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

In loving memory of Nolan Williams (1982-2025): ⁠https://stan.md/3Qle2zp⁠ In this Huberman Lab Essentials episode, my guest is Dr. Nolan Williams, MD, a triple board-certified psychiatrist and neurologist. We discuss cutting-edge treatments for depression and post-traumatic stress disorder (PTSD), including transcranial magnetic stimulation, neuromodulation, and psychedelic-assisted therapies. We also discuss the neurobiology and therapeutic potential of specific psychedelic compounds, including psilocybin, MDMA, ibogaine, and ayahuasca. Read the episode show notes at hubermanlab.com. Thank you to our sponsors AG1: https://drinkag1.com/huberman Function: https://functionhealth.com/huberman BetterHelp: https://betterhelp.com/huberman Timestamps (00:00:00) Nolan Williams (00:00:21) Depression (00:02:45) Heart & Mind Connection, Transcranial Magnetic Stimulation (TMS) (00:05:15) TMS for Depression (00:07:47) Sponsor: Function (00:09:24) SSRIs & Chemical imbalance, TMS, Psychedelics (00:15:24) Psilocybin, MDMA, Trauma (00:18:21) MDMA Clinical Trials & PTSD; Psilocybin & Depression (00:20:18) Sponsor: BetterHelp (00:21:38) Psilocybin, Brain Connectivity & Depression (00:23:59) Ibogaine, Empathy; Psychedelic Breakthrough & Risk (00:30:36) Ayahuasca, Behavior Change, Prisoners (00:34:46) Sponsor: AG1 (00:36:05) Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) (00:40:07) Acknowledgements Disclaimer & Disclosures Learn more about your ad choices. Visit megaphone.fm/adchoices

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Andrew D. 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.

• 0:29Speaker 01

  Yeah.

• 0:29Andrew D. Huberman?

  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. 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.

• 0:56Speaker 01

  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. So recently, the American Heart Association added depression as the fourth major risk factor for coronary artery disease. 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. And depression ended 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.

• 1:39Speaker 01

  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. The 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.

• 2:23Speaker 01

  And I came to this because, 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.

• 2:44Andrew D. Huberman?

  Many people out there probably think of the relationship between the, the heart and the mind as kind of woo or kind of a, a soft biology, but here you're talking about an actual physical connection.

• 2:55Speaker 01

  Yep.

• 2:55Andrew D. Huberman?

  What area of the brain is it?

• 2:57Speaker 01

  You know, 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 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 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, 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

• 3:41Speaker 01

  down into the intercingulate, and the insula, and the amygdala, and ultimately, the tract goes into something called the nucleus tractus solitarius, and ultimately into the vagus nerve, into the heart. So that 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. 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, other folks work, Martin Arns in, in, in Europe, the Netherlands work, showing the same connections. I think it's been replicated like four or five times.

• 4:24Speaker 01

  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, 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 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 is 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

• 5:07Speaker 01

  it govern these deeper regions. In depression, the deeper regions govern the prefrontal cortex. In one case, it's like the coach telling the player what to do. Exactly. And it's like the player telling the coach what to do. That's right. 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 dorsolateral does not sufficiently clamp down on it. And what therapy appears to do is to kind of restore that. What we see with

• 5:48Speaker 01

  TMS over that region is that we just exogenously do the same sort of thing. We 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

• 6:32Speaker 01

  very dense stimulation approach where we can stimulate people really rapidly over a five-day block. By 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 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

• 7:15Speaker 01

  of years, when they get, they were mid early in the week, by the end of the week, they're like going to the beach and they're like totally having what people describes 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, 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. So.

• 7:46Andrew D. Huberman?

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• 8:30Andrew D. Huberman?

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• 9:14Andrew D. Huberman?

  Visit functionhealth.com/huberman and use the code huberman for a $50 credit towards your membership. Again, that's functionhealth.com/huberman. I want to make sure that before we dive into ketamine and psilocybin, that we do touch on SSRIs, selective serotonin reuptake inhibitors, because 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 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?

