One Dose That Heals Addiction, PTSD, and Brain Injury? Dr. Nolan Williams on The Science of Ibogaine

For decades, psychiatry has relied on treatments that are slow and often ineffective. But what if one intervention could reset the brain, break the grip of addiction, and open the door to an entirely new model of care? On this episode of The Dr. Hyman Show, I sit down with Dr. Nolan Williams, a Stanford neuropsychiatrist pioneering new therapies for substance use disorders, depression, PTSD, and traumatic brain injury. We dive into these fascinating topics and more; watch the full conversation on YouTube or listen wherever you get your podcasts. You’ll learn: • Why ibogaine is unlike any other psychedelic—and how it could reset the brain • Its promise for treating substance abuse disorders and breaking cycles of addiction • The safety step that makes ibogaine treatment possible for real patients • Why psychiatry is shifting from trial-and-error to targeted brain circuits Talks like this remind me just how close we are to real breakthroughs in mental health. Dr. Williams calls it psychiatry 3.0. It’s a new era of treatments that actually heal the brain, and it gives me great hope for the future of medicine. View Show Notes From This Episode Get Free Weekly Health Tips from Dr. Hyman https://drhyman.com/pages/picks?utm_campaign=shownotes&utm_medium=banner&utm_source=podcast Sign Up for Dr. Hyman’s Weekly Longevity Journal https://drhyman.com/pages/longevity?utm_campaign=shownotes&utm_medium=banner&utm_source=podcast Join the 10-Day Detox to Reset Your Health https://drhyman.com/pages/10-day-detox Join the Hyman Hive for Expert Support and Real Results https://drhyman.com/pages/hyman-hive This episode is brought to you by Seed, Sunlighten, Function Health,Timeline, AirDoctor and Pique. Visit seed.com/hyman and use code 25HYMAN for 25% off your first month of Seed's DS-01® Daily Synbiotic. Visit sunlighten.com and save up to $1400 on your purchase with code HYMAN. Join today at FunctionHealth.com/Mark and use code HYMAN100 to get $100 toward your membership. Support essential mitochondrial health and save 10% on Mitopure. Visit timeline.com/drhyman to get 10% off today. Get cleaner air. Right now, you can get up to $300 off at airdoctorpro.com/drhyman. Receive 20% off FOR LIFE + a free Starter Kit with a rechargeable frother and glass beaker at Piquelife com/Hyman.

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

• 0:00Speaker 00

  Coming up on this episode of the Dr. Hyman Show. What you said blew my mind, which is that there's this compound out there that can abruptly interrupt a withdrawal from addiction, that can help treat PTSD, depression, traumatic brain injury, better than anything else we have out there on the market, and orders of magnitude more.

• 0:17Speaker 01

  Dr. Nolan Williams. Is a triple board-certified neuropsychiatrist. And founder of Stanford's Brain Stimulation Lab.

• 0:23Speaker 02

  He's redefining how we treat depression, PTSD, and addiction. Using brain stimulation, psychedelics, and neuroscience instead of meds.

• 0:31Speaker 03

  I mean, there was a WHO statistic that really struck me, which is one out of two people will have a DSM diagnosis at some point in their lifetime.

• 0:40Speaker 00

  I think this is like a really paradigm shifting moment, where work like yours have really started to push the envelope and say, hey, wait a minute, like, we're thinking about mental illness all wrong. We're talking about like, one dose, one day, having an effect to reverse your brain age by a year and a half and a month. That's pretty remarkable. Is it dangerous for these people to do it?

• 1:02Speaker 00

  All right, Nolan, great to have you on the podcast. Thanks for being here.

• 1:05Speaker 03

  Thanks for having me.

• 1:06Speaker 00

  You know, I followed your work. I first heard you talk about, three, four years ago, what you said blew my mind, which is that there's this compound out there that can abruptly interrupt a withdrawal from addiction, that can help treat PTSD, depression, traumatic brain injury, better than anything else we have out there on the market, and orders of magnitude more. And I became very interested in following this conversation about this incredible compound called Ibogaine, that we're going to learn more about today. And it comes from a bark of a tree in Gabon in West Africa. It's used in ritual ceremony there for different kinds of ritual transitions through life.

• 1:50Speaker 00

  It's got a fascinating history. Maybe I would love to start by helping us understand, you know, what is it exactly? And When was it first sort of discovered to be useful in mental health? Which is really the focus of your work at Stanford and a lot of the published trials you've done and the exciting work to actually scale this up and make it more affordable and accessible and usable to many, many people who suffer. Because you know, the truth is, one in four people have had sexual abuse, which is crazy. Trauma is a real thing, whether it's micro traumas because your parents neglected you or big traumas, Gabor Matyak's about big T, little T trauma. They can register in your nervous system and have lifelong effects on your mental

• 2:33Speaker 00

  health, on your functioning, on your perceptual worldview. And all that influences your ability to be happy and function in the world and have a filled life. You know, psychiatric medicine is just very antiquated. It's very crude. It's tremendous side effects of the drugs we use. Many of them don't work very well. And we're kind of in this unfortunate situation where mental health crisis is bigger than ever. We have fewer things that really work. And this seems to hold a promise of something really quite different.

• 3:04Speaker 03

  Yeah, thanks for the intro there. Yeah, it's, you know, it's an interesting compound. It's been around for a long time. It's an African root bark psychedelic, as you suggested, from Gabon and central west Africa, so kind of neighboring areas. And the group of people that use it are called the Bouiti. And Bouiti just means that you've taken iboga in ritual ceremony, right? And so folks have been doing this for quite a long time. And they've been doing it because it has a, it produces this kind of what people would call a transformative psychological experience.

• 3:45Speaker 03

  So people will go into this, they'll have kind of a massive change in consciousness over the course of, you know, 24 to 36 hours. And during that time, they'll have a psychological experience of reevaluating earlier life, emotionally salient memories. And for maybe all of us, for a lot of us, those are, you know, trauma at various scales, you know? And people will take a look at those earlier life, kind of emotionally salient events, but they'll do it from a position, kind of a third-party position of seeing it from neutrality. So unlike MDMA where people will take that and they'll need to,

• 4:28Speaker 03

  while taking that, kind of be led into a memory and then they have this kind of positive emotion about it. Ibane, you know, from the subjective sense, people will report, seems to produce kind of a neutrality and it kind of automatically puts people in that space. So you're not being, you're not being guided or there's no therapist. The drug just automatically puts your brain into this mode, it seems. And then people have what they call this life review or slideshow where they're looking at these emotionally salient memories over time. And when they do that, they're able to see, they're able to see the, you know, the memories from a different lens. And, you know, it looks

• 5:12Speaker 03

  like they reconsolidate the memories and then they're able to, with that reconsolidation, really be able to kind of tolerate them or see them in a different way or accept them. And that's pretty powerful. To your point, you know, psychiatric medicine has created tools that look a lot like, you know, medieval or 15th century, whatever, keys, right? Like, we've thought about the brain like a single-toothed key that you put the key into the lock and you turn it and the key unlocks the door. But the brain is probably much more like a modern-day key with a lot of different pins and a lot of different interactions. So when you put the key into the lock, it really needs to interact with a lot of different

• 5:55Speaker 03

  systems. The problem with, in my view, with kind of current psychopharmacology and the way that we see it, is that we still think that it's a single neurotransmitter, a single receptor problem.

• 6:09Speaker 00

  Serotonin's low, so take serotonin-reptine inhibitors like Prozac or, your dopamine's low, so take basically speed, otherwise known as Adderall or Ritalin.

• 6:19Speaker 03

  If you look at the pharmacology of Ibogaine, it's very broad-acting, right? So it actually interacts with a lot of, I mean, essentially all of the neurotransmitter systems in a unique way. And it's probably...

• 6:34Speaker 03

  It, you know, if this were to, you know, ultimately be as therapeutic as the initial signals are, and we're able to see in big multi-site trials, the sort of data that we're seeing now in, in our studies and studies coming out of, that are going to be completed soon out of Texas, then it tells us something about the way we're thinking about pharmacology and that this kind of idea of a dirty drug or a kind of a multi-receptor drug system is probably correct. And this idea of a single neurotransmitter system, low serotonin or whatever, where we're simplifying things down is probably oversimplified, you know, and then those tools are too coarse.

