Andrew Huberman interviews Stanford psychiatrist Dr Nolan Williams on TMS, psychedelics, and emerging treatments for depression
Andrew Huberman speaks with Dr Nolan Williams, a dual-trained neurologist and psychiatrist at Stanford, about cutting-edge approaches to treating depression and trauma.
Summary
Dr. Nolan Williams, a dual-trained neurologist and psychiatrist at Stanford, joins Andrew Huberman to examine the neuroscience of depression and a range of emerging treatments, from transcranial magnetic stimulation (TMS) to psychedelics including psilocybin, MDMA, ibogaine, and ayahuasca. Williams argues that depression is best understood not as a chemical imbalance but as a circuit-level dysfunction — specifically, a failure of the left dorsolateral prefrontal cortex to regulate the anterior cingulate — and that this framing opens the door to rapid, targeted interventions. He presents data from Stanford's accelerated TMS protocol (Stanford Neuromodulation Therapy, or SNT), which compresses months of treatment into five days and achieves full remission in 60–90% of cases. Williams also discusses clinical trial results for psilocybin in depression and MDMA in PTSD, and describes his team's first-in-human neurobiological study of ibogaine in special operations veterans, reporting dramatic reductions in PTSD symptoms and moral injury.
He frames the evolution of psychiatry across three eras: psychiatry 1.0 (Freudian psychotherapy and family-based explanations), psychiatry 2.0 (the chemical imbalance model), and psychiatry 3.0 (circuit-level dysfunction that is directly recalibratable), arguing that this third framework is both scientifically more accurate and therapeutically more empowering for patients.
Key Takeaways
FULL TRANSCRIPT
Introduction and the Global Burden of Depression
Andrew Huberman: 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. 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.
Dr Nolan Williams: 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. Recently, the American Heart Association added depression as the fourth major risk factor for coronary artery disease — alongside hypertension, high blood pressure, hyperlipidemia, high cholesterol, and diabetes. Those three have been on the list for a long time, and depression ended up being added as the fourth one.
A lot of what we're doing in the lab is measuring brain-heart connections. 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, so it's actually a direct probe of that connection.
We've been very interested in a particular clinical set of problems around the most severe and highest acuity settings that people with depression end up in — emergency settings, inpatient units. The field really hasn't developed a way of consistently being able to treat that problem. People end up getting the same standard oral antidepressants they've been getting as outpatients. I came to this because I dual-trained as a neurologist and psychiatrist, went back and forth between the two, saw that in neurology we have all of these ways of treating acute brain-based problems, and really wanted to emulate that in psychiatry — to find ways to develop and engineer new brain-based solutions.
The Brain-Heart Connection and How TMS Works
Andrew Huberman: Many people out there probably think of the relationship between the heart and the mind as kind of soft biology. But here you're talking about an actual physical connection. What area of the brain is it?
Dr Nolan Williams: The first place where the stimulation goes is called the dorsolateral prefrontal cortex — it's kind of the sense of control, the governor of the brain. What we know is that when you use a magnet — what we call Faraday's law, this idea of using a magnetic pulse to induce an electrical current in electrically conducting substances, in this case brain tissue but not skull or scalp or hair — you have a direct depolarization of cortical neurons, the surface neurons of the brain in this dorsal prefrontal region.
If you do that inside the actual scanner, which we can do, you can see that the signal distributes down into the anterior cingulate, the insula, and the amygdala, and ultimately the tract goes into something called the nucleus tractus solitarius and ultimately into the vagus nerve and into the heart. So the heart very consistently seems to be the end organ of the dorsolateral prefrontal cortex. If you do the same stimulation over visual cortex or motor cortex, you don't get any of those findings — it's really specific to this control region of the brain.
It's our work and other people's work — Martin Arns in the Netherlands showing the same connections. I think it's been replicated four or five times.
Where I think TMS is really interesting: we had a lot of patients who told me their therapist said they weren't trying hard enough in therapy. These are moderate to pretty severe depressed patients. As soon as we get them well with the TMS approaches — a rapid five-day approach — the next week they come in and say, "You know what I did all weekend? I looked at my therapy books and now I can understand it." So I actually see TMS as a way of providing exogenously the sorts of cognitive functions that in milder forms of depression we can pull off with psychotherapy — this idea of being able to turn that prefrontal cortex on and have 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, and in the other case it's like the player telling the coach what to do. You restore order to the game.
