#714: A Glimpse of the Future: Electroceuticals for 70%–90% Remission of Depression, Brain Stimulation for Sports Performance, and De-risking Ibogaine for TBI/PTSD

Brought to you by Nordic Naturals https://www.nordic.com/products/ultimate-omega/ Ultimate Omega fish oil, Eight Sleep’s Pod Cover https://eightsleep.com/Tim sleeping solution for dynamic cooling and heating, and AG1 https://drinkag1.com/tim all-in-one nutritional supplement. Welcome to a very special episode of The Tim Ferriss Show http://tim.blog/podcast, an episode that might be an example of peeking around corners and catching a glimpse of the future of mental health treatments in the next five to ten years. My guest is Nolan Williams, MD (@NolanRyWilliams https://twitter.com/NolanRyWilliams). Nolan is an associate professor within the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine and director of the Stanford Brain Stimulation Lab https://bsl.stanford.edu/faculty/. He has a broad background in clinical neuroscience and is triple board certified in general neurology, general psychiatry, and behavioral neurology and neuropsychiatry. Themes of his work include examining spaced learning theory and neurostimulation techniques, development and mechanistic understanding of rapid-acting antidepressants, and identifying objective biomarkers that predict neuromodulation responses in treatment-resistant neuropsychiatric conditions. Nolan specializes in looking at cutting-edge treatments and new technologies that can be applied to treatment-resistant psychiatric disorders—so, treatment-resistant depression, disorders that are notoriously difficult to address, such as OCD, and many others. Nolan's work resulted in an FDA clearance for the world's first noninvasive, rapid-acting neuromodulation approach for treatment-resistant depression. And I've tested this myself, and we get into this in the conversation. He has published papers in Brain, American Journal of Psychiatry, and Proceedings of the National Academy of Sciences. Results from his studies have gained attention in Science and NEJM Journal Watch. He has received two NARSAD Young Investigator Awards, the Gerald L. Klerman Award, and the National Institute of Mental Health Biobehavioral Research Award for Innovative New Scientists. We also discuss things like ibogaine that are seemingly unrelated to neuromodulation, as Nolan is very well-versed in multiple disciplines and in multiple toolkits, both pharmacological and non-invasive neuromodulatory. It's this combination, actually, this rare Venn diagram, that makes him incredibly interesting to me. I really enjoyed this conversation. I think it is very important, highly tactical, and I hope you enjoy it as much as I did. * This episode is brought to you by Nordic Naturals https://www.nordic.com/products/ultimate-omega/, the #1-selling fish-oil brand in the US! More than 80% of Americans don’t get enough omega-3 fats from their diet. That is a problem because the body can’t produce omega-3s, an important nutrient for cell structure and function. Nordic Naturals solves that problem with their doctor-recommended Ultimate Omega fish-oil formula for heart health, brain function, immune support, and more. Ultimate Omega is made exclusively from 100% wild-caught sardines and anchovies. It’s incredibly pure and fresh with no fishy aftertaste. All Nordic Naturals’ fish-oil products are offered in the triglyceride molecular form—the form naturally found in fish, and the form your body most easily absorbs. Go to Nordic.com and discover why Nordic Naturals is the #1-selling omega-3 brand in the U. S. https://www.nordic.com/products/ultimate-omega/Use promo code TIM for 20% off your order of Ultimate Omega. * This episode is also brought to you by Eight Sleep http://eightsleep.com/Tim! Eight Sleep’s Pod Cover http://eightsleep.com/Tim is the easiest and fastest way to sleep at the perfect temperature. It pairs dynamic cooling and heating with biometric tracking to offer the most advanced (and user-friendly) solution on the market. Simply add the Pod Cover http://eightsleep.com/Tim to your current mattress and start sleeping as cool as 55°F or as hot as 110°F. It