• 7:12Speaker 00

  You know, in medicine, we call the, the sort of multiple effect phenomenon pleiotropic effects, which means they work on many, many different pathways and systems. You know, I want to get into sort of more of the applications of it and what you, what you found, but the mechanism of action is really interesting because we're sort of still deciphering that. But it works on both the structure and the function of the brain. So it doesn't just change it in the moment. It seems to have lasting changes, which is why, and I think we're still trying to figure out, you know, why, why if you take it once, if you're a heroin addict, that your addiction cravings go away and your withdrawal symptoms don't happen, which is something you, is a physiological response. It's not like they're psychologically

• 7:55Speaker 00

  suppressing the withdrawal symptom. They just don't have them.

• 7:58Speaker 03

  Yeah.

• 7:59Speaker 00

  And that's really fascinating. And I think, you know, for PTSD, you've got the NDA receptors, which are the sort of excitatory receptors that get calmed down, which get overexcited with trauma. It does affect somehow the serotonin system. It affects brain factors like PDNF, which is otherwise known as brain-derived neurotrophic factor that helps stimulate brain growth and connectivity, neurogenesis, neuroplasticity, more brain cells, more connections between brain cells. So they do all these really interesting things that repair the brain, heal the brain, even in traumatic brain injury, which is where you get banged on the head from something where you're in a war zone and you get some kind of traumatic brain injury. It seems to work on that too. So it seems to have all these varying effects. And they also sort of...

• 8:44Speaker 00

  Inhibit what we call the default mode network, which is what a lot of other psychedelics do. It's sort of the ego and the self-protection part of your brain, which is, you know, makes us feel separate and disconnected. And when that is suppressed, whether you meditate for 40 years, or you take psilocybin, or LSD, MDMA, or Ibogaine, that quiets down quickly and your, your sense of disconnection and separateness is suspended for a moment. And it allows you to sort of see how you're actually part of a greater, greater whole. And that, and so I kind of would love you to unpack some of the, the mechanisms and how they work in these different disease states. Cause it's like, seems like a one size fits all. You know, you got PTSD, you got depression, you got anxiety, you got trauma, you got brain injury. Can you kind of unpack those for us and talk about, you know, how they

• 9:29Speaker 00

  affect across these various pathways in the brain?

• 9:32Speaker 03

  Yeah, that's a great question. So the other mechanism that, that we've thought a lot about, that's unique to Ibogaine is glial-derived neurotrophic factor, right? So glial-derived neurotrophic factor is a neurotrophic factor that, that's involve a dopamine neuron kind of health, right? And so it up-regulates dopamine neuron health. And so there was a study, you know, 20 years ago or something where they took mice and mice or rats and they trained them to self-administer, meaning that they basically, you know, it's a mouse, you know, rat model of addiction, you know, where they're drinking alcohol

• 10:11Speaker 03

  out of a, out of a tube. And if you take a mouse and you do that-

• 10:18Speaker 00

  No little rat bartender there?

• 10:20Speaker 03

  Something like that. Yeah, they, they pull up to the bar. They'll, they'll drink until eventually they die, right? And if you take a mouse like that and you give them Ibogaine, you can actually reverse it. They'll stop self-administering alcohol, which is cool. If you take a mouse and you inject glial-derived neurotrophic factor into the ventral tegmental area- Which is the dopamine producing area that's involved with more of the reward system, you can also produce the same effect. They will stop self administering. Inject just Ibogaine just into that area, you can recapitulate the effect, right?

• 11:02Speaker 03

  And people have also shown that you can produce this effect by directly stimulating into those areas, right? And so it's probably that at least the anti addiction mechanism of Ibogaine is that it's restoring dopamine function within that ventral tegmental area in a way that resets the reward system. The next piece of data that we have, we published in Nature of Mental Health, I don't know, a week ago or something, which is a really interesting study where people with, that in our trial that received Ibogaine had EEG like brainwave

• 11:44Speaker 03

  tests before, after, and one month after they received Ibogaine. And what we saw is this kind of general slowing of all of the kind of different power spectra of the EEG, right? So people had a general kind of physiologic slowing of their brain after. And the slowing actually was correlated with the strength of the trip, like the amount that they had a psychological effect. Yeah. But also, interestingly, the reduction in PTSD symptoms and the improvement in cognition. And so, you know, that's, it's a, it's a first step study, you know, that it was pretty

• 12:29Speaker 03

  good, I think, in the sense we got in Nature of Mental Health. But, you know, we need to do some more work on this. So I'm not claiming that this is definitive, but it's likely that if you, you have an EEG, you may be able to tune the dose.

• 12:46Speaker 03

  To the physiology of the brain, instead of getting a subjective readout, you just, you increase the dose and then that may also allow for you to tune the PTSD effects, which is really cool, right? So you're kind of, you know.

• 13:01Speaker 00

  Some people need more, some need less. You can tell by the EEG who needs what and then can upper.

• 13:07Speaker 03

  That would be the promise, right? That would be, you know, if, if it plays out, that would be, and we do this already in medicine, as you know, we use biz monitors and anesthesia to, to kind of measure the level of anesthesia. Or if somebody is, you know, being fully anesthetized with like propofol, you can actually, you can actually burst suppress them. And you, you know, you're using an EEG to help you dose a drug, you know? So that's not a new concept in, in neurology. It's just a new concept within kind of psychiatry, right?

• 13:40Speaker 00

  Right.

• 13:41Speaker 03

  And so being able to figure that out, I think is useful.

• 13:44Speaker 00

  Well, that, that's the old joke is neurologists pay no attention to the mind and psychiatrists pay no attention to the brain. And here you are, you know, looking at psychiatry through the lens of the brain, not just the mind. You know, Freud kind of took us down the path of mind only psychiatry and talk therapy and psychoanalysis. And it's sort of striking because, you know, you hear, oh, well, yeah, I heard psychoanalysis say, well, you can come to psychoanalysis five days a week for the next 20 years and then you'll maybe see some improvement. And here you're like, well, you can go, you know, to Mexico and do one I begane journey and like that takes care of like 20 years of psychotherapy. I mean, it's kind of crazy.

• 14:26Speaker 03

  Yeah. I mean, you know, there's a lot of work to do to, to kind of totally prove that. I mean, that's what, that's certainly what people will say. That's what Claudio Noronho said, I think, in, in, you know, the Argentinian psychiatrist many, many decades ago about I begane. It's just one of these things where we're going to have to do.

• 14:48Speaker 00

  Do the work.

• 14:48Speaker 03

  You know, do the good work to figure it out. But I think that. The problem in the kind of common theme of what we've been working on, the problem in psychiatry that's kind of out there right now is this problem of things taking too long, to your point, you know, people can have an entire, you know, tragic life problem over the course of the time it would take, you know, for many of our treatments to work. I mean, psychotherapy, psychoanalysis for 10 years is one, just normal oral antidepressants, you know, I mean, we've seen, you know, people start out on oral antidepressant and lose their job by the time it it starts to have any effect, right?

• 15:32Speaker 03

  And so you end up being in this situation where we're not really meeting, we're not really matching the speed of the illness and the speed of the disability from the illness with the speed of the treatment.

• 15:42Speaker 00

  It's kind of an exciting moment in psychiatry because we're, we were in a very reductionist, phenomenologically driven framework for psychiatry where psychiatric illnesses were described by their symptoms, not by their causes or their mechanisms. And what's really exciting to me in psychiatry, because I, I've been thinking about this for decades, I wrote a book almost 20 years ago called The Ultra Mind Solution, which details how the brain is influenced by everything happening in your body and, and you can actually use those physiological levers to change psychiatric symptoms. So if we can treat inflammation or mitochondrial function or the microbiome or, you know, with psychedelics, you're altering some kind of structure or function of your brain, that

• 16:26Speaker 00

  you can kind of change things that seem fairly fixed and permanent in somebody that we, and we ascribe all kinds of meaning and we have all these stigmas against these things. And, you know, if someone's limping because their meniscus is torn in their knee, we don't go, oh, you're, you're, you're a fuck up. But when someone has a mental illness, there's a stigma of, oh, there's something wrong with you. Like, it's, it's kind of, you're crazy, it's your fault. But actually, there's literally physiological and structural things happening within the brain that make it not work, just like if your knee doesn't work or you're limping because you've got a meniscus tear. But now we're able to start to image those things, to see those changes and patterns.

