulation, we can actually decelerate the heart rate. We can capture that heart rate deceleration, um, over the mood regulatory regions, and so actually a direct probe of that connection. We've been very interested in a very particular, um, clinical set of problems around the, the most severe and the most high acuity settings that, uh, folks with depression end up being in, and that's in, you know, emergency settings where they go into inpatient units. The field really hasn't developed a way of, um, you know, of consistently being able to treat that problem, and folks end up getting the same standard oral antidepressants that they've been getting outpatient. And, and I came to this because I've, you know, dual trained as a neurologist and psychiatrist, went back and forth between neurology and psychiatry, saw that in neurology we have all of these ways of treating acute brain-based problems and really wanted to emulate that in psychiatry and find ways to develop and engineer new, you know, brain-based solutions.

   7. AHAndrew Huberman2:50

      Many

3. 2:51 – 5:21

   Heart & Mind Connection, Transcranial Magnetic Stimulation (TMS)

   1. AHAndrew Huberman2:51

      people out there probably think of the relationship between the, the heart and the mind as kind of woo or kind of a-

   2. NWDr. Nolan Williams2:57

      Mm-hmm

   3. AHAndrew Huberman2:57

      ... a soft biology, but here you're talking about an actual physical connection.

   4. NWDr. Nolan Williams3:01

      Yep.

   5. AHAndrew Huberman3:02

      Uh, what area of the brain is it?

   6. NWDr. Nolan Williams3:03

      You know, the first place where the stimulation goes is called the dorsolateral prefrontal cortex.

   7. AHAndrew Huberman3:08

      Mm-hmm.

   8. NWDr. Nolan Williams3:08

      It's kind of the sense of control, kind of governor of the brain.

   9. AHAndrew Huberman3:11

      Mm-hmm.

   10. NWDr. Nolan Williams3:12

       And then it'll... And then what we know is that when you use a magnet, kind of what we call Faraday's law, this idea of, um, using a magnetic pulse to induce, uh, an electrical current in electrically conducting substances, so in this case brain tissue, but not skull or sc- scalp or any of that, or hair. You avoid all that, just the brain tissue. Then you have a direct depolarization of cortical neurons, you know, the surface of the brain's neurons in this dorsolateral prefrontal. And if you do that in the actual scanner, which we can do, you can see that that distributes down into the anterior cingulate, in the insula, in the amygdala, and ultimately the tract goes into something called the nucleus tractus solitarius and ultimately into the vagus nerve into the heart. So the, the heart, uh, very consistently seems to be the end organ of the, uh, dorsolateral prefrontal cortex. And if you do that over visual cortex, you don't get that. Or motor cortex, you don't get any of those findings. It's really specific to this kind of control region of the brain. And so, yeah, it seems to... You know, it's our work. Other, uh, other folks' work, Martin Arens in, um, in, in Europe, uh, Netherlands work showing the same connections. I think it's been replicated like four or five times. Where I think TMS is really interesting actually, we had a lot of patients who've told me, like, "My, my therapist told me that I wasn't trying hard enough in therapy." These are, you know, moderate or pretty severe depressed patients. And as soon as we get them well with, with the TMS approaches, you know, kind of rapid, you know, five-day approach, and then the next week we come in and see them and they'll say, "You know what I did all weekend is I looked at my therapy books and now I can understand it." And so, you know, I actually see TMS as a way of having kind of exogenous sorts of cognitive functions that in milder forms of depression we can pull off with psychotherapy. You know, this idea of being able to kind of turn that prefrontal cortex on and have it govern these deeper regions. In depression, the deeper regions govern the prefrontal cortex.

4. 5:21 – 7:52

   TMS for Depression

   1. AHAndrew Huberman5:21

      In one case it's like the coach telling the player what to do.

   2. NWDr. Nolan Williams5:24

      Exactly.

   3. AHAndrew Huberman5:24

      And in the other case it's like the player telling the coach what to do, and you-

   4. NWDr. Nolan Williams5:26

      That's right

   5. AHAndrew Huberman5:27

      ... you restore order to the game.