• 9:48Speaker 01

  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. 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 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,

• 10:31Speaker 01

  right? 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. 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 psychotherapy and its origins.

• 11:09Speaker 01

  It was a lot around, you know, your family and those experiences in 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? And so, we've transitioned from that to the, 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

• 11:51Speaker 01

  of, there's something missing with me, whether it be my experiences I had no control of, over when I was a child, or a chemical in my brain. What I think's really powerful with, with TMS, you know, really powerful TMS, and a level even powerful of the psychedelic story, is it's saying something different. You know, TMS works, and there's no serotonin coming in or out of the brain, right? And we're doing a rapid form of TMS that works in one to five days, 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 hypothesis as being kind

• 12:33Speaker 01

  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's a really nice, you know, 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 sub genuine default mode network connection that we see is changing with our

• 13:18Speaker 01

  Stanford neuromodulation therapy technique. It's that same set of brain regions that ketamine and 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 correctable. And 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 have some set of experiences early in life that are, that are going to forever trap me in these psychiatric diagnoses. And so it kind of challenges that idea.

• 14:02Speaker 01

  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 is something that are recoverable. People can get better. People, you know, we've seen with our TMS techniques, we've seen with some of the psychedelic work that we've done where people are actually in normal levels of mood for sustained periods of time.

• 14:27Andrew D. Huberman?

  Within five days.

• 14:28Speaker 01

  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, 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 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.

• 15:13Speaker 01

  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 D. Huberman?

  And that brings me to this question about psychedelics and, and the frankly, the altered thinking and perception that occurs in. 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.

• 15:52Speaker 01

  That's right.

• 15:53Andrew D. Huberman?

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

• 16:05Speaker 01

  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, 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 heard of folks who 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.

• 16:41Andrew D. Huberman?

  Highly adaptive.

• 16:42Speaker 01

  That's highly adaptive, right? We hold on to those things from, I think, an evolutionary neurobiology standpoint. But what seems to, for whatever reason, kind of alleviate that are these, 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.

• 17:25Speaker 01

  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, you know, we re-consolidating it in that state, for whatever reason, may drive, 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 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. And if it doesn't,

• 18:10Speaker 01

  then we clearly shouldn't use it, right? The, the work that's been done so far, the first psilocybin trial, the first MDMA trial was published in Nature of Medicine recently.

• 18:20Andrew D. Huberman?

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

• 18:24Speaker 01

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

• 18:44Andrew D. Huberman?

  So does that mean that for people that have trauma, who do a, and again, we're talking about in a clinical setting, they, they take a one or two doses of, of MDMA. I think the standard MAPS dose is 150 to 750 milligrams. Again, doing this with a physician, et cetera, controlled clinical trial, legal.

• 19:01Speaker 01

  Exactly.

• 19:02Andrew D. Huberman?

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

• 19:12Speaker 01

  It's about two thirds of people had a, had a clinically significant change in their PTSD symptoms.

• 19:20Andrew D. Huberman?

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

• 19:22Speaker 01

  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 it 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 D. Huberman?

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

• 19:42Speaker 01

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

• 19:59Andrew D. Huberman?

  So for psilocybin, what is the rough percentages on, and this would be relief not from trauma, but from depression?

• 20:06Speaker 01

  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 blinded trials, it was more like a third or so of people.

• 20:18Andrew D. Huberman?

  I'd like to take a quick break and acknowledge our sponsor, BetterHelp. BetterHelp offers professional therapy with a licensed therapist carried out entirely online. Now, I've been doing therapy for a long time, and I can tell you that it's a lot like physical workouts. There are times when I want to do it, and there are times when I don't want to do it. But whenever I finish a therapy session, I come away feeling better, and I have specific actionable items that hadn't occurred to me that when I implement, improve various aspects of my life. The data tell us that there are just so many benefits that come through effective therapy. 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

• 21:01Andrew D. Huberman?

  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. 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/huberman to get 10% off your first month. Again, that's betterhelp.com/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?