You restore order to the game, and what it looks like is that depression is a bunch of kind of spontaneous content that's semi-volitional, being generated out of this conflict detection system — the cingulate. In depression, it looks like the left dorsolateral does not sufficiently clamp down on it. What therapy appears to do is restore that. What we see with TMS over that region is that we 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. The degree to which you can re-time or re-regulate the left dorsolateral over the cingulate, the more of an antidepressant effect you have.
TMS is almost like exercise for the brain. You're exercising this region over and over again with a physiologically relevant signal and turning that system on.
What's interesting is we had probably five or six people who told me this: 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 at zero on the depression scales, even better than most people walking around, really no anxiety, no depression at all. By Thursday, the first person who told me this came in and said, "I was driving back to my hotel and I decided to go to the beach, and I just sat there and was totally present in the present moment for an hour. I read about this in my mindfulness books, but I experienced it last night and I've never experienced anything like this before."
I didn't tell any more patients about that. But about five people over the last couple of years, when they get well early in the week, by the end of the week they're going to the beach and having what people describe as a pretty mindful, present-moment experience. I don't have full scientific data to tell you what that is, but it's an interesting anecdote — that when you push people through this point of feeling clinically well, some of them end up reporting this additional set of features.
SSRIs: What They Do and Don't Do
Andrew Huberman: I want to make sure that before we dive into ketamine and psilocybin, we touch on SSRIs — selective serotonin reuptake inhibitors — because we can't really have a discussion about depression without talking about them. My understanding is that SSRIs are powerfully effective for certain forms of obsessive-compulsive disorder and may also be effective for treatment of depression. How should we think about SSRIs? Are they useful?
Dr Nolan Williams: SSRIs clearly work. Many meta-analyses prove that out — in a subpopulation of individuals, they achieve great benefit for depression, for obsessive-compulsive disorder, for generalized anxiety disorder, panic, all of these things. You can see an improvement in those symptoms with SSRIs.
The issue is that they don't work immediately. They don't work the same day you start taking them. That suggests that probably it's not exactly the serotonin being present that's directly driving the effect — it's much more likely that they have some brain plasticity effects. There's not a deficit of serotonin. You're not born with what people call a chemical imbalance. Psychiatry has known this for a while. It's not actually new information — it's kind of a rehashing of things we've known for some time. But in the lay press it's hit in a way that it didn't seem to grab attention with previous publications.
This idea that the chemical imbalance model is wrong — I think that part's important. What I'll call psychiatry 1.0 was a lot around Freud, psychotherapy, and its origins — your family, those experiences, psychotherapy going in and helping you figure things out, showing you being able to see, so that you can eventually arrive at certain cognitions that aren't helping you. Things like the schizophrenogenic mother — that was a concept at some point. We've transitioned from that to, for a long time, the chemical imbalance, which I'll call psychiatry 2.0. The trouble there for a patient is that it sends a message: there's something missing with me — whether it be experiences I had no control over as a child, or a chemical in my brain.
What I think is really powerful with TMS, and at some level with the psychedelic story, is that 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, so it's very unlikely that there's some long-term upregulation of serotonin driving that. Our work actually pushes back on the serotonin hypothesis as being the center of depression, because it says: we're not giving anybody any serotonin. We're simply turning these brain regions on. We're focused on the circuitry. That's psychiatry 3.0.
Neuromodulation is a really nice use case for psychiatry 3.0 because it's a way to focally and directly perturb brain regions. But there are also a lot of groups 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 — suggesting that those same brain regions converge. The subgenual default mode network connection that we see changing with our Stanford Neuromodulation Therapy technique is that same set of brain regions that ketamine and psilocybin seem to act on. These connections between brain networks seem to shift.
So it refocuses the story on something that's highly correctable — it's basically electrophysiology, basically recalibrating a circuit that is recalibratable — instead of "I have something missing" or "I have a set of experiences early in life that are going to forever trap me in these psychiatric diagnoses." It challenges that idea. That's what's so powerful about psychiatry 3.0: focusing on the circuit, because it gets us thinking about psychiatric illnesses as something that are recoverable. People can get better.
We've seen it with our TMS techniques, we've seen it with some of the psychedelic work we've done, where people are actually at normal levels of mood for sustained periods of time.
Andrew Huberman: Within five days.
Dr Nolan Williams: Within five or fewer days. And in the case of the psychedelics, within a few days. 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 TMS, there was never a drug in their system. And it just tells us that 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 get somebody better.
What's empowering — and what a lot of patients have told me — is they say, "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 things I couldn't control in my childhood are going to be there and drive this problem forever." And I think that's what's so powerful about this.