   6. NWDr. Nolan Williams5:28

      You restore order to the game. And what it looks like is de- depression is a bunch of kind of spontaneous content that's semi-volitional that's being kind of generated out of this conflict, um, detection system, the cingulate. In depression, it looks like the left dorsolateral does not sufficiently clamp down on it. And what therapy appears to do is to kind of restore that. What we see with TMS over that region is that we just exogenously do the same sort of thing. We restore the governanceOf the left dorsolateral over the cingulate area, and that is correlated with treatment improvement. So the degree in which you can re-time or re-regulate in time the left dorsolateral over the cingulate, the more of an antidepressant effect you have. TMS is almost like exercise for the brain, right? You're kind of exercising this region over and over again with a physiologically relevant signal and kind of turning that system on. And what's interesting for this show is, you know, we had a couple of folks, um, you know, probably five or six folks that have actually told me this, where if they remit early enough in the week, we have this very dense stimulation approach where we can stimulate people really rapidly over a five-day block. By Wednesday, they're like totally zero down on the depression scales, you know, even better than most people walking around, like really no anxiety, no, no depression or anything. By Thursday, the first guy that, that told me this, he came in and he said, "You know, I was driving back to my hotel and I decided to go to the beach, and I just sat there and I was totally present in the present moment for an hour." And he's like, "I read about this in my mindfulness books, but I experienced it last night, and I've never experienced anything like this before." And I was like, "Hmm, that's interesting," but kinda wasn't sure, and then, and then I didn't tell any, you know, obviously any more patients about that. And then about five over the last couple of years, when they get... They remit early in the week, by the end of the week, they're like going to the beach and they're like totally having a, what people describe as a pretty mindful present moment sort of experience, which is really interesting, you know, what that is. I mean, I don't have p- full-on scientific data to tell you, but it, it's just, it's a, it's an interesting anecdote, right? That, that folks, when you push them through this point of, of feeling kind of clinically well, that some people end up reporting this additional set of features,

5. 7:52 – 13:51

   SSRIs & Chemical imbalance, TMS, Psychedelics

   1. NWDr. Nolan Williams7:52

      so.

   2. AHAndrew Huberman7:52

      I want to make sure that before we dive into ketamine and psilocybin, that we do touch on SSRIs, selective serotonin reuptake inhibitors, 'cause we can't really have a discussion about depression without talking about SSRIs. My understanding is that the SSRIs are powerfully effective for certain forms of obsessive- obsessive compulsive disorder and may also be effective for treatment of depression. Is that right? And how should we think about SSRIs? Are they useful? Are they not useful?