• 21:47Speaker 01

  Yeah, definitely. So David Nutt and Robin Card Harris's work around neuroimaging psychedelics are kind of the, some of the first folks to do that work. And, 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 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 think about. And so, you know, small world, meaning there's a lot, there's kind of a much more kind of focused kind of cortical function, or you know, sub cortical function, or whatever it is. And what you see is a

• 22:27Speaker 01

  difference in that, in that level of engagement of brain regions, the connectivity, kind of global connectivity kind of increases. And so, it's interesting, you know, I think to kind of have a convergent 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, but it's certainly suggestive that there's pretty profound changes in, in brain activity and brain connectivity after. And what we've found to be really interesting is that the antidepressant effects of psilocybin have a particular connectivity change that we also see with our TMS approaches,

• 23:11Speaker 01

  right? And it's this connectivity between the subgenial 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 valanced 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, 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, you know, kind of attached on to the self-representation, and people feel stuck, right? And then, when you, when

• 23:54Speaker 01

  you do whatever you do that's effective, it, it un, it unpairs those two systems.

• 23:59Andrew D. Huberman?

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

• 24:07Speaker 01

  Ibogaine is a, is one of the

• 24:11Speaker 01

  Alkyloids that you can extract from a 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 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

• 24:56Speaker 01

  life review. They also call it 10 years of psychotherapy in a night. So these are the terminology that people talk about. How long does it last? Is it truly one night? Depending upon how fast you metabolize it, sometimes 24, sometimes 36 hours, sometimes it can be shorter, but it is a long time. It's a very long time. So 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, to do this first in human, kind of full neurobiological, clinical, neurocognitive evaluation of what ibogaine is doing. In

• 25:36Speaker 01

  this case, in, in special operations, special forces, individuals, former Navy SEALs, former Army Rangers, that, that kind of crew folks, and look at the pre-post changes that we, that their experience 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

• 26:12Speaker 01

  Both seemingly the most potent and most, seemingly to me at least, most powerful psychedelic, but 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 reduce the risk quite a bit, and that's what we all did. But that's why people haven't really studied it as much. And it isn't as, in addition, there's no, nobody goes to rave on Ibogaine. There's no recreation at all with it. It's not fun. People say that it's relieving, but it's hard work, right? Because, yeah, you're reexamining things.

• 26:53Speaker 01

  So then we see these folks after, and 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 they, maybe they accidentally blew something up and it had a kid in it or something like that, you know? You know, if they're in Afghanistan or Iraq, maybe a child died on accident, or maybe, maybe, you know, a civilian died, or whatever it was, right? And then 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 forgiven themselves, you know, which is huge, right? And then part of that is being able to see themselves in a different light and having

• 27:38Speaker 01

  empathy finally for themselves and being able to kind of have that experience of forgiving. And so there's this kind of Timothy Leary kind of socio-cultural 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, neither of us ever partake in, you know, as kind of straight scientists looking at this, right? If you can kind of rid yourself of all those socio-cultural constructions and then reexamine this. These, if we just discovered these today, we would say that these sorts of drugs are

• 28:20Speaker 01

  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 SSRIs, with psychotherapy, but kind of combined, right? Psychotherapy plus drugs in a substance that kind of allows you to reexamine these things. And so 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 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

• 29:01Speaker 01

  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 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 this whole kind of cultural thing that was going on there.

• 29:41Speaker 01

  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 were very worried about that and the doctor has to evaluate you for that every week, that the idea that some of these substances would go outside of very strict medical supervision is kind of preposterous, actually. It's kind of, it's kind of a dumb moment, I think, 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

• 30:24Speaker 01

  and they're really for the pure purposes of really powerfully changing cognition for a while and letting people have these. What seemed to be relatively therapeutic states.

• 30:36Andrew D. Huberman?

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

• 30:49Speaker 01

  Yeah, yeah, definitely. Ayahuasca is another psychedelic. It's used as a sacrament in Brazil and Peru and Ecuador and Colombia. So a lot of the South American countries. 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, 10,000 to 20,000 plant species in the Amazon. And somehow, somebody

• 31:33Andrew D. Huberman?