also splits your bed in half, so your partner can choose a totally different temperature. Conquer this winter season with the best in sleep tech and sleep at your perfect temperature. Many of my listeners in colder areas enjoy warming up their bed after a freezing day. Go to eightsleep.com/Tim http://eightsleep.com/tim and save $250 on the Pod Cover by Eight Sleep this winter. Eight Sleep http://eightsleep.com/Tim currently ships within the USA, Canada, the UK, select countries in the EU, and Australia. * This episode is also brought to you by AG1 https://drinkag1.com/tim! I get asked all the time, “If you could use only one supplement, what would it be?” My answer is usually AG1 https://drinkag1.com/tim, my all-in-one nutritional insurance. I recommended it in The 4-Hour Body in 2010 and did not get paid to do so. I do my best with nutrient-dense meals, of course, but AG1 https://drinkag1.com/tim further covers my bases with vitamins, minerals, and whole-food-sourced micronutrients that support gut health and the immune system. Right now, you’ll get a 1-year supply of Vitamin D free with your first subscription purchase—a vital nutrient for a strong immune system and strong bones. Visit DrinkAG1.com/Tim https://drinkag1.com/tim to claim this special offer today and receive your 1-year supply of Vitamin D (and 5 free AG1 travel packs) with your first subscription purchase! That’s up to a one-year supply of Vitamin D as added value when you try their delicious and comprehensive daily, foundational nutrition supplement that supports whole-body health. * [00:00] Start [07:49] How SAINT helped Deirdre Lehman. [13:59] Typical vs. atypical sequences of activation. [21:00] Psychiatry 1.0, 2.0, 3.0. [26:41] How SAINT (Stanford Accelerated Intelligent Neuromodulation Therapy) came to be. [34:00] TMS vs. ECT. [35:26] Rewards and risks of shortening treatment timeframe. [43:43] Numbers treated and common side-effects. [46:32] Patient demographics. [49:51] Where to find current open trials. [51:01] Observed benefits of SAINT over more conventional treatments. [52:45] Adapting treatment when symptoms prove misleading. [58:03] SAINT remission numbers versus those of alternative therapies. [1:02:50] Delayed remission speculation. [1:07:06] How Nolan became The Ibogaine Bachelorette. [1:11:37] The origin of Nolan’s interest in ibogaine. [1:12:40] Amazing results of the quickest-recruiting study Nolan has ever run. [1:15:19] Dealing with alexithymia and self-reporting inaccuracies in research. [1:19:41] Ibogaine research gets federal funding (approved since this conversation took place)! [1:21:09] Isolating the ibogaine effect. [1:21:49] The value of life review on ibogaine. [1:25:56] How ibogaine differs from other psychedelic treatments. [1:30:05] The challenge behind synthesizing naturally occurring compounds. [1:31:54] Coping with ibogaine’s cardiac risks. [1:39:37] Understanding habitual action through ibogaine, Ozempic, caffeine, and alcohol. [1:45:43] Ibogaine for TBI. [1:50:08] Ibogaine for alleviating opioid withdrawal symptoms. [1:51:34] Ibogaine in Kentucky. [2:00:59] Weighing ethics with potential outcomes in research. [2:04:31] Can ibogaine be sourced (or synthesized) sustainably? [2:08:24] Does 5-MeO-DMT complement ibogaine enough to justify its collection? [2:16:48] What might Psychiatry 4.0 look like? [2:25:12] Could we develop therapies to change hand dominance? [2:28:08] Boosting performance. [2:34:01] Parting thoughts. * For show notes and past guests on The Tim Ferriss Show https://tim.blog/podcast, please visit tim.blog/podcast https://tim.blog/podcast/?utm_source=podcast&utm_medium=podcast&utm_campaign=podcast-description. For deals from sponsors of The Tim Ferriss Show https://tim.blog/podcast, please visit tim.blog/podcast-sponsors https://tim.blog/podcast-sponsors Sign up for Tim’s email newsletter (5-Bullet Friday) at tim.blog/friday https://go.tim.blog/5-bullet-friday-1/. For transcripts of episodes, go to tim.blog/transcripts https://tim.blog/transcripts. Discover Tim’s books: tim.blog/books https://tim.blog/books. Follow Tim: Twitter: twitter.com/tferriss https://twitter.com/tferriss Instagram: instagram.com/timferriss