Psilocybin, Trauma, and Why the Brain Holds On to Unhelpful Rules
Andrew Huberman: That brings me to the question about psychedelics and the frankly altered thinking and perception that occurs in high-dose psilocybin clinical sessions. Many people do report improvements in trauma-related symptomology and depression after taking psilocybin, because during those sessions something comes to mind spontaneously. They report a new way of seeing the old problem. The old problem could be the voice that says they're no good, that 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?
Dr Nolan Williams: I think it's an evolutionary neurobiology answer. We end up being a result of biology that's probably not that useful in the modern era. For PTSD — a lot of veterans come back and experience PTSD symptoms that are not at all useful back home. They hear a loud noise and all of a sudden they're behind a car. I've heard of people jumping and running behind a trash can in the middle of San Francisco when they hear a loud noise.
Andrew Huberman: But if you put them back in the battlefield —
Dr Nolan Williams: Highly adaptive. We hold on to those things from an evolutionary neurobiology standpoint. But what seems to alleviate that — for whatever reason — are these substances. Some newer, like MDMA; some that have been around for thousands of years, like psilocybin. They seem to have a therapeutic effect that's pretty long-lasting for these phenomena.
It's curious that in the absence of these substances, these things will keep going on and on, but in the presence of that exposure, you see a resolution of the problem. We have work now treating Navy SEALs, and the anecdotes we're getting are that people come back and say these PTSD symptoms are finally gone. This idea that going into what's probably a highly plastic state, re-experiencing memories, and then reconsolidating them in that state — for whatever reason — may drive a therapeutic effect.
My business is to find treatments that help people. I'm pragmatic about it. If this sort of thing — which has a lot of cultural baggage — 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.
MDMA for PTSD and Psilocybin for Depression: Clinical Trial Results
Andrew Huberman: What do the clinical trials generally say? Let's start with psilocybin and MDMA.
Dr Nolan Williams: MDMA appears to have, in one to a few sessions, an anti-PTSD effect that seems to be outside of the standard assumed levels of PTSD improvement you can observe in individuals with this level of PTSD.
Andrew Huberman: So for people who have trauma — and again, we're talking about a clinical setting, they take one or two doses of MDMA, the standard MAPS dose is 150 to 175 milligrams, doing this with a physician in a controlled clinical trial — they do it once or twice, and broadly speaking, what percentage of people who had trauma report significant relief afterward?
Dr Nolan Williams: About two-thirds of people had a clinically significant change in their PTSD.
Andrew Huberman: That's impressive. And how long-lasting was that?
Dr Nolan Williams: It appears to last for a while. In the earlier trials where they followed people out, it seemed to last in the years range for some people. It's pretty compelling. Contrast that with ketamine, which on average only lasts about a week and a half for a single infusion — a much shorter duration.
Andrew Huberman: So they have to get repeated infusions of ketamine every ten days or so?
Dr Nolan Williams: For some people, or they end up getting a bunch of doses over a couple of weeks, and for some people that seems to last a while. But I think the psilocybin story for depression and the MDMA story for PTSD seem more interesting to me.
Andrew Huberman: So for psilocybin, what are the rough percentages for relief from depression?
Dr Nolan Williams: In open-label studies, it's closer to half to two-thirds of people ending up getting better, depending upon their level of treatment resistance. In the blinded trials, it was more like a third or so of people.
The Neurochemistry of Psilocybin
Andrew Huberman: Since you mentioned psilocybin, let's talk a little bit about its neurochemistry. What's going on when one takes psilocybin, and why is it interesting in light of depression?
Dr Nolan Williams: David Nutt and Robin Carhart-Harris's work around neuroimaging psychedelics — they were some of the first people to do that work. To their great surprise, they thought there was going to be an increase in activity on psychedelics, and what they found was the opposite: there's an overall decrease in the level of activity in the brain with psychedelics. But they've also looked at connectivity — there's this small-world versus large-world connectivity that you think about. Small-world meaning there's much more focused cortical or subcortical function, and what you see is a difference in the level of engagement of brain regions. The global connectivity kind of increases.
To have a convergent theory on this is still to be determined — there's a lot of work that needs to be done. But it's certainly suggestive that there are pretty profound changes in brain activity and brain connectivity after psychedelics.
What we 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 — the connectivity between the subgenual anterior cingulate and the default mode network. When we do effective Stanford Neuromodulation Therapy stimulation, we see a downregulation of 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, suggesting a convergent mechanism.
It makes sense: you've got an overconnected, negatively valenced system — a conflict system — that's kind of attached onto the self-representation, and people feel stuck. When you do whatever you do that's effective, it unpairs those two systems.