  Someone tried them all.

• 31:34Speaker 01

  Combined 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 reversible monoamine oxidase inhibitor prevents 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.

• 32:15Speaker 01

  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 like sweet spot that somehow ayahuasca practitioners have found, being able to get DMT into the brain from an oral source with this combination of a monoamine oxidase inhibitor is curious. 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 was a psychiatrist down at UCLA Harbor who's done a lot of work with this where where he's looked at children

• 32:59Speaker 01

  even that have been exposed to small doses of ayahuasca as a kind of a sacrament within Amazonian 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 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

• 33:43Speaker 01

  they gave half of the prisoners, you know, some sort of inert substance and half of the prisoners a ayahuasca session. And the recidivism rate or the return to prison rate in the ayahuasca exposed individuals was statistically significantly lower than the recidivism rate in the in the control group, suggesting that, 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. You know, I am also in no way saying that we should just be giving psychedelics

• 34:23Speaker 01

  to to folks in prison and all of that. I think 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 what is it about that that would drive people to to change those behaviors? And why, why do people make those behavioral decisions?

• 34:46Andrew D. Huberman?

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• 35:29Andrew D. Huberman?

  If you'd like to try AG1, you can go to drinkag1.com/huberman to get a special offer. For a limited time, AG1 is giving away a week's supply of AGZ, which is their sleep supplement, and a free bottle of vitamin D3K2 with your subscription. AGZ is something that I helped design, it tastes great, and it's the only sleep supplement I take. It has a collection of different things in it that has dramatically improved my sleep, both my slow-wave deep sleep and my rapid eye movement sleep, and I absolutely love it. Again, that's drinkag1.com/huberman to get a week's supply of AGZ and a bottle of D3K2 with your subscription. Before we wrap, I do want to give you the opportunity to talk about the SANT study.

• 36:09Speaker 01

  Yeah, SANT, or what we're calling at S and T now, Stanford Accelerated Intelligent Neuromodulation Therapy, or now we're calling Stanford Neuromodulation Therapy. The idea there is that TMS is a device that delivers a treatment, 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

• 36:51Speaker 01

  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 this problem that 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 spaced learning theory. And so you probably know about the spaced learning theory. The idea for the viewers is if I'm 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 spaced learning theory.

• 37:35Speaker 01

  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 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 spaced 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.

• 38:18Speaker 01

  So we figured out it's not just one day, we're going to give five times the normal dose, we're going to have seven and a half months worth in five days using spaced learning theory. So every hour? Every hour for 10 hours. For five days? 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, within one to five days, 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 durability.

• 39:01Speaker 01

  So that's the part we have to figure out now about dosing and how to keep people well. But for some people, we've had four years of remission, a year of remission, and 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 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 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 hand, your own hippocampus's hand, as you're sending the same signal the hippocampus normally signals out.

• 39:40Speaker 01

  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, is that people, when they, when they kind of exit out of that, they end up, they end up saying they don't have any, any side effects from it and they feel back to normal.

• 40:06Andrew D. Huberman?

  Thank you so much 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 therapeutic compounds, how they work. We've talked about a lot of things today and you've, you've shared so much knowledge. And even as I say that, I, I very much want to have you back to talk about 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 avoiding often suicidal depression. It's just incredible work and incredible generosity and just thank you so much.

• 40:47Speaker 01

  Absolutely. Thank you.

• 40:53Speaker 02

  Mr. President, my company tore me of the explosion on our rig on October 2nd. Causing massive water displacement and triggering a tsunami. They all heap the blame on me.

• 41:03Speaker 03

  Tom Cruise is. Digger got us into this mess and Digger's gonna dig us up. From the director of Birdman and the Revenant.

• 41:10Speaker 04

  What would happen if I stopped going? You start, you freeze in there, that's what.

• 41:14Speaker 03

  With great power comes great deniability.

• 41:17Speaker 04

  I'm not the first then.

• 41:19Speaker 03

  Digger, see the trailer online, only appears October 2nd. Rated R, under 17, not a middle without parent.