• 17:09Speaker 00

  And to to actually treat the the structure and function of the brain through a multi-pronged approach. Most psychiatric illnesses are inflammatory problems in the brain. So if you have inflammation in your knee, it hurts, but if your brain doesn't hurt, it just creates all these crazy psychiatric symptoms. I think this is like a really paradigm shifting moment where work like yours have really started to push the envelope and say, hey, wait a minute, like, we're thinking about mental illness all wrong and looking at the wrong end of the stick. And to me, that's exciting because so many people are suffering, but it's not happening fast enough. You're involved in the whole field, but I think there is, and there is funding now going into research. And I think in Texas, there's $50 million allocated for research effort on Ibogaine, which is like, I was sort of shocked to see. Your work is kind of taking it to a new level. And the thing

• 17:53Speaker 00

  that I think, you know, we're in now is this both metabolic nutritional psychiatry evolution and this psychedelic psychiatry evolution. They're two, I think, synergistic. I'd like to see them work together more.

• 18:14Speaker 00

  The question with psychedelics is, there's a lot of them out there. And people I think maybe are confused. There's MDMA, there's psilocybin, there's LSD, there's ketamine, you know, and now there's Ibogaine. And probably people are less familiar with Ibogaine, but it seems to be significantly different in its effects than many of these other psychedelics, which have a lot of benefits. So how is it, how does it differ from other psychedelics mechanistically and even experientially for people?

• 18:43Speaker 03

  To your point, there's a, there's a wide range of psychedelics to, you know, right now, there's not really an approval for any classic psychedelics, you know, there's no, and that, you know, there is some interest at the level of the current administration and the Health and Human Services Secretary and all of that, as far as kind of getting that done. But as, as of now, you know, there's not, there's not an approval. And so there's, you know, there's a lot of trials around MDMA for PTSD, psilocybin primarily for depression. People are trying LSD for generalized anxiety disorder, other things. And Ibogaine is probably the the latest person to the party, or you know,

• 19:28Speaker 03

  whatever to the party, in the sense that the

• 19:32Speaker 00

  It's plant to the party.

• 19:33Speaker 03

  The latest, the last plant to the party. The the reason for that is because Ibogaine has the most complexity to it and the most inherent risk to it. And so the problem with Ibogaine as an inherent risk problem is that it has this cardiac risk, right? So it actually will prolong the QT interval. For people that don't know, it's a kind of a part of the physiology of the heart. Lots of drugs do that. Antipsychotics do that, right? Giadon, in particular, does that at a great degree. So it's not a unique, you know, within psychiatry, lots of drugs that do that. Within medicine, as you know, there's lots of drugs that do that.

• 20:17Speaker 03

  But, you know, it prolongs the QT quite a bit for a very short period of time. And there have been, there have been a couple of deaths, you know, because people were getting administered Ibogaine in unmonitored or minimally monitored settings. And so the problem with doing Ibogaine research is that, you know, it's it's been a problem of how do you do a study with a drug that you don't have any human data on because everybody's scared to do the study because of of the kind of case reports of risk? So we started, you know, the work that we did, actually studying people that were already going to Mexico to take Ibogaine, right?

• 21:02Speaker 03

  So they were already headed down there. They were already kind of consented to go down there. And then our job was, you know, simply to kind of do an observational study around that phenomenon that was already happening. And and that allowed us to get some data and enough public visibility to then be able to justify what's going on now, which is to try to get an IND to do this in the United States and all that stuff. And so, you know, people have a varying

• 21:31Speaker 00

  IND is just for people listening, is investigational new drug application. So how do we? Go to the FDA and ask for permission to study something, you need an application for that.

• 21:41Speaker 03

  You need an application and there's a chicken and egg problem of like, how do you take such a complicated drug and get an IND? And so there's a lot of that that goes on and so people have had a hard time doing this. And you could say, well, you know, there's, this is a drug with risk, you know, should we be doing this or not? The reality is, is that, you know, there are drugs that are more risky from a Hertz standpoint that are already approved by the FDA than Ibogaine. And so Tecosin is a cardiac drug. And if you ask the electrophysiologist, you know, cardiac electrophysiologist and you show them the Ibogaine data, they say, well, this is a risk, but Tecosin's just as much of a risk and we've got an approval for Tecosin. And so what ends up happening, which is really

• 22:26Speaker 03

  interesting, is I think what has happened with Ibogaine is because of the stigmatization of mental illness and the issue of how to think about it, people end up being in a scenario where they're looking at this and they're saying, is this problem that you have worth the risk? And Tecosin's used for like atrial fibrillation and for other kinds of arrhythmias. And so people say, well, this has a 100 risk of a Torsades event, but like, if we don't do it, then somebody's going to die from a stroke from Afib. So we can justify this risk with that risk, right? And we know in opiate use disorder that there's going to,

• 23:06Speaker 03

  there's a huge overdose risk in a person that's untreated. And so we're, the problem at a fundamental level is we're saying, well, by not allowing you to study Ibogaine, you're saying, well, this risk isn't actually real, or its personality, or whatever it is, whatever kind of justification that we come up with. And that justification allows us to say, no, actually, we're not going to study this.

• 23:31Speaker 00

  Right. Instead of understanding how many years of quality of life are lost. Which is a real metric. What you're.

• 23:37Speaker 03

  Yeah, absolutely, or real death risk.

• 23:40Speaker 00

  Death risk from overdose. Yeah, it is a bit of a double standard because it's, I think it's part of the bias in stigmatization of mental illness. It's not a real thing. You know, your, your heart arrhythmia is a real thing, but, but your depression is not a real thing. Your PTSD is not a real thing. But yeah, it's, it's amazing. And, and so they work not just differently in terms of the effect on this risk, which is why it's different, but it has profoundly different effects on the brain that are very different than many other psychedelics. I mean, the first, the first story I heard about it was, you know, maybe 50 years ago, there was some drug addict who was in Amsterdam and somebody said, hey, try these cool pills, man.

• 24:22Speaker 00

  He did, and the next day his addiction was gone, his cravings were gone. So that was sort of the beginning of the understanding of its effect in addiction medicine, but, but it's just got all these broader effects. So it's, it's different than, than, and seems to be longer lasting and more powerful in terms of resetting the brain and the, the sort of like almost a neurochemical reset than, than many of these other compounds, which work, but don't have these persistent lasting effects as much.

• 24:49Speaker 03

  Yeah, so Howard Lotzoff was the first, so, so just in the history of all this, you know, we know the Boiteau were using this for at least 300 years, you know, probably, you know, most likely much longer than that. The French started, discovered this in the Western world in about 1900. It was on the French, French formulary from 1930 to 1966. And it was actually a, a lower doses called labyrinth and was like a daily microdose essentially. And so we, there's 36 years.

• 25:27Speaker 00

  For what?

• 25:27Speaker 03

  For attention problems and depression and things like that.

• 25:30Speaker 00

  Wow.

• 25:31Speaker 03

  And so for 36 years, it was used by the French and then placed on the French version of the Controlled Substances Act in 66. And, and you know, and it was put on the US Controlled Substances Act, even though it doesn't really meet criteria for the, for a controlled substance, for the description of a controlled substance. It is neither, people don't self administer it. There's, there's no, there's no animal data to suggest that there's a self administration. In fact, it reverses self administration of other. Addictive compounds.

• 26:01Speaker 00

  It's not a party drug.

• 26:02Speaker 03

  It's not a party drug, so it stops self-administration and, you know, it has this profound, you know, kind of psychological effect that doesn't really, it's not really reinforcing, right? And so it doesn't really meet controlled substances description, but it was lumped in to the US Controlled Substance Act, Schedule I Substance, which is where it stayed, you know, since then and really prevented folks from using it. And so Howard Lotsoff had the story that you're describing, had this resolution of his addiction and spent his entire life trying to get this, you know, kind of out of the, off the controlled substances list and as a therapeutic.

• 26:46Speaker 03

  And it's a very complicated timeline for folks to kind of get through. And I think we're getting a signal now that finally we may be able to see that happen in our lifetimes that, you know, it could be that we could actually study this thing and make a real decision of whether or not it's useful. And even if it doesn't work, like, let's say all of this is just a bunch of psychological effects and it doesn't really do any of the things that people think it does and all that stuff, that's an important study to do anyways from a public health standpoint, right? Like, the idea that we make plants illegal and then make them inaccessible for science is like, it's a, in 300 years, we're going to look at that and think that's just the

• 27:30Speaker 03

  craziest thing, I think.

