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

0:00Andrew Huberman: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 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. But before we get into that discussion, I want to ask you about depression, broadly speaking. I heard you say in a wonderful talk that you gave that depression is perhaps the most debilitating condition worldwide.

0:43Yet in contrast to other medical conditions like cancer, we actually have a fairly limited number of tools to approach depression.

0:52Andrew Huberman:And yet the number of tools and the potency of those tools is growing. Depression is the most disabling condition worldwide. What's interesting about depression is it's both a risk factor for other illnesses, and it makes other medical and psychiatric illnesses worse, right? So recently, the American Heart Association added depression as the fourth major risk factor for coronary artery disease, right? So alongside the risk factors that we know, hypertension, high blood pressure, hyperlipidemia, high cholesterol, and diabetes, high blood sugar, those three have been on the list for a long time.

1:31And depression end up being added to the list as the fourth one. A lot of what we're doing in the lab actually 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 over the mood regulatory regions. And so actually a direct probe of that connection. We've been very interested in a very particular clinical set of problems around the most severe and the most high acuity settings that folks with depression end up being in. And that's in emergency settings where they go into inpatient units.

2:11The field really hasn't developed a way 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 I came to this because I'm dual trained as a neurologist and psychiatrist, went back and forth between neurology and psychiatry, saw that in neurology we have all these ways of treating acute brain-based problems, and really wanted to emulate that in psychiatry and find ways to develop and engineer new brain-based solutions.

2:44Andrew Huberman:Many people out there probably think of the relationship between the heart and the mind as kind of woo or kind of a soft biology. But here you're talking about an actual physical connection. What area of the brain is it? The first place where the stimulation goes is called the dorsolateral prefrontal cortex. It's kind of the sense of control, kind of governor of the brain. And then what we know is that when you use a magnet, kind of what we call Faraday's law, this idea of using a magnetic pulse to induce an electrical current in electrically conducting substances. So in this case, brain tissue, but not skull or scalp or any of that or hair.

3:24You 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 and the insula and the amygdala and ultimately the tract goes into something called the nucleus tractus solitarius and ultimately into the vagus nerve and to the heart. So the heart very consistently seems to be the end organ of the 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.

4:06It'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 folks work, Martin Arns in Europe, the 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 therapist told me that I wasn't trying hard enough in therapy. These are, you know, moderate, pretty severe, depressed patients. And as soon as we get them well with the TMS approaches, you know, kind of rapid, you know, five-day approach, and 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.

4:47And 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.

5:14Andrew Huberman:In one case, it's like the coach telling the player what to do. And in the other case, it's like a player telling the coach what to do. And you restore order to the game. You restore order to the game. And what it looks like is depression is a bunch of kind of spontaneous content that's semi-volitional, that's being kind of generated out of this conflict detection system, the cingulate. In depression, it looks like the left or so lateral 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.

5:52We restore the governance of the left dorsolateral over the cingulate area. And that is correlated with treatment improvement. So the degree in which you can re-time, 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, 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.

6:38By Wednesday, they're like totally zeroed out 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 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 kind of 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 were met 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 full-on scientific data to tell you, but it's just, it's an interesting anecdote, right?

7:36That folks, when you push them through this point of feeling kind of clinically well, that some people end up reporting this additional set of features.

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9:35Andrew Huberman:My understanding is that the SSRIs are powerfully effective for certain forms of 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? Well, SSRIs clearly work. You know, many, many meta-analyses kind of proving that out, right? That in a subpopulation of individuals, they achieve great benefit for depression, for obsessive compulsive disorder, for generalized anxiety disorder, panic, you know, all these things. You can see an improvement in those symptoms with what we call SSRIs or selective serotonin reuptake inhibitors.

10:13The issue is that they don't work immediately, right? So they don't work the same day you start taking them. And 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. There's not a deficit of serotonin. You're not born with what people call a chemical imbalance. And psychiatry has known this. This is not actually new information to anybody. You know, 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 grab attention before with previous publications.

10:55But 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 psychotherapy and its origins. it was a lot around, you know, your family and those experiences and psychotherapy kind of going in and correcting or helping you to figure out or, 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?

11:33And so we've transitioned from that to the, For a long time, the chemical imbalance, which I'll call psychiatry 2.0, this idea that there's something chemically missing. The trouble there for a patient is that it's sending a message of there's something missing with me, whether it be my experiences I had no control over when I was a child or a chemical in my brain. What I think is really powerful with TMS, really powerful TMS, and a level even powerful with the psychedelic story, is it's saying something different. TMS works and there's no serotonin coming in or out of the brain. We're doing a rapid form of TMS that works in one to five days.

12:22It's very unlikely that there's some long-term upregulation of serotonin that's driving that. So our work actually kind of pushes back on this serotonin 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. Neuromodulation is a really nice use case for psychiatry 3.0 because it's a way to focally and directly perturb brain regions 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 in those same brain regions converge so the subgenual default mode network connection that we see is changing with our our stanford neuromodulation therapy technique.

13:21It's that same set of brain regions that ketamine and psilocybin seem to act on, these connections between brain networks that seem to shift. And so it refocuses the story on something that's highly correctable. And it's basically electrophysiology. And it's basically kind of recalibrating a circuit that is recalibrateable instead of I have something missing or have some set of experiences early in life that are that are going to 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 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.

14:15People can get better. We've seen with our TMS techniques, we've seen it with some of the psychedelic work that we've done where people are actually in normal levels of mood for sustained periods of time. Within five days. Within five or less days. And in the case 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 psychedelics, it was never a drug in their system in the case of TMS. And it just tells us that it's fixable. It's just like an arrhythmia in the heart. It's like a broken leg.