   3. NWDr. Nolan Williams8:17

      SSRIs clearly work. Um, you know, many, many m- uh, meta-analyses kind of proving that out, right? That, that in a subpopulation of individuals, they achieve great benefit. For depression, for obsessive compulsive disorder, for generalized anxiety disorder, panic, you know, all of these things, you can see a, an improvement in those symptoms, um, with what we call SSRIs or selective serotonin reuptake inhibitors. The issue is that they don't work immediately, right? So they don't work like the same day you start taking them, and that, that suggests that probably it's not exactly the serotonin being in there that's directly driving it, that it's much more likely that it may have some brain plasticity effects, right? There's not a deficit of serotonin. You're not born with, uh, what people call a chemical imbalance, and psychiatry's known this. This is not actually new information to anybody. You know, it, it's, it's kind of a rehashing of a bunch of information we've known for a while now. But in the lay press, it's kind of hit in a way that it didn't seem to, to grab attention, um, before with previous publications, but this idea that this chemical imbalance idea is wrong. I really think that part's important because I think that what I'll call psychiatry 1.0, right, this kind of idea of Freud and, and psychotherapy and its, and its origins, um, it was a lot around, you know, the, your family and those experiences and psychotherapy kind of going in and correcting or helping you to figure out or, and, you know, show... You being able to see or people hear you so that you can eventually come to the conclusion of certain cognitions that aren't helping you, right? Things like the schizophrenogenic mother and all of that, you know, that was a concept at some point, right? And so we've transitioned from that to, to the ch- you know, for a long time, the chemical imbalance, which I'll call psychiatry 2.0, you know, this idea that there's something chemically missing. The trouble there for a patient, right, is that it's telling, it's sending a message of there's something missing with me, whether it be my experiences I had no control of- over when I was a child or, um, a chemical in my brain. What I think is really powerful with, with TMS, um, you know, really powerful with TMS and a, a lovely even powerful with the psychedelic story is it's saying something different. You know, TMS works and there's no serotonin coming in or out [chuckles] of the brain, right? And we're doing a rapid form of TMS that works in one to five days, so there's no... There's, it's very unlikely that there's some long-term kind of upregulation of serotonin that's driving that. So our work actually kind of pushes back on this serotonin hyp- hypothesis as being kind of the center of depression because it says, look, we're not giving anybody any serotonin. We're simply turning these brain regions on, and we're focused on the circuitry, and that's psychiatry 3.0. It's not just like neuromodulation. Neuromodulations are a really nice u- you know, use case for psychiatry 3.0 'cause it's a, a way to focally and directly perturb brain regions in, in whatever modality you're using. But, you know, there are a lot of, a lot of groups that are actually doing neuroimaging before and after, and they're able to see circuit level changes for something like psilocybin or ketamine long after the drug is gone, right? Suggesting and those same brain regions converge, so the subgenual default mode network connection that we see is changing with our, our, our stan- um, Stanford neuromodulation therapy technique. It's that same set of brain regions that, that ketamine and, uh, psilocybin seem to act on, act on these connections between brain networks that seem to shift. And so it refocuses the story on something that's highly correctableAnd it's, it's basically electrophysiology, and it's basically kind of recalibrating a circuit that is recalibratable instead of I have something missing or I have some set of experiences early in life that are, um, that are gonna forever trap me in these, these psychiatric diagnoses. And so it kind of challenges that idea, and I think that's what's so powerful about Psychiatry 3.0, um, this idea of focusing on the circuit because it gets us, gets us into thinking about psychiatry and psychiatric illnesses as something that are recoverable. People can get better. People... You know, we've seen with our TMS techniques, we've seen it with, with some of the psychedelic work that we've done where people are actually in normal levels of mood for sustained periods of time or-

   4. AHAndrew Huberman12:56

      Within five days

   5. NWDr. Nolan Williams12:57

      ... within five or less days, and in the case of, of the psychedelics, within a few days, right? So we can get people out of these states. They're totally well. There's no drug in their system at that point in the case of the psychedelics. There was never a drug in their system in the case of, of TMS. And it, and it just tells us that, that it's, it's, it's fixable. It's just like an arrhythmia in the heart. It's like a broken leg. We can go in and do something, and we can get somebody better. Then I think what's, what's empowering and what a lot of patients have told me is they say, "You know, I've gotten dep-" You know, some people will relapse and need more stimulation or need more psychedelics or whatever it is, but they'll tell me, "I don't fear that I'm chronically broken. I don't fear that the chemical imbalance is still imbalanced. I don't fear that these things that I couldn't control in my childhood, you know, are gonna be there and drive this problem forever." And I think that's, that's what's so powerful

6. 13:51 – 16:48

   Psilocybin, MDMA, Trauma

   1. NWDr. Nolan Williams13:51

      about this.

   2. AHAndrew Huberman13:51

      And that brings me to this, uh, question about psychedelics and, and the, frankly the altered thinking and perception that occurs in s- in high-dose psilocybin-

   3. NWDr. Nolan Williams14:01

      Yeah

   4. AHAndrew Huberman14:01

      ... uh, clinical, uh, sessions. Many people do report improvements in, uh, trauma-related symptomology and depression, as I understand it-

   5. NWDr. Nolan Williams14:09

      Yeah

   6. AHAndrew Huberman14:09

      ... from my read of the clinical trials, after taking psilocybin because during those sessions, something comes to mind spontaneously. They will report, for instance, a new way of seeing the old problem.

   7. NWDr. Nolan Williams14:20

      That's right.

   8. AHAndrew Huberman14:21

      And the old problem could be the voice that they're no good, they'll never, nothing will ever work out, or could be even more subtle than that. Why do you think the brain would ever hold on to rules that, um, uh, don't serve us well?