• 27:32Speaker 00

  And we have to study these things. And, you know, if the initial data that you've done and others have done actually bear out to be true, it's revolutionary in psychiatry.

• 27:45Speaker 03

  I hope so.

• 27:46Speaker 00

  I mean, I think it could really, you know, impact this incredible degree of trauma and PTSD and depression, anxiety, traumatic brain injury. That's even fascinating to me, the brain injury stuff. But the pathways that it works on are a lot of different pathways that reduce inflammation, oxidative stress, that increase neural protection, resilience of your cells, and...

• 28:13Speaker 00

  You know, it just, it almost seems too good to be true of how this works. But it does have to be administered in a way that's safe because it, if, it is risk of cardiac arrhythmias is high and then you have to monitor that. But, but with the magnesium therapy, which is, you know, what we use, it's funny to me that, you know, I used to work in the emergency room and we had this thing called the crash cart. If someone comes in with cardiac arrest, you give them all these drugs. You give them epinephrine, you give them this drug, you give them that drug. And then finally, like if every other drug fails and they're still in this terrible arrhythmia, you give them IV magnesium.

• 28:47Speaker 03

  That's right.

• 28:48Speaker 00

  As like the last straw. I'm like, why don't we start out with that, you know?

• 28:52Speaker 03

  That's right.

• 28:52Speaker 00

  You know, I've given a lot of IV magnesium in my life. It's very safe. We use it all the time in medicine for pre-eclampsia or hypertension, pregnancy for preterm labor. And doctors don't somehow think of it as a, you know, as a, as a compound that we should be using, except in these extreme situations. But it's actually one of the most important minerals and many of us are low in it or insufficient in it. And I think stress causes it to be low, it brings also caffeine, alcohol, a lot of things that we do actually cause us to deplete magnesium. A lot of people are on anti-hypertensive drugs that cause you to lose magnesium, diuretics. So you basically, you know, can mitigate a lot of these effects by taking people up on magnesium, if it's done in a controlled way.

• 29:35Speaker 00

  And that, that's mitigated all those potential risks. If you've ever had a case in the magnesium administered patients that you've used, I began with, right?

• 29:44Speaker 03

  I mean, I, you know, I, I personally don't administer it. I just talk to, talk to folks in, in places that do. And what they, what they tell me is that, for instance, one clinic wasn't really using it until a couple of years ago, you know, and they'd had a, you know, a bad outcome. And then they, you know, started using it and they hadn't had. Any cases since then and the rationale is, you know, as you, as you point out that magnesium is actually the treatment and the American Heart Association guidelines treatment for, for torsades, the fatal arrhythmia that's the result of Ibogaine. If you give magnesium, you can get some people out of torsades.

• 30:29Speaker 03

  And so the view here is if you're prophylactically administering magnesium before you give Ibogaine, then maybe what you're doing, and this is such a low risk drug, if you want to even call it that, is that you're bathing the heart in, in this kind of stabilizing agent so that when the Ibogaine interacts with the, with the potassium channels that are involved in, the HERG potassium channels are involved in this arrhythmia, that they won't throw the heart into the rhythm. And that's the idea because the drug, you know, comes and goes and then nobody has a risk of like post-treatment arrhythmia. It's only during the kind of the peak levels of the drug.

• 31:09Speaker 03

  And so if you can give magnesium and stabilize the heart, you can prevent this from happening.

• 31:15Speaker 00

  Right now, you know, there's, it seems to me we're just sort of at this beginning of this sort of a phase of research, which is going to help us unpack the underlying benefits, the mechanisms, safety, and that'll lead to a path to potentially approval as a pill that you can take. But the question is, you know, do you still think people are going to need to be in a moderate setting with Ibogaine in order to actually safely take it? Because it sounds like, it sounds like you can just sort of like prescribe people, right?

• 31:44Speaker 03

  A bunch of different answers for that, but you know, the kind of short answer is yes, I can't foresee a time when Ibogaine isn't going to be a monitored drug. Now, Ibogaine at the current doses that people use, the kind of what we call flood doses. Now, the, the deal is, is that there's a bunch of companies that are trying to modify the Ibogaine molecule to make it not have the cardiac effects. If they're successful in doing that, then you're in a situation where the one of these Ibogaine analogs may be the solution. Maybe you could take that at home or whatever. And a lot of them aren't particularly psychedelic, right? And so there's this, as you know, big open question of do you need to have the trip? Do you need to have this experience?

• 32:29Speaker 03

  Or can you just have an agent that just changes brain plasticity and that's it? And so that's a TBD sort of question. But that may be a way to do it. There are other, you know, Ibogaine alkaloid, I'm sorry, Iboga alkaloids that have, you know, more or less cardio toxicity. So that's a question. And then we haven't really studied the dose ranges of Ibogaine well at all, you know? And so it may be, and there's some, you know, very early kind of anecdotal data around this, that people with Parkinson's and that sort of thing, taking micro doses actually show improvements. And so it's one of these things where the Texas effort's going to be important to really hashing out what this is.

• 33:14Speaker 00

  You know, these effects of dopamine and other things are powerful. The ability for us to sort of navigate different mental illnesses with these drugs is fascinating to me because we've never really had these drugs that are compounds that are so diverse in their effects and affect so many different conditions and have such a magnitude effect greater than what we have. So maybe you could spend a minute sort of talking about your more recent study in magnesium and Ibogaine in the veterans and what you found in terms of the orders of magnitude improvement compared to conventional therapies around depression, TBI, brain injury, PTSD, and what you found in terms of the connectivity in the brain, what you found

• 33:57Speaker 00

  in terms of the sort of physiological change that you saw with looking at functional MRIs and EEGs and other assessment techniques. Because we're now looking at what's happening in the brain in ways that we couldn't really do before and that nobody really looked at.

• 34:11Speaker 03

  So Ibogaine is a compound that, like I said, produces that physiologic kind of EEG-based change that we just published on. We have more data that's kind of in review now. We actually took, we took the MRI brain scans and fed them into an analysis pipeline around AI guessing the brain age. So as Mark, you probably already know, you can take a brain MRI and you can have AI guess a brain age. You can scan them the second time and it'll be very close to the first one. You scan them a third time, it's gonna be very close. So three different scans fed into the algorithm guesses within

• 34:55Speaker 03

  a very close range of each other, but not necessarily of your chronological age. Right? And so, you know, you're, you're, you're a young guy in the sense you look very young, right? And I would suspect your brain looks very young. And I would suspect that it's younger than your chronological age. You're talking about me specifically? Yeah. Yeah, I'm 65. I hope it's younger than that. That's what I'm saying, right? So let's say, let's say we scan your brain and maybe, maybe your brain is 55. Yeah. And that's what AI, and, and so it's not very good at predicting what the chronological age is because that has much more to do with your lifestyle choices. But it's very

• 35:36Speaker 03

  good at being consistent about what that brain age is and mapping it onto other folks' brain age, right? And so, and, and, you know, as an alternative, right? There are some people at your age that are already developing Alzheimer's or, you know, MCI or whatever it is, and their brain age is 75. And if you scan them three times, you're gonna see that it's 75. And what this, what this is showing is, as a group average, people have about a year and a half younger looking brain at one month. Wow. Does it compound if you keep doing it? This is what everybody keeps asking me. I have no idea about that question, but it's, it's a good question, right? Is, is can you, can you lock the brain into an age

• 36:21Speaker 03

  if you just keep re-exposing it? You know, it's a much further along the road question, but it's an intriguing one. Like I didn't, you know, my postdoc who's kind of obsessed with brain age did, you know, ran all these analyses and came to me and said, hey, you know, we're seeing this, we're seeing it de-age the brain. But what we don't see is any real, I mean, there's a little bit of change right after, but it takes a month. Before you really start to see the brain age change.

• 36:46Speaker 00

  I wonder if it's like affecting epigenetic expression or gene expression in some way, because it seems like that's a pretty profound effect.

• 36:53Speaker 03

  Yeah, and it actually makes sense.

• 36:56Speaker 00

  We're talking about like one dose, one day, having an effect to reverse your brain age by a year and a half at a month. That's pretty remarkable.

• 37:03Speaker 03

  Yeah, I mean, it's, it's a, you know, it's an open question in the sense that, you know, you need to, you know, we need to do the work, but what you don't see is much of a change right after. And so whereas you do see that with PTSD and depression, everything else, you see it really quickly. But with traumatic brain injury disability and with the brain age, it takes the month. And it makes sense. Like if these are more hard neurological issues, you're not going to be able to change the brain in five days or whatever. It's going to take some time.