14:50We can go in and do something and we can get somebody better. And I think what's empowering and what a lot of patients have told me is they say, you know, I've gotten to, 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 going to be there and drive this problem forever. And I think that's, that's what's so powerful about this.

15:23Andrew Huberman:And that brings me to this question about psychedelics and, and the, frankly, the altered thinking and perception that occurs in high-dose psilocybin clinical sessions. Many people do report improvements in trauma-related symptomology and depression, as I understand it, 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. And the old problem could be the voice that they're no good, nothing will ever work out, or it could be even more subtle than that.

15:58Andrew Huberman:Why do you think the brain would ever hold on to rules that don't serve us well? I think it's an evolutionary neurobiology answer, right? I think that we end up being a result of probably a lot of biology that's not that useful in the modern era. And I think in the brain for, let's say, PTSD, right? 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 heard of folks jump and run behind a trash can or whatever in the middle of San Francisco when they hear a loud noise.

16:38But if you put them back in the battlefield, that's highly adaptive, right? We hold onto those things from I think an evolutionary neurobiology standpoint, but what seems to, for whatever reason, And kind of alleviate that 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 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.

17:22And 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 re-experience memories and then, as you know, we reconsolidating it in that state for whatever reason may 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 this sort of thing, which has a lot of cultural baggage, 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.

18:09And if it doesn't, then we clearly shouldn't use it, right? The work that's been done so far, the first psilocybin trial, the first MDMA trial that's published in Nature Medicine recently.

18:20Andrew Huberman:And what do those generally say? Let's start with psilocybin and MDMA. So MDMA appears to, in one to a few MDMA sessions, have an anti-PTSD effect that seems to be outside of the kind of standard assumed levels of PTSD improvement that you can observe in individuals with this level of PTSD, right? So does that mean that for people that have trauma who do a, and again, we're talking about in a clinical setting, they take one or two doses of MDM. I think the standard MAPS dose is 150 to 175 milligrams. Again, doing this with a physician, et cetera, controlled clinical trial, legal. Exactly. They do it once or twice.

19:04Andrew Huberman:And broadly speaking, what percentage of people who had trauma report feeling significant relief from their trauma afterward? word. It's about two thirds of people had a clinically significant change in their PTSD. That's impressive. And how long lasting was that? 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. In contrast with ketamine, which only on average lasts about a week and a half for a single infusion. So it's a much shorter.

19:38Andrew Huberman:So they have to get repeated infusions of ketamine every 10 days or so? For some people, or they end up getting like a bunch of doses for a couple of weeks. And then for some people, that seems to last a while. That's where I think the psilocybin story for depression and the MDMA story for PTSD seem more interesting to me. So for psilocybin, what is the rough percentages? And this would be relief not from trauma, but from depression. 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.

20:13In the blinded trials, it was more like a third or so of people.

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20:49Andrew Huberman:And effective therapy involves having a good rapport with your therapist, getting insights from them and with them, and coming away with specific actionable tools that you can apply outside of therapy. With BetterHelp, they make it very easy to find an expert therapist who can help provide those benefits that come through effective therapy. They have a short questionnaire to help match you to a therapist. And while BetterHelp has an industry-leading match rate, if you aren't happy with your match, you can switch to a different therapist at any time. Also, because BetterHelp is done entirely online, it's extremely efficient.

21:20Andrew Huberman:There's no driving to a therapist's office looking for parking or anything like that. You simply log on and do your session wherever you happen to be. If you would like to try BetterHelp, go to betterhelp.com slash Huberman to get 10 % off your first month. Again, that's betterhelp.com slash Huberman. Since you mentioned psilocybin, let's talk a little bit about the neurochemistry of psilocybin. What's going on when one takes psilocybin and why is it interesting in light of depression? Yeah, definitely. So David Nutt and Robin Carhart-Harris's work around neuroimaging psychedelics are kind of some of the first folks to do that work.

21:55And to their great surprise, they thought there was gonna be an increase in activity on psychedelics. and what they found is the opposite, right? There's kind of an overall decrease in the level of activity in the brain with psychedelics. But they have also looked at connectivity, and there's this kind of small world, large world connectivity that you think about. And so small world meaning there's kind of a much more kind of focused kind of cortical function or subcortical function or whatever it is. And what you see is a difference in that level of engagement of brain regions, the global connectivity kind of increases.

22:36And so it's interesting. I think to kind of have a convergent theory on this, it's still to be determined. There's still a lot of work, I think, that needs to be done. But it's certainly suggestive that there's pretty profound changes in brain activity and brain connectivity after. And what we've found to be really interesting is the antidepressant effects of psilocybin have a particular connectivity change that we also see with 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 Stanford neuromodulation therapy stimulation, we see a down regulation, the connectivity between the negatively valenced mood state in the case of depressed individuals and the self-representation of the brain.

23:32And you see that same connectivity change occur post psilocybin, you know, suggesting there's a convergent mechanism. And it makes sense, right? You've kind of got an over-connected, negatively valanced system, conflict system that's kind of attached on to the self-representation and people feel stuck. And then when you do whatever you do that's effective, it unpairs those two systems.

23:59Andrew Huberman:I want to ask you about Ibogaine. Is it legal in the U.S. as a clinical tool? Who's using it and for what purposes? Ibogaine is one of the alkaloids that you can extract from an iboga tree root bark that's typically growing in the country of Gabon, Africa. So what 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 detached empathy and being able to see this as almost a third party, even though they were there.