   9. NWDr. Nolan Williams14:33

      I think it's an, it's an, it's an evolar- evolutionary neurobiology answer, right? I think that w- we end up being a result of, of probably a lot of biology that's not that useful in the modern era, and I think in the brain for, for say, let's say PTSD, right, a lot of, a lot of veterans come back and they experience these PTSD symptoms, and they're not at all useful back home, right? They hear some loud noise, and all of a sudden they're behind a car, or they're behind a, you know, I've, I've heard of folks, you know, jump and run behind a trash can or whatever in the middle of San Francisco when they hear a loud noise. But if you put them back in the battlefield, you know, that-

   10. AHAndrew Huberman15:10

       Highly adaptive

   11. NWDr. Nolan Williams15:11

       ... that's highly adaptive, right? We hold onto those things from an, I think an evolutionary neurobiology standpoint, but what seems to, for whatever reason, kind of alleviate that are these, um, are these substances, some new like MDMA, some that have been around for thousands of years like psilocybin, seem to have a therapeutic effect that seems to be pretty long-lasting for these phenomenon. And so it's, it's just curious, right? It's curious that in the absence of that, these things will keep going on and on. But in the presence of that exposure, then all of a sudden you see a resolution of the problem. And we have some work now, we're treating folks with Navy SEALs. The anecdotes that we're getting, right, are folks are coming back and they're saying these set of PTSD symptoms are finally gone. And so this idea that for whatever reason, going into what's probably a highly plastic state and reexperience memories and then a- as you know, you know, we, we reconsolidating it in that state, for whatever reason, um, may drive, um, drive a therapeutic effect. My business is to find treatments that help people, and so I'm much more, like pragmatic about it, you know? If, if this sort of thing, which, um, has a lot of cultural baggage, um, but if this sort of thing ultimately ends up being therapeutic, if we can design trials that convince me and others that it is, then we should absolutely use it. And if it doesn't, then we clearly shouldn't use it, right? The, the work that's been done so far, the first psilocybin trial, um, the first MDMA trial was published in Nature of Medicine recently,

7. 16:48 – 18:46

   MDMA Clinical Trials & PTSD; Psilocybin & Depression

   1. NWDr. Nolan Williams16:48

      um-

   2. AHAndrew Huberman16:49

      And what do those generally say? Let's, let's, uh, start with psilocybin and MDMA.

   3. NWDr. Nolan Williams16:53

      So MDMA appears to in, in, um, you know, one to a few MDMA sessions have, uh, an anti-PTSD effect that seems to be, you know, um, outside of the kind of, uh, standard assumed levels of PTSD improvement that you can observe in individuals, um, with this level of PTSD, right? So-

   4. AHAndrew Huberman17:13

      So does that mean that, um, for people that have trauma who do a... And again we're talking about in a clinical setting. They t- they take, uh, one or two doses of, of MDMA. I think the standard MAPS dose is 150 to 175 milligrams. Again, doing this with a physician, et cetera, controlled clinical trial, legal.

   5. NWDr. Nolan Williams17:30

      Exactly.

   6. AHAndrew Huberman17:31

      They do it once or twice, and w- broadly speaking, what percentage of people who had trauma report feeling significant relief from their traum- trauma afterward?

   7. NWDr. Nolan Williams17:41

      It's about 2/3 of people had a, had, um, a clinically significant, uh, change in their PTSD symptom-

   8. AHAndrew Huberman17:48

      That's impressive. And how, how long lasting was that?

   9. NWDr. Nolan Williams17:50

      It appears to last for a while. In the earlier trials where they followed people out, it seemed to last for kind of in the years range for some people, and so it's, you know, it's pretty, it's pretty compelling. And contrast that with ketamine, which only on average lasts about a week and a half for a single infusion, so it's a much shorter-

   10. AHAndrew Huberman18:07

       So they have to get repeated infusions of ketamine every 10 days or so?

   11. NWDr. Nolan Williams18:11

       For some people, or they end up getting, like-like s- like a bunch of doses for a couple of weeks, and then for some people, that seems to last a while. Um, you know, that's where I think, I think the, the psilocybin story for depression and the, um, and the MDMA story for PTSD seem more interesting to me.