• 37:35Speaker 00

  One of the things that I heard is that the, there's a metabolite of Ibogaine called noribogaine that lasts longer. And I'm wondering if that explains some of the tale of these effects of the addiction inhibition, withdrawal inhibition, and maybe some of these other deeper neurological effects. And, and that, and I don't know if that noribogaine has the same cardiac risks, or if anybody's looking at studying that.

• 38:02Speaker 03

  So noribogaine does have a similar cardiac profile. Ibogaine is metabolized into noribogaine normally through 2D6. And so you see people with getting Ibogaine and they metabolize to noribogaine in roughly 12 hours, eight to 12 hours or something like that. And so, you know, there's lots of folks, Deborah Mash is the biggest proponent, but lots of folks saying, well, why don't we give noribogaine as a treatment? And that's an open question, you know, and that work needs to be done. The, the issue, I think, with noribogaine, if you think about PTSD, is that the Ibogaine seems to be the thing that produces the earlier life re-remembering stuff, not the noribogaine part.

• 38:47Speaker 00

  Interesting. So the life review, watching a movie of your life, seeing what happened, re-metabolizing it in a way that allows you to be at peace with it and kind of move on from that, doesn't happen with the noribogaine. It happens with the.

• 39:01Speaker 03

  That's, that's based off of the subjective effects and the timeline of the drug. That's what it looks like, right? And so. If you want to have the, you know, if the goal is to have the experience drive some of the therapeutic effect, then it probably requires the IBN. And what we found with the EEG stuff that I published a week ago is the degree of that subjective effect is correlated with the degree of the PTSD improvement. So if you take that out, you may be taking out at least-

• 39:35Speaker 00

  Some of the benefit.

• 39:36Speaker 03

  Some of the, at least the PTSD benefit.

• 39:38Speaker 00

  I have this theory, and I wanted to know if you've ever thought of this, which is when you look at the global population and you look at the obesity epidemic, it's staggering. There's over two and a half billion people overweight in the world. Obesity is exploding across the planet. And in America, we're, you know, 75% of us are overweight, 42% are obese. The Yale Food Addiction Scale is a way of measuring food addiction. And Kelly Brennall and others developed it. And 14% of the global population is addicted to food, including 14% of kids.

• 40:13Speaker 03

  Yeah.

• 40:13Speaker 00

  You know, that's about the same as alcohol. Alcohol addiction is about 14%. And I wonder if, you know, everybody's talking about Ozempic and GUP1s, but could this be like an unlock for people with food addiction, who are addicted to sugar, who are struggling, who may have underlying dopamine receptor issues? I think there's, you know, when you look at genetics, there's genetics involved in people who tend to move towards more addiction. They don't benefit as much from this dopamine stimulation. They need more to feel the same pleasure. And so, you know, how does somebody eat a whole sheet cake? I couldn't ever do that, but people do. And I think that, you know, is an application. It seems to be a

• 40:57Speaker 00

  multi-billion dollar application.

• 41:00Speaker 03

  So our data, we also collected alcohol use. And what we found was, and we're going to publish this soon, that people's alcohol use really precipitously dropped, almost close to- To zero. And so just almost everybody just really dramatic improvements in alcohol. And it maintained it. And so, and we also have some biology around that that we're looking at. And so, you know, all those guys, if you asked them, are you going down there to stop drinking? They would have told you, no, I'm trying to deal with my like TBI or whatever. And then, you know, nearly everybody came back and reported they really didn't want to drink coffee anymore.

• 41:43Speaker 03

  They really didn't. And so, so I always think that, so placebo is expectancy, right? And the degree of the expectation that you have about how a drug is going to work drives a lot of the effect. So like, you probably have seen this New England Journal of Medicine Total Knee Replacement Study, where they, they did a total, they either did an incision and did nothing, or did a total knee. And the total knee patients in the, in the kind of the fake surgery incision folks had no difference in outcomes. Pretty amazing. It looks like it was driven primarily by, by expectancy. And so if the person's being told in medicine, I'm going to do this thing.

• 42:27Speaker 03

  And when I do this thing, this, that thing that I'm going to do is going to drive this outcome. Then the person has this expectation of that outcome. And that's hard, right? Like that's, somebody's going down there and they think this is a TBI treatment or whatever it is, then it's hard to, to feel good about the data, you know, related to that, not placebo. But what I like to see is when you have off-target effects. Like, we intended to look at TBI disability in this study, but now everybody stopped drinking coffee. Yeah. Or now everybody stopped drinking alcohol. And if you asked them their pre-treatment, kind of pre-test probability of any of that was going to happen, they'd tell you no. Like, they'd say, I didn't know that was going to happen. Yeah.

• 43:11Speaker 03

  They all just came back fascinated with this thing that happened that they didn't have any expectancy for. Yeah. You know, we don't know for sure, but the signal is certainly there. That this, this appears to be, you know, if, if you kind of read the, the, the limited data that we have, this appears to be kind of a global dopamine reward system reorg.

• 43:36Speaker 03

  And that we've just seen it work in opiate use disorder because those are the kinds of folks that are in many ways desperate enough to have taken Ibogaine in the last several decades.

• 43:45Speaker 00

  So there's all kinds of effects we're just sort of learning about. And I think with obesity, nobody's probably looking at that is my guess, right? With Ibogaine?

• 43:52Speaker 03

  Yeah, I mean, the, yeah, nobody that I know of, yeah.

• 43:55Speaker 00

  I think it could be an interesting offshoot study, like, does it, does their food behavior change? Does their cravings for sugar change? Does their cravings for, you know, like, because I think it's like, that, that, I mean, you're talking about opioid addiction killing 70,000 people a year, but the food addiction part, you know, kills a lot, lot more, you know, chronic disease related to food is, you know, killing a million plus people a year.

• 44:17Speaker 03

  Hundred percent.

• 44:18Speaker 00

  In America. So it's like, to me, I think it'd be an interesting little kind of side hustle to kind of look at that and your data and see what happens if people change their diets and they change their weight loss. Like, there's other things you can look at. So I encourage you to check that out because I have this theory, but if it, because if it works, it's a, it's a big unlock, you know, and it's probably a lot, a lot better than taking Ozempic. So I want, I want to sort of help people understand that this is not just like an incremental therapy because, you know, as we sort of started out talking about, a lot of the psychiatric treatments we have don't really work well or have marginal benefits or have a lot of side effects. And with Ibogaine and some of these other psychedelic therapies, we're talking about, you know, 80 to 90% reductions

• 45:01Speaker 00

  in symptoms and things that you just don't see. So can you talk about the magnitude of the effects and how it's different than traditional psychiatric treatments?

• 45:09Speaker 03

  Yeah, I mean, it's the degree of the effects that we observe were quite striking. The, um, you know, the data is limited, you know, so that needs to get replicated. And I've heard, you know, that there's another group out of Texas that they're seeing very similar effects to us. And so if that holds, and that's really the case, then, you know, that's going to be helpful. In this hypothetical future scenario where you're right and these are the degrees in which people change compared to conventional treatments, it's a huge difference. I mean, if you look at oral antidepressant differences between active and placebo for some of the pivotal trials that led to approval for something like Prozac, you're talking

• 45:52Speaker 03

  about a two to three point difference on a 60-point scale and the inner raider reliability on that scale is two points.

• 46:02Speaker 00

  Yeah, so basically it's like nothing.

• 46:04Speaker 03

  So the noise between raiders is the same amount of change as the change observed. Now, on average, they're seeing the change greater in the active group than in the placebo group. I'm not arguing that, but like, yeah, the observer, you know, differences are that level. So it's very hard to discern if you've got totally skilled raiders and they have that problem, how effective these drugs really can be.

• 46:43Speaker 00

  So those are not, but then the Ibogaine is far more.

• 46:46Speaker 03

  Yeah, I mean, we're seeing, you know, in some cases, a 20 or 30-point change on a 60-point scale where that scale is a generality, people don't really score above mid-30s on. On the Montgomery Asper depression rating scale, that scale doesn't have a, if you're above 30, 35, you're in really bad shape. You know, you need to go to the hospital or something like that. And so we're seeing a, you know, 20-point change in a lot of people on that scale.