Ibogaine: The Longest-Acting Psychedelic and Its Use in Veterans
Andrew Huberman: I want to ask you about ibogaine. Is it legal in the US as a clinical tool? Who's using it and for what purposes?
Dr Nolan Williams: Ibogaine is one of the alkaloids you can extract from the iboga tree root bark, which typically grows in Gabon, Africa. What individuals taking ibogaine will say is that with eyes open they don't see anything, but with eyes closed they go back through and re-experience earlier life memories — and they're able to experience those from a place of empathy, not only for themselves but for others, with a kind of detached empathy, being able to see it almost as a third party even though they were there.
Ibogaine is in no way a recreational substance. You're essentially having what they call a life review. They also call it ten years of psychotherapy in a night. Those are the terms people use.
Andrew Huberman: How long does it last? Is it truly one night?
Dr Nolan Williams: Depending upon how fast you metabolize it — sometimes 24 hours, sometimes 36 hours, sometimes it can be shorter. But it is a long time. It's definitely the longest-acting psychedelic substance I know of.
Over the last couple of years, we've been able to do this first-in-human, full neurobiological and clinical neurocognitive evaluation of what ibogaine is doing — in this case in special operations and special forces individuals: former Navy SEALs, former Army Rangers, that crew of people. We've looked at the pre-post changes they're experiencing and been able to fully quantify all of that. We've captured all the clinical scales — depression scales, PTSD scales, all the standard stuff — neurocognitive batteries covering executive function, verbal memory, all of that — and then neuroimaging and EEG. This will be the first human study of ibogaine for those populations.
The reason ibogaine hasn't been studied as much is that it's both seemingly the most potent and most powerful psychedelic, but also the one with the most risk, because it has a cardiac effect. It seems that you can screen people out who are at risk based on their electrocardiogram and reduce the risk quite a bit, which is what we did. But that's why people haven't really studied it as much. And there's no recreational use — nobody goes to a rave on ibogaine.
Andrew Huberman: It's not fun. People say it's relieving, but it's hard work.
Dr Nolan Williams: Exactly — you're re-examining things. So we see these folks afterward, and I'll tell you, we haven't fully analyzed the data yet, but from what my people are telling me, it's pretty dramatic. People come back and they're doing a lot better.
Soldiers experience something called moral injury — maybe they accidentally blew something up and there was a child in it, or a civilian died. They suffer these moral injuries as part of the job. It's almost one of the vocational risks. They come back and say they've forgiven themselves, which is huge. Part of that is being able to see themselves in a different light, having empathy for themselves finally, and being able to have that experience of forgiving.
There's this Timothy Leary kind of sociocultural construct that ends up being overlaid over psychedelics. What I think is that if you rid yourself of all those preconceived notions — the counterculture movement, all that stuff — and as straight scientists looking at this, you re-examine these substances: if we just discovered these today, we would say they are a huge breakthrough in psychiatry. They allow us to do a lot of the sorts of things we've been thinking about with SSRIs and with psychotherapy, but combined — psychotherapy plus drugs in a substance that allows you to re-examine these things.
There's a lot to do to figure out if that's true. As it stands right now, we don't know if that statement is true — there's a lot more work that needs to happen for it to be proven. 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 things you can't do with normal waking consciousness.
But also, why we have to really think carefully about this: these drugs can't be recreational drugs. They really shouldn't be recreational drugs. They're too powerful to be used in the context of recreation. This generation of psychedelic researchers is really clear about that. I think the '60s folks were not clear about that — they felt like there was this whole cultural thing going on. But this cohort of individuals really understands that in order to make this work, we have to understand that if you need a prescription for an SSRI — which doesn't change your consciousness a whole lot, and we're very worried about that, and the doctor has to evaluate you for it regularly — then the idea that some of these substances would go outside of very strict medical supervision is kind of preposterous. It's a dumb moment for all of medicine if we don't do this right. We've got to do it in such a way that's so protected, so safe, that people know these things are not recreational — they're really for the pure purpose of powerfully changing cognition for a while and letting people have what seem to be relatively therapeutic states.
Ayahuasca: Pharmacology, Safety, and the Brazilian Prison Study
Andrew Huberman: Tell me about ayahuasca as a plant. Is it useful for the same sorts of conditions we've talked about? And could you tell me a little about the Brazilian prisoner study?
Dr Nolan Williams: Ayahuasca is another psychedelic. It's used as a sacrament in Brazil, Peru, Ecuador, and Colombia — a lot of South American countries. What they do is 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.