   12. AHAndrew Huberman18:27

       So for g- uh, psilocybin, what is the, um, r- rough percentages on... And this would be relief not from trauma, but from depression.

   13. NWDr. Nolan Williams18:34

       Yeah, exactly. So it's, you know, in open label studies, it's closer to, like, half to two-thirds of people end up getting better depending upon their level of treatment resistance. In the, in the, uh, blinded trials, it was more like a, a third or so of people.

8. 18:46 – 21:07

   Psilocybin, Brain Connectivity & Depression

   1. AHAndrew Huberman18:46

      Since you mentioned psilocybin, let's talk a little bit about the neurochemistry of psilocybin. What's going on when one takes psilocybin, and, um, h- why is it interesting in light of, uh, depression?

   2. NWDr. Nolan Williams18:55

      Yeah, definitely. So David Nutt and Robin Carhart-Harris' work around neuroimaging psychedelics are kind of the f- some of the first folks to do that work. And, um, you know, and to their great surprise, they thought there was going to be an increase in activity on psychedelics, and what they found is the opposite, right? There's kind of a, an overall decrease in the level of activity in the brain, um, with psychedelics. But they, they've also looked at connectivity, and there's this kind of small world, you know, large world connectivity that you, you, you think about. And so, you know, small world meaning there's a lot, there's kind of a much more f- kind of focused kind of cortical function or, you know, subcortical function or whatever it is. And, uh, and what you see is a difference in that, um, in that level of engagement and of, of brain regions. So the connectivity, kind of global connectivity kind of increases. And so it's interesting. You know, I think to, to kind of have a conversion theory on this, it's still, you know, to be determined. There's still a lot of work, I think, that needs to be done. But, um, but it's certainly, um, suggestive that there's pretty profound changes in, um, in brain activity and brain connectivity after. And what we've found to be really interesting is the, the antidepressant effects of psilocybin have a particular, um, connectivity change that we also see with our, our TMS approaches, right? And it's this connectivity between the subgenual anterior cingulate and the default mode network. And so when we do this effective s- Stanford neuromodulation therapy stimulation, we see a downregulation, the connectivity between the negatively valenced mood state in the case of depressed individuals and the self-representation of the brain, and you see that same connectivity change occur post psilocybin s- you know, suggesting there's a convergent mechanism. And it makes sense, right? You've kind of got an over-connected, negatively valenced system, conflict system that's kind of, you know, kind of attached onto the self-representation, and people feel stuck, right? And then when you, when you do whatever you do that's effective, it, it un- it unpairs those two

9. 21:07 – 27:44

   Ibogaine, Empathy; Psychedelic Breakthrough & Risk

   1. NWDr. Nolan Williams21:07

      systems.

   2. AHAndrew Huberman21:07

      I want to ask you about ibogaine. Is it legal in the US in term- as a clinical tool? Who's using it and for what purposes?

   3. NWDr. Nolan Williams21:16

      Ibogaine is a, um, is one of the alkaloids that you can extract from a, um, an iboga tree root bark that's f- um, typically growing in the country of Gabon, Africa. So what, uh, individuals taking ibogaine will say is that open eyes, they don't see anything. But closed eyes, they'll go back through and re-experience earlier life memories, and they will be able to experience it from a place of empathy, not only for themselves, but from others, and kind of a deta- a detached empathy and being able to see this as almost a third party even though they were there. Ibogaine is in no way a recreational substance. You're essentially having this, what they call a life review. They also call it 10 years of psychotherapy in a night. So these are the terminology that people talk about. The issue-

   4. AHAndrew Huberman22:12

      How long does it last? Is it truly one night?

   5. NWDr. Nolan Williams22:15

      Depending upon how fast you metabolize it, sometimes 24, sometimes 36 hours. Sometimes it can be shorter. But it is a long time.

   6. AHAndrew Huberman22:22

      Wow.