• 47:15Speaker 00

  The use case for this drug is across like a whole bunch of different issues that seem not necessarily related, like what does brain injury have to do with PTSD, have to do with depression? And how do you think that we sort of start to apply these compounds to these conditions in a more systematic way where deliberately working on different pathways that these drugs work on?

• 47:38Speaker 03

  It's an open question, you know? I think we've got to spend the time to understand what the different alkaloids do and then use those. It's kind of like where GW Pharmaceuticals was as it relates to cannabinoids, you know? And so. There is an approval, I don't know if it's like a full approval or an orphan approval, but there's an approval for CBD, cannabidiol, for pediatric epilepsy syndromes. So Lennox-Gastaut and Dravet syndrome, right? And so those two epilepsy syndromes in kids are really devastating. Sometimes kids have 200 to 300 seizures a day.

• 48:21Speaker 03

  You have to put them on potassium bromide, which is like what we give dogs for epilepsy, you know? And you end up being in a situation where, you know, kid's still seizing. And so the kind of interesting story there, which is another story like the veteran's story, where there are all these families that figured out that if they could give their kid lots of CBD, the kid would stop seizing. Wow. Right? And so they were administering- On their own. On their, moving, at the time, moving to Denver. This was, you know, Sanjay Gupta did like a special on this 15 or 20 years ago. So all these families that with Lennox-Gastaut kids moving to Denver and then figuring out

• 49:04Speaker 03

  on their own, buying cannabis and then extracting it, extracting CBD. So they called it Charlotte's Web, which is this pure CBD cannabis, and they extract that out. And so GW Pharmaceuticals says, well, let's, you know, let's, in the UK, farm, you know, and this is like not, doesn't make people, like CBD doesn't really make people high. Maybe it's a little anxiolytic, but it doesn't make people high. You know, the kids were actually waking up and they were less encephalopathic when they would take it. Yeah. And, you know, you give this to a kid and they, they come out of an epilepsy fit, you know? And so all these families were seeing this, kids, potassium bromide and all this stuff,

• 49:47Speaker 03

  and then you give them high dose CBD and they wake up. You know, for the first time. And so what GW did is they said, okay, we're gonna make a pure CBD drug, and we're gonna get that through. And they were gonna make a whole host of other cannabinoid drugs to try to really discern, to your point, what's driving what with variable actions on different neurotransmitter systems and all of that. And I think that's what's gonna happen with with these iboga alkaloids, right, is that we have to-

• 50:16Speaker 00

  You don't think it's just the whole plant, and you need to take the whole thing as opposed to breaking it down, which is what we do in medicine, and break things down into their component parts, and then it doesn't necessarily have the benefit of the whole plant.

• 50:27Speaker 03

  That is the open question. So there's gonna be an experiment on this, you know, Colorado is gonna, is basically gonna allow for whole-plant-derived iboga alkaloids to be used for people, you know, out inside of Colorado. And so the question ends up being, is that the road? Is it isolating ibogaine? Is it isolating other alkaloids? I'm a pragmatist, like, I don't have a, I don't have like a philosophical view on this other than, you know, if somebody's gonna die, and you give them this thing, and their probability of dying goes way down, we should probably be doing that. And I think that's like, so if that's what happens in Colorado, then that'd be good. I mean, I have some

• 51:12Speaker 03

  open concerns about it because of the cardiac, you know, risk, and I'm pretty public about that. But they're not, they're gonna do it no matter what I think. And so it's one of these things where that's gonna happen. And then there's gonna be a kind of a more pure Western medicine pharma play that's gonna happen, or several. And then there's this kind of organic chemistry thing where they're changing the molecule thing, too, that's maybe that's not even psychoactive. And I think we'll get in totality the answer over the next 10 years.

• 51:41Speaker 00

  Yeah.

• 51:41Speaker 03

  And the reality is, is that- If it all works, that's amazing. If one of them works, we know a lot more about how the brain works. I mean, hopefully, it's we're not in a situation where none of them work, but that's possible, too. But at least we, you know, we gave it a college try for sure. But it's the beauty is, I think, that's all happening, and we're going to be able to really actually sort it out. And fingers crossed.

• 52:03Speaker 00

  Yeah, pretty amazing. Yeah, this is sort of an interesting moment where we have these new compounds we never had before, where we're looking at them. But the MDMA stuff is interesting, because that's undergoing a phase three trials and other, other sort of data that's looking at the effectiveness of this. But it's usually combined with psychotherapy.

• 52:22Speaker 03

  Yep.

• 52:23Speaker 00

  But what you're talking about, I began not needing the psychotherapy component. Do people need follow up, support, treatment, integration? Does it have to be done in a psychiatric context where there's more continuity of care? It's just like go in and take it, close your eyes, wake up 12 hours later, and that's it?

• 52:40Speaker 03

  So there is a, there's a pre, post-therapy requirement. There's a within dosing therapy nonrequirement, it appears, right? Although, like, nobody's really, you know, could be very helpful. We don't know. But what happens with MDMA is, you know, is, you know, I think you've studied is, if you, if you give somebody MDMA, they have a positively balanced experience.

• 53:08Speaker 00

  Yeah.

• 53:08Speaker 03

  Right? They have this, they feel good, and they feel good about, you know, the people around them. And they feel good about the memories they've had. And so if they look at traumatic memories, they're going to see those memories from kind of a, an alternative perspective, because they're seeing the world through a lens. And I think that's very useful as a tool. I think it's also very tricky as a tool. There's a analysis of the, you know, events that happened in Israel with the rave, right? And in that situation, there was a certain percentage of those people that are actually on MDMA. I don't know if you know, but

• 53:43Speaker 00

  Yeah.

• 53:43Speaker 03

  They actually saw a statistically significantly lower PTSD onset in individuals that were on MDMA compared to people that weren't for that experience, for that kind of traumatic.

• 53:55Speaker 00

  Hamas came in and terrorized the Delma Festival in Israel on October 7th and the people who took the MDMA were less traumatized after than the ones who didn't.

• 54:04Speaker 03

  Correct, yeah. And so, you know, what it's terrible story, obviously, what's interesting about that data is that it tells you something about it being protective, right? And those folks, you know, I'm sure it was clearly still traumatizing to them, but for some reason it didn't lock them into, you know, as many people into a permanently traumatized state because they were seeing things from a positively balanced place. But, you know, it's probably true that you need to, you know, have a guide to guide people with that drug. With Ibogaine, what's really interesting about it is you can prepare people, you tell them what's gonna happen, tell them what you think could happen, or a variety of things

• 54:47Speaker 03

  that could happen. And then they take it and they have this long experience and then they come out of it and they have to unpack all of the stuff that they saw, right? They have to unpack all of the earlier life, you know, in many cases traumatic memories that they have to kind of get through. And in that situation, it's driven by the drug. It's not driven by a therapist telling them, hey, go look at this memory. It's like the drug is doing that. But then the person has to come out of it and really actually sort it out.

• 55:19Speaker 00

  Yeah.

• 55:20Speaker 03

  For themselves mentally, yeah.

• 55:21Speaker 00

  That they need help with generally.

• 55:23Speaker 03

  And they, yeah, basically all need help with, yeah.

• 55:25Speaker 00

  I'm fascinated because, you know, the, there's effects on disease states or, you know, things that are problematic for people like PTSD, traumatic brain injury, depression, et cetera. But then there's the brain enhancement component. And I've known a number of people who've gone down there into Mexico and didn't have these problems, but used it as a way to sort of create neurocognitive and neuropsychiatric enhancement. And you mentioned briefly about the reversal of the brain age as sort of a hint at that. Can you talk more about how it might be used as a sort of enhancement drug? In other words, that it doesn't just treat disease and it may actually improve your overall cognitive

• 56:05Speaker 00

  function, memory, mood, neuroplasticity, neurogenesis and things that we all would like to have better brains, right?

• 56:12Speaker 03

  Yeah, so what we observed in the veterans was that they had an improvement in cognition, a statistically significant improvement in some aspects of cognition, particularly around frontal control. It's an open question as to whether or not in a non-TBI, non-PTSD individual, you're going to see that too. But at least you can see in a diseased population an improvement there. Whereas with a lot of the oral antidepressants and whatnot, you're not really seeing an improvement in cognition. There's not really a good drug in psychiatry that's approved for depression that improves cognition. And so at least we're getting signals of it with Ibogaine, but it's got to be studied.