What's really curious is that there are, as I understand it, ten to twenty thousand plant species in the Amazon, and somehow somebody —
Andrew Huberman: Someone tried them all.
Dr Nolan Williams: — combined these two plants together in certain proportionality and cooked this for five to ten hours, to the point where you cook the dimethyltryptamine out of one of the plants and cook the reversible monoamine oxidase inhibitor out of the other plant, in such a way that the reversible monoamine oxidase inhibitor prevents the gastrointestinal breakdown of the dimethyltryptamine, allowing it to cross the blood-brain barrier and get into the brain. If you didn't add the reversible monoamine oxidase inhibitor plant into this combination, it would never cross into 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. So this kind of sweet spot that ayahuasca practitioners have found — getting DMT into the brain from an oral source with this combination — is curious.
That substance has been explored as an antidepressant agent and some studies have looked at that. It also appears to be very safe. There's a psychiatrist at UCLA Harbor who's done a lot of work with this, looking at children even who've been exposed to small doses of ayahuasca as a sacrament within Amazonian tribes, and found no neurocognitive effects — no neurocognitive effects in adults either. So it appears to be safe. It's been incorporated into various religions, including merged with Catholicism in South America, which is very interesting. In some sects of Catholicism in Brazil it's used as a sacrament during religious ceremonies.
So it became interesting to Brazilian researchers as to whether or not they could affect recidivism rates for prisoners in Brazilian prisons. They gave half the prisoners some sort of inert substance and half an ayahuasca session. The recidivism rate — the return-to-prison rate — in the ayahuasca-exposed individuals was statistically significantly lower than in the control group, suggesting that whatever is going on there seems to have an effect on whatever drives criminal behavior.
I don't have the details on the exact nature of the crimes, and I am in no way saying we should just be giving psychedelics to people in prison — I think that's a very edgy thing to do and probably not something anybody should try. But it does bring up this curious question of what it is about that experience that would drive people to change those behaviors, and why people make those behavioral decisions.
Stanford Neuromodulation Therapy (SNT): Compressing Six Weeks into Five Days
Andrew Huberman: Before we wrap, I do want to give you the opportunity to talk about the SNT study.
Dr Nolan Williams: SNT — what we're now calling Stanford Neuromodulation Therapy, previously Stanford Accelerated Intelligent Neuromodulation Therapy or SAINT. The idea is that TMS is a device that delivers a treatment, and the treatment is the protocol — the stimulation parameter set in a specific brain region for a specific condition. Whether it be transcranial magnetic stimulation, transcranial direct current stimulation, or deep brain stimulation, in all of those cases the device itself is a physical conduit of a stimulation protocol that's therapeutic for a given condition in a given brain region.
We decided: given this problem I talked about at the beginning — that we don't have a treatment for people in these high-acuity psychiatric emergency states — 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.
The idea for viewers: if I'm cramming for a test, I write out sixty note cards and read each one for a minute until I get back to the first note card — about an hour later. That's spaced learning theory. You need to see the material about every hour to an hour and a half, and that optimizes learning.
What we found was that the old way of doing TMS — once a day, every day, five days a week for six weeks — didn't utilize spaced learning theory. It's like studying just a little bit once a day for a month or two. You remember some of that stuff, but it's not as potent as that week where you're cramming. We realized that if we could reorganize the stimulation in time, we could take the whole six-week course and do it in a day. And then we also figured out that people were being underdosed — if you just kept going after six weeks, out to months three, four, and five, more and more people got better. So it's not just one day. We're going to give five times the normal dose — the equivalent of seven and a half months of treatment in five days, using spaced learning theory.
Andrew Huberman: Every hour, for ten hours —
Dr Nolan Williams: For five days. So it's a fifty-hour block. It's ninety minutes of actual stimulation but spread out through the day in the same way as spaced learning.
What we've found is that within one to five days — in more cases than not, somewhere between 60 and 90% of the time depending on whether you're looking at open-label or trial data — people will go into full remission in the sense that they're totally normal from a mood standpoint at the end of this. With variable durability, which is the part we have to figure out now in terms of dosing and how to keep people well. But for some people we've had four years of remission, a year of remission.
It's really that cramming of the test. You're laying in that information to exactly the right spot. The signal is a simple signal but a profound one — turn on, stay on, remember to stay on. You're sending this memory signal into the brain in such a way that you're taking it out of the hippocampus's hands and sending the same signal the hippocampus normally sends out, but now directing it into the prefrontal cortex — utilizing the brain's own communication style to get it out of this state.
What's very cool is that when people exit out of that, they say they don't have any side effects and they feel back to normal.