   7. NWDr. Nolan Williams22:22

      It's a very long time. So it's, it's definitely the longest acting psychedelic substance I know of. And so, you know, we have over the last couple of years been able to, um, to do this first in human kind of full neurobiological, clinical neurocognitive evaluation of what ibogaine is doing, in this case, in, in, uh, special operations, special forces individuals, former Navy SEALs, former a- Army Rangers, that, that kind of crew of folks, and look at the pre/post changes that we, um, that they're experienced to be able to totally quantitate all of that. And so we've been able to capture all the clinical scales, you know, depression scales, PTSD scales, all that standard stuff. Neurocognitive batteries, so how does your executive function work specifically? How does your verbal memory, all of that. And then neuroimaging and EEG. So this will be the first human study of ibogaine for those. And the reason why is because ibogaine's kind of the, both seemingly the most potent and most, um, a- and, and mo- seemingly, to me at least, most powerful s- um, psychedelic, but the, the one that has the most risk too because it has a cardiac effect. It seems to be that you can screen people out that have risk off of their electrocardiogram and, and reduce the risk quite a bit, and that's what we, we all did. But, um, but, but that's why people haven't really studied it as much. Um, and it's, and it isn't as, uh... In addition, there's like [chuckles] no re- nobody goes to a rave on ibogaine. There's no recreation at all with this.

   8. AHAndrew Huberman23:53

      It's not fun.

   9. NWDr. Nolan Williams23:55

      People say that it's relieving, but it's hard work, right? Because yeah, you're re, you're reexamining things. So then we see these folks after, and I'll, I'll tell you, you know, we haven't fully analyzed the data yet, but I'll tell you that from what my folks are telling me, it's pretty dramatic. You know, people come back and they're doing a lot better. Soldiers experience something called moral injury, right, where theyMaybe they accidentally blew something up and it had a kid in it or something like that. You know, if they're in Afghanistan or Iraq, maybe a, you know, child died on accident or maybe, maybe a w- you know, a, a civilian died or whatever it was, right? And they, and they suffer these moral injuries as part of the job, and it's almost one of the kind of, you know, vocational risks. They come back and say that they've, they've, they've, um, forgiven themselves, you know, which is, which is huge, right? And then, and part of that is being able to see themself in a different light and having empathy finally for themself and being able to kind of have that experience of forgiving. And so there's this kind of Timothy Leary kind of sociocultural construct that ends up being overlaid over psychedelics. And what I think is that if you rid yourself of all of those preconceived notions of what it is and isn't and the counterculture movement, all that stuff that neither of us were ever involved in [chuckles] neither of us ever partake in, you know, as, as kind of straight scientists looking at this, right? If you can kind of rid yourself of all those sociocultural constructions and then reexamine this, these-- if we just discovered these today, we would say that these sorts of drugs are a huge breakthrough in psychiatry because they allow for us to do a lot of the sorts of things we've been thinking about with, with SSRIs, with psychotherapy, but kind of in combined, right? Psychotherapy plus, plus drugs in a, in a substance that kind of allows you to reexamine these things. And so it's, it's interesting. It'll-- you know, there's a lot to do to try to figure out if that's true, you know? And, and I can say that as it stands right now, we don't know if it's-- that statement is true, right? There's a lot more work that needs to happen for that statement to be proven to be true. But the hypothesis is if it is true, then it's very likely that this will be seen as a breakthrough because it allows you to do these sorts of things that you can't do with normal waking consciousness. But also why we have to really think about this and, you know, these drugs can't be recreational drugs. They really shouldn't be recreational drugs, right? They're really too powerful to be used in the context of recreation because they can put you into these states. And, and the-- this generation of psychedelic researchers are really clear about that. You know, I think the '60s folks were not clear about that, and they, they felt like there was a wh- this whole kind of cultural thing that was going on there. But I think this cohort of individuals really understands that in order to really make this happen, we have to understand that if you need a prescription for an SSRI, which doesn't change your consciousness a whole lot, and we- we're very worried about that, and the doctor has to evaluate you for that every week, that the idea that some of these substances would, would go outside of, of very strict medical supervision is, uh, is kind of preposterous [chuckles] actually. It's kind of, it's kind of a, a dumb moment, I think, for, for all of medicine to say, "Look, we've... You know, if we're going to do this right, we've got to do it in such a way that's so protected, that's so safe that we make sure people know these things are not recreational, and they're really for the pure purposes of, of really powerfully changing, um, cognition for a while and letting people have these, what seem to be, you know, relatively therapeutic states."