• 56:53Speaker 00

  Yeah, it would be interesting as it's more of like a longevity enhancement drug. And we don't really think much about those things in medicine at all. We think about things that suppress or inhibit or block some pathway rather than things that optimize, enhance, and improve the functioning of human physiology. Probiotics are an example of something that can optimize health as opposed to an antibiotic. And in functional medicine, that's a lot we think about is what are the ways to enhance function? What are the pro drugs as opposed to anti-drugs? And it seems like it has that kind of potential.

• 57:28Speaker 03

  What we really need to understand, I think, is why were the Boite taking this for hundreds of years? And why did the French think this was helpful for 36?

• 57:36Speaker 00

  Yeah.

• 57:37Speaker 03

  And I think that could give us a signal about what it could do for that, right? Because it seems to me that...

• 57:47Speaker 03

  You have a, even in the 30s to 66, you know, which is kind of a different era, obviously, to have a drug on the formulary for 36 years that wasn't doing anything for the French, it seems unlikely, it's possible, but unlikely that that would have stuck around and been sold for 36 years. And so my suspicion is, is that there were some disease treatment effects, but maybe, maybe these effects too, who knows?

• 58:13Speaker 00

  Yeah, I wonder if there's any people around who took it back then, who are in their 90s probably now, from what the effect on them. I think this is such an exciting moment in psychiatry and medicine. And I think, you know, a lot of people are stuck in mental health issues. And we live in increasingly stressful society. And there's just such a limited set of tools for people. Therapy can help a little bit, and some of the medication can help a little bit. But there's really, this is like a whole revolution. And I wonder if you've, if you've thought about, you know, combining the things that you're doing with other kind of metabolic psychiatry stuff that your colleagues doing at Stanford around

• 58:54Speaker 00

  nutritional psychiatry and metabolic psychiatry, and combining both modalities as a way of even improving health outcomes and mental health outcomes?

• 59:03Speaker 03

  A hundred percent, yeah. I mean, I think we, I've taken the stance that if you look at like MI care, like people having a heart attack, what do we do now? We throw an aspirin, we throw a statin, we, you know, we do a heart cath, we do all these things in summation that all independently were shown in isolation to benefit.

• 59:25Speaker 00

  Right. We pay a cocktail therapy as opposed to a single therapy, right?

• 59:29Speaker 03

  The challenge, right, right now is to, we're in cardiology 1950s, right? And so we're having to, we maybe have a pacemaker, we have, you know, a couple of drugs or whatever it is, and we need to now figure out what to do with all the limited tool set to make more tools and improve those tools, and, and do the trials in each one of the tools. Now,

• 59:55Speaker 03

  Or my kids, or you know, whatever the, the, um, you know, the folks that are gonna end up, or my students, or your students, the, the folks that end up combining all of these therapeutics together because there've been trials to show synergy, I think absolutely, you know, I think that's gonna be the way we deal with things in the future is we say, okay, well, we're gonna, you know, and you're doing a lot of this already, we're gonna measure all of these things, we're gonna modify your diet, your metabolic, you know, all of that good stuff, we're gonna do brain-based things. I think the interesting question ultimately is if we're in such a diseased society that we end up being so far off of like the normal

• 1:00:38Speaker 03

  range metabolically, stress, all of that stuff, and people end up being way over here, do you need multiple therapies to get you back on track? But then if we just had the right dietary interventions to begin with, that maybe we don't need to do all this other stuff. To me, that's one of the big questions that, you know, yourself and others are trying to tackle, which is, you know, a lot of folks now in government is this question of if we can just have kids eat healthy, is there a world where we have less mental illness? And it's an important question, and one that we have to, we have to ask, you know, we have increasing rates, we don't know why, and so maybe it is because of diet.

• 1:01:19Speaker 00

  Oh, yeah, I mean, it's huge. I mean, but I, I don't think that the dietary change alone, or nutritional metabolic changes alone, can, can do the kinds of things that these psychedelic compounds do.

• 1:01:33Speaker 03

  Yeah.

• 1:01:34Speaker 00

  And what's fascinating is we've sort of, and it's always fascinating to me, I don't know if you have a theory about this, but how, how is it that all these plants have compounds that interact with our biology in these profound ways that change us? And I wonder if somehow we co-evolve with these plants. And if you look across all indigenous societies, they all have some sort of psychedelic something that they play with, with ayahuasca and, you know, shibboleth, Indians in South America, or peyote in North America, whatever.

• 1:02:04Speaker 03

  If you look at the thinking that the 1700s physicians had about vitamin C containing fruits, like citrus fruit, and the way they thought about it as it relates to scurvy, you kind of understand where we're at today. Many of them thought these were, you know, there weren't that many limes and lemons in Europe at the time, right? This was considered a South American or an African exotic plant. And so, most of the physicians of the day actually rejected citrus fruit as a treatment for scurvy. And so, as you know, the story of anti-fruters, right?

• 1:02:46Speaker 03

  There were lots of people in the British Royal Society that said that the limes and lemons may actually be making scurvy worse. And I think that's the situation that we maybe find ourselves in now, or used to find ourselves in, where somehow we've conflated the solution with the problem in this very weird way, and that we blame a plant because man didn't make it. And I think it actually has a greater philosophical problem with the way that we have, you know, that we see the world and are hubris, that for some reason, we have this view that SSRI, that's totally fine because man made that and we understand it. Plant, not so sure about that, you know?

• 1:03:29Speaker 03

  And I think that's, that's the way we've been looking, looking at plant-based psychedelics for a long time, and hopefully that changes.

• 1:03:35Speaker 00

  Pretty amazing. And this, and the sort of, I keep kind of doubling down on the magnitude and size of the effect, and I want to sort of double down on it because I think when you look at the 30 special ops, you know, special forces veterans who had brain injury, you know, you found really large effect sizes, you know, like the disability ratings dropped dramatically from moderate disability to like no disability, had PTSD drop by 88%, depression drop by 87%, anxiety by 81%, improved cognition. Seems like too good to be true, right?

• 1:04:06Speaker 03

  When my postdoc showed me the data, I didn't believe him, and I told him to go back and reanalyze it.

• 1:04:11Speaker 00

  Yeah.

• 1:04:12Speaker 03

  You know, and so we, you know, we, that's why I don't, I don't make claims about it, you know, because I, I think that we have to at least be replicated by another group in order to justify. So, we need to be replicated by another group in order to justify it. Now, I'm hearing from my colleagues in, out of Texas that they are seeing various Similar effects, right? And so I want them to formally see that.

• 1:04:36Speaker 00

  Yeah.

• 1:04:36Speaker 03

  If that's what it is and publish that. And then, and then we can say it wasn't, you know, our site or whatever, that, that at least in an open label way, this is what this looks like. And then the next step is to do the big trials. But it would be unusual to have that level of an effect for, for this sort of level of expectancy.

• 1:04:57Speaker 00

  I mean, they didn't expect that big of a change. So they would, you would less likely to see it.

• 1:05:01Speaker 03

  Yeah.

• 1:05:02Speaker 00

  The veterans had, have you followed them ongoingly or they still have the lasting effects?

• 1:05:06Speaker 03

  So we have day, day down to year. It isn't published yet. It's kind of in review now, actually. And that looks really good. Uh, most people hold it.

• 1:05:14Speaker 00

  And you're, you're talking now more about this idea of circuit based psychiatry, which helps explain some of the things we're seeing. Can you kind of unpack what that is and how it differs from our current view of psychiatry?

• 1:05:24Speaker 03

  If you think about psychiatry in epochs, you know, the first one being talk therapy. And, and we learned something important there that spoken word can have effects on, you know, mental states and it affect, you know, and, and now more recently data suggesting that it's having an effect on the brain itself. And that's, that was useful psychiatry 2.0, this idea that pharmacology can have an effect at the level of synapse. And that was also very useful, right? I got a lot of people that say schizophrenia out of asylums and that sort of thing.

• 1:06:01Speaker 00

  And like Thorazine.

• 1:06:02Speaker 03

  Yeah, like Thorazine. Yeah.

• 1:06:03Speaker 00

  Chemical straight jackets, we call them.

• 1:06:05Speaker 03

  And then psychiatry 3.0, this idea that you can actually look at the psychiatry 1.0 and 2.0 innovations from the frame of the circuit and improve upon them, right? Cause at the end of the day, lots of the psychiatric treatments that we have are suboptimal for patients desires, right? ECT is a great example of that.

• 1:06:31Speaker 00

  Yeah. Like magic shock therapy. Yeah.