10. 27:44 – 31:54

    Ayahuasca, Behavior Change, Prisoners

    1. AHAndrew Huberman27:44

       Tell me about ayahuasca, um, and as a plant, is it useful for the same sorts of conditions that we've talked about, um, thus far? And if you could, um, perhaps tell me a little bit also about the, um, Brazilian prisoner study.

    2. NWDr. Nolan Williams27:58

       Yeah. Yeah.

    3. AHAndrew Huberman27:59

       Um.

    4. NWDr. Nolan Williams27:59

       Definitely. Ayahuasca is another psychedelic. It's used as a sacrament, um, in, um, in Brazil and, um, in Peru and Ecuador and Colombia, so a lot of the South American countries. And, um, and what they do is they combine two plants together where one plant of the two plant combination would effectively do nothing. But the two plant combination together is capable of producing this very profound psychedelic effect. And what's really kind of curious is that there are, as I understand it, 10 to 20,000 plant species in the Amazon, and somehow somebody-

    5. AHAndrew Huberman28:42

       Someone tried them all. [laughs]

    6. NWDr. Nolan Williams28:43

       ... combined [chuckles] these two plants together in certain proportionality and cooked this for five, 10 hours to the point where you cook out the dimethyltryptamine out of one of the plants and cook out the reversible monoamine oxidase inhibitor out of the other plant. It's such a way that the m- reversible monoamine oxidase inhibitor prevents the, the GI breakdown of the dimethyltryptamine in such a way that it's then allowed to cross the blood-brain barrier and get into the brain. And if you didn't add the reversible monoamine oxidase inhibitor plant derived into this combination, then it would never cross the brain. If you put people on a standard psychiatry prescribed monoamine oxidase inhibitor that wasn't reversible, you'd throw them into serotonin syndrome, right? So this kind of l- like sweet spot that somehow ayahuasca practitioners have found of being able to get DMT into the brain from an oral source with this combination of a monoamine oxidase inhibitor is curious. Um, and so that, that substance has been explored as an antidepressant agent, and some studies have looked at that. It also seems to be very safe. There, um, there was a, there's a psychiatrist down at u- um, UCLA Harbor who's done a lot of work with this where, um, where he's looked at children even that have been exposed to s- to kind of small doses of ayahuasca as a, as a kind of a sacrament within Amazonian, uh, tribes and found no neurocognitive effects, no neurocognitive effects in adults. And so it appears to be safe. It's kind of part and brought into various religions, including kind of merged with Catholicism in South America, which is kind of very interesting. And so, you know, in some-sects of Catholicism in Brazil, it's used as sacrament during religious, um, ceremonies. And so it became interesting to Brazilian researchers as to whether or not they could affect recidivism rates for prisoners in Brazilian prisons, right? So they gave half of the prisoners, um, you know, some sort of inert substance and half of the prisoners a, um, an ayahuasca session. And the, the, uh, recidivism rate or the return to prison rate in the ayahuasca exposed individuals was statistically significantly lower than the recidivism rate in the, uh, in the control group, suggesting that, um, you know, whatever is going on there seems to have an effect on whatever drives criminal behavior, whatever criminal behavior that happened to be. And I don't have the, the details on the exact nature of the crime. Um, you know, no- I am also in no way saying that we should just be giving psychedelics to, to, to folks in prison and all of that. I think that, that, that, that is a very edgy thing to do and probably not something that anybody should try. But, but it does, it does kind of bring up this, this curious question of, of what is it about that that would drive people to, um, to change those behaviors? And, and why, why do people make those behavioral

11. 31:54 – 35:56

    Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT)

    1. NWDr. Nolan Williams31:54

       decisions

    2. AHAndrew Huberman31:54

       Before we wrap, I do want to give you the opportunity to talk about the SAINT study.

    3. NWDr. Nolan Williams31:59

       Yeah. SAINT, or what we're, we're calling it SNT now, um, Stanford Accelerated Intelligent Neuromodulation Therapy, or now what we're calling Stanford Neuromodulation Therapy, the idea there is that TMS, um, is a device that delivers, um, that delivers a treatment. [smacks lips] And the treatment is the protocol, and the protocol is the stimulation parameter set in a specific brain region for a specific condition, whether it be transcranial magnetic stimulation or transcranial direct current stimulation or deep brain stimulation, like what Casey Halpern talked about. In all of those cases, the device itself is a physical layer conduit of a stimulation protocol that's therapeutic for a given condition in a given brain region. We decided, gosh, you know, this problem I talked about at the beginning of the show where you have these... you know, this problem that we, we don't have a treatment for people who are in these high acuity psychiatric emergency states, right? This idea that we're going to engineer a treatment where we can reorganize the stimulation approach in time to be much more efficient by utilizing something called space learning theory. And so you, you probably know about the space learning theory. It's the idea for the, for the viewers is if I'm s- cramming for a test, what I do is I write out 60 note cards, and I read each one for a minute until I get to the first note card and again, and that's about an hour later, right? That's space learning theory. It's this idea that you need to see it about every hour to an hour and a half, and that optimizes learning. What we found was is that the old way of doing TMS, this idea of just doing it once a day, every day, five days a week for six weeks, didn't utilize the space learning theory. It's like studying for a month or two just a little bit once a day. Like, you remember some of that stuff, but it's, like, not as potent as that week where you're kind of cramming, right? And what we realized is that if we could reorganize the stimulation in times that we took the whole six-week course, we actually figured out a way to do it in a day. And then what we also figured out is that people were underdosing TMS because if you just keep going after six weeks out to month three, four, or five, more and more people got better. So we figured out it's not just one day. We're going to give five times the normal dose. We're going to give seven and a half months worth in five days using space learning theory.

    4. AHAndrew Huberman34:17

       So every hour.

    5. NWDr. Nolan Williams34:18

       Every hour for 10 hours.

    6. AHAndrew Huberman34:19

       For five days.

    7. NWDr. Nolan Williams34:20

       For five days. So it's a 50-hour block. It's 90 minutes of actual stimulation but spread out through the day in the same way of learning. What we've found is that folks will, um, will within one to five days, you know, in, in more cases than not, and depending upon if you're looking at this open label or in trials, somewhere between 60 and 90% of the time, they will go into full-on remission in the sense they're totally normal from a mood standpoint at the end of this. And like I said, with variable dura- durability, so that's the part we have to figure out now about dosing and how to keep people well. But for some people, you know, we've had four years of remission, you know, a year of remission, and it's, it's really that cramming of the test. It's really that idea that you're laying in that information in the exact right spot, and the, the signal is a simple signal, but it's a profound one, which is turn on, stay on, remember to stay on. You know, that idea that you're s- you're sending this memory signal into the brain and you're doing it in such a way that you're telling the system, you're kind of taking it out of the hippocampus's ha- your own hippocampus's hand as you're sending the same signal the hippocampus normally signals out. Now you're sending that signal into the prefrontal cortex and kind of utilizing the brain's own communication style to get it to get out of the state. And what's very cool about this is that, um, is that people when they, when they kind of exit out of that, they end up, um, they end up saying they don't have any, any side effects from it, and they feel back to normal.

12. 35:56 – 36:43

    Acknowledgements

    1. AHAndrew Huberman35:56

       Thank you so much, uh, for taking us on this incredible voyage through the neurocircuitry underlying certain aspects of depression, the coverage of the different types of depression, the various, uh, therapeutic compounds, how they work. We've, um, talked about a lot of things today, and you've, you've shared so much knowledge. And even as I say that, I, um, I very much want to have you back to talk about-

    2. NWDr. Nolan Williams36:18

       Oh, cool

    3. AHAndrew Huberman36:19

       ... many other things as well that we didn't have time to cover. But to take the time to sit down with us and share all this knowledge that really is in service to mental health and, and humans feeling better and, in fact, a- avoiding often suicidal depression, it's just incredible work and incredible generosity. And just thank you so much.

    4. NWDr. Nolan Williams36:38

       Absolutely. Thank you. [outro music]

Episode duration: 36:43