• 1:06:33Speaker 03

  Can you use insights from before and make things much safer and better and much more tolerated with patients? And that's really, uh, that's really been, I think, the emphasis for our work. And so when we look at IBM, we're looking at it from the lens of the circuit. When we're looking at, uh, it's a stimulation of the brain, we're looking at it from the lens of the circuit. And that's helpful because, you know, the whole brain doesn't need. Necessarily need to be exposed to things really, at least in depression, it looks like from our OCD data, that you can get big effects from just isolating one brain circuit and modifying it.

• 1:07:10Speaker 00

  Amazing. Well, we're in a kind of revolutionary time in psychiatry, which is exciting to me because I remember first working in a psych hospital in residency. I was like, I spent a month there. I was like, this is just nuts. And I don't mean that as a pun. I just mean the way we treated people, the amount of suffering that's going on, the lack of really good treatments. It feels really hopeful. It feels like a hopeful moment. But it doesn't feel like we're going fast enough to me. It feels like we're still in this sort of glacial pace of change. And science proceeds that way, unfortunately. But I think many people listening go, wow, you know, can I try it? What do I do? What if I want to go do it? I have this addiction issue. I've got PTSD. I've got trauma. There's a few

• 1:07:55Speaker 00

  places people go, like in Mexico, beyond, or Ambio, and also Mexico. There's a few places out there. What do you say to people who want to go sort of explore this?

• 1:08:05Speaker 03

  Yeah, I mean, the good news is, is that we, you know, it looks like there's actually going to be some US trials soon, you know? And so being able to do this from inside of the US is is kind of the ultimate goal. You know, folks go to these places and, you know, these other countries. But the the ultimate goal is is really to see that that folks can do this safely in the US. And so I think, you know, five, 10 years ago, I wouldn't be able to say anything right now with you asking me this. But now, at least we have the ability. And the hope is, is if everything goes through the FDA, there'll be a normal, healthy control study. The FDA will have that IND, that new investigational

• 1:08:50Speaker 03

  new drug application through, and you'd be able to actually give people Ibragen that are normal, healthy controls, right? And so that's

• 1:08:58Speaker 00

  And see what happens.

• 1:08:58Speaker 03

  And see what happens. And so it is is coming soon. You know, we'll have to see what happens with the FDA. But but yeah, I think that's, that's an exciting moment for folks and, you know, being able to To have access to to an experimental therapeutic like this.

• 1:09:16Speaker 00

  And if people want to go down and try this in Mexico, do you advise against it? You say it's your own risk, you?

• 1:09:22Speaker 03

  It's definitely a people's own risk. I mean, I, look, it's one of these things where we still don't know that much about this. Like in our, in our Stanford study, we were really clear with people that they had to have already signed up to have anything to do with.

• 1:09:37Speaker 00

  Couldn't encourage them to do it, yeah.

• 1:09:39Speaker 03

  Yeah, we couldn't encourage them to to do it. We didn't really participate in any of the processes for them to do it. We simply just studied people that were already going down there.

• 1:09:50Speaker 00

  I want to ask you a question about a particular flavor of mental illness that is incredibly difficult to treat, that is really generally from a lot of trauma, which is personality disorders.

• 1:10:03Speaker 03

  Yeah.

• 1:10:04Speaker 00

  Borderline personality, narcissistic personality, it's so effective, there's all these personality disorders, which are more like fixed personality traits that are hard to change. And I'm curious if this kind of life review, this sort of narrative unfolding of your life like a movie during an Ibragen experience, has any impact on these more embedded, like deep-seated traumas that are harder to undo?

• 1:10:28Speaker 03

  It's a great question. I mean, the, you know, the Hopkins group demonstrated this profound personality change that they observed out to a year, I think, early on with their trials of psilocybin. And so there's definitely data that there's personality change, you know, in and around psilocybin use. It's an open question. And the other thing that's interesting, which is data that isn't published yet, but was collected, was around folks that will say they're, you know, they're, they're religious or not. And so actually, people that, I think it was like 16% of people were not religious prior to to taking Ibragen.

• 1:11:11Speaker 03

  And there's a increased kind of sense of, of a higher.

• 1:11:16Speaker 00

  Higher power out there.

• 1:11:17Speaker 03

  Higher power or whatever, after, like, almost, you know, two thirds of people. And so. This question of how do people see the world that they live in is really interesting. But yeah, you know, nobody's done a personality inventory study with I begane. So it's still an open question.

• 1:11:34Speaker 00

  Is it dangerous for these people? They do, you think?

• 1:11:36Speaker 03

  It's certainly dangerous for people with with a psychotic history, you know? I think people with bipolar disorder, that's going to be dangerous. Maybe somebody with severe borderline, maybe, you know, it just depends. It depends on a kind of individual basis. The problem at a fundamental level is we just haven't studied this enough to really know.

• 1:11:56Speaker 00

  We don't have enough data sets to know what's going on with these people. Yeah, interesting. So where do you see in closing? Where do you see this in five to 10 years in terms of psychiatry, psychedelic therapy in general? And I begin specifically?

• 1:12:08Speaker 03

  We have to do, we have a lot of work to do to kind of get this to the next step. A lot of studies to do, but you know, if somehow this is able to get all the way to the finish line. I think that, you know, society will be in a much better place from a mental health standpoint. If all the data continues to look like it does, just because of, you know, the profound suffering that's out there. I mean, there was a WHO statistic that really struck me, which is one out of two people will have a DSM diagnosis at some point in their lifetime.

• 1:12:41Speaker 00

  That's a psychiatric.

• 1:12:42Speaker 03

  Purely psychiatric or dementia.

• 1:12:44Speaker 00

  One out of two.

• 1:12:44Speaker 03

  One out of two.

• 1:12:45Speaker 00

  That's a lot. Half of the population of the world is going to have some mental illness at some point in their life.

• 1:12:52Speaker 03

  It's a scaling problem. Think about it. I mean, at the end of the day, we would never be able to actually effectively deal with that.

• 1:12:58Speaker 00

  Definitely not through therapy.

• 1:13:00Speaker 03

  Definitely not through therapy. You'd have to have half the world become therapy. I mean, maybe with AI, you know, all of us are trying to figure out.

• 1:13:05Speaker 00

  That's right. AI therapists are pretty damn good. This psychedelic revolution to me is very promising. And then combined with the metabolic psychiatry revolution, which we're going to do a podcast about soon. That that also is is another unlock, I think, in terms of mental health. It's harder for people to do that because it requires a lot of lifestyle change. Whereas this is a sort of a brain reset that that seems like it would facilitate behavioral lifestyle change. It's almost like this could set the stage and then you can have an easier time doing doing that other hard work. What studies are on the horizon for you that you're you're looking at doing?

• 1:13:37Speaker 03

  We're looking forward to seeing what happens, the this Texas effort. And hopefully there's, you know, some funding for Texas based universities to do this, you know, and to do. Do the, you know, these treatments, but yeah, it's an open question about what, you know, what's going to happen with the FDA. And I think if the FDA comes through and lets us do the studies, there'll be a normal, healthy control study. We're hoping to add some biology to that. And then subsequently, hopefully some traumatic brain injury studies.

• 1:14:05Speaker 00

  When you say biology, you mean biomarkers, blood tests, or what would be the things you're looking at in addition to functional MRIs and the EEGs, which are brain imaging and brain electrical studies?

• 1:14:14Speaker 03

  We hope to do, you know, some of that, at least the EEG side of things. But yeah, it's a, it's a great question. Maybe something interesting to talk about later, but you know, around is there blood, you know, any kind of blood-based biomarkers that would be of interest to, because we'll have IVs in everybody, you know?

• 1:14:28Speaker 00

  Fascinating work. Incredible what you're doing. It's, you're definitely going out of limb in the psychiatric world. I think, you know, you're brave and, you know, but you're at Stanford and respected institution, and they seem to be in support of you doing this work, which is amazing. And, you know, we need a Hail Mary in psychiatry because we are in a bad state as a world. We're all divided and disconnected and isolated and struggling with various forms of just anxiety of living in the 21st century to more serious mental illness. And the unlock that you and your colleagues are trying to get with this work and the whole psychedelic field is just amazing. So thanks for doing what you do.

• 1:15:13Speaker 03

  Yeah, thanks for having me.

• 1:15:15Dr. Mark Hyman?

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• 1:15:59Dr. Mark Hyman?

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• 1:16:43Dr. Mark Hyman?

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