https://instagram.com/timferriss/ YouTube: youtube.com/timferriss https://www.youtube.com/timferriss Facebook: facebook.com/timferriss https://www.facebook.com/TimFerriss/ LinkedIn: linkedin.com/in/timferriss http://linkedin.com/in/timferriss Past guests on The Tim Ferriss Show http://tim.blog/podcast include Jerry Seinfeld https://tim.blog/2020/12/08/jerry-seinfeld/, Hugh Jackman https://tim.blog/2020/06/26/hugh-jackman/, Dr. Jane Goodall https://tim.blog/2020/04/16/jane-goodall/, LeBron James https://tim.blog/2018/11/27/lebron-james-mike-mancias/, Kevin Hart https://tim.blog/2020/05/20/kevin-hart/, Doris Kearns Goodwin https://tim.blog/2018/09/07/doris-kearns-goodwin-leadership/, Jamie Foxx https://tim.blog/2015/12/06/jamie-foxx/, Matthew McConaughey https://tim.blog/2020/10/19/matthew-mcconaughey/, Esther Perel https://tim.blog/2017/05/21/esther-perel/, Elizabeth Gilbert https://tim.blog/2020/05/08/elizabeth-gilbert/, Terry Crews https://tim.blog/2017/12/20/terry-crews-how-to-have-do-and-be-all-you-want/, Sia https://tim.blog/2020/08/12/sia/, Yuval Noah Harari https://tim.blog/2020/10/27/yuval-noah-harari/, Malcolm Gladwell https://tim.blog/2016/06/21/malcolm-gladwell/, Madeleine Albright https://tim.blog/2020/05/27/secretary-madeleine-albright/, Cheryl Strayed https://tim.blog/2017/03/30/cheryl-strayed/, Jim Collins https://tim.blog/2019/02/18/jim-collins/, Mary Karr, https://tim.blog/2020/11/11/mary-karr/ Maria Popova https://tim.blog/2014/10/21/brain-pickings/, Sam Harris https://tim.blog/2020/05/15/sam-harris-2/, Michael Phelps https://tim.blog/2021/01/21/michael-phelps-grant-hackett/, Bob Iger https://tim.blog/2020/01/16/bob-iger/, Edward Norton https://tim.blog/2019/10/31/edward-norton-motherless-brooklyn/, Arnold Schwarzenegger https://tim.blog/2015/02/02/arnold-schwarzenegger/, Neil Strauss https://tim.blog/2014/06/24/neil-strauss/, Ken Burns https://tim.blog/2019/09/12/ken-burns/, Maria Sharapova https://tim.blog/2017/08/26/maria-sharapova/, Marc Andreessen https://tim.blog/2016/05/29/marc-andreessen/, Neil Gaiman https://tim.blog/2019/03/28/neil-gaiman/, Neil de Grasse Tyson https://tim.blog/2019/10/03/neil-degrasse-tyson/, Jocko Willink https://tim.blog/2016/09/21/jocko-willink-on-discipline-leadership-and-overcoming-doubt/, Daniel Ek https://tim.blog/2020/12/03/daniel-ek/, Kelly Slater https://tim.blog/2020/09/08/kelly-slater/, Dr. Peter Attia https://tim.blog/2019/11/27/peter-attia-fasting-metformin-longevity/, Seth Godin https://tim.blog/2016/02/10/seth-godin/, Howard Marks https://tim.blog/2018/09/25/howard-marks/, Dr. Brené Brown https://tim.blog/2020/02/06/brene-brown-striving-self-acceptance-saving-marriages/, Eric Schmidt https://tim.blog/2019/04/09/eric-schmidt/, Michael Lewis https://tim.blog/2020/05/01/michael-lewis/, Joe Gebbia https://tim.blog/2018/03/08/joe-gebbia-co-founder-of-airbnb/, Michael Pollan https://tim.blog/2018/05/06/michael-pollan-how-to-change-your-mind/, Dr. Jordan Peterson https://tim.blog/2021/03/01/jordan-peterson/, Vince Vaughn https://tim.blog/2017/05/31/vince-vaughn/, Brian Koppelman https://tim.blog/2020/04/23/brian-koppelman/, Ramit Sethi https://tim.blog/2019/05/07/ramit-sethi/, Dax Shepard https://tim.blog/2020/11/18/dax-shepard/, Tony Robbins https://tim.blog/2014/10/15/money-master-the-game/, Jim Dethmer https://tim.blog/2020/05/18/jim-dethmer/, Dan Harris https://tim.blog/2020/11/19/dan-harris/, Ray Dalio https://tim.blog/2017/09/13/ray-dalio/, Naval Ravikant https://tim.blog/2015/08/18/the-evolutionary-angel-naval-ravikant/, Vitalik Buterin https://tim.blog/2021/03/08/vitalik-buterin-naval-ravikant/, Elizabeth Lesser https://tim.blog/2021/03/16/elizabeth-lesser/, Amanda Palmer https://tim.blog/2019/04/18/amanda-palmer-2/, Katie Haun https://tim.blog/2021/02/18/katie-haun/, Sir Richard Branson https://tim.blog/2017/10/09/richard-branson/, Chuck Palahniuk https://tim.blog/2020/09/02/chuck-palahniuk/, Arianna Huffington https://tim.blog/2017/10/18/arianna-huffington/, Reid Hoffman https://tim.blog/2015/08/31/the-oracle-of-silicon-valley-reid-hoffman-plus-michael-mccullough/, Bill Burr https://tim.blog/2017/09/17/bill-burr/, Whitney Cummings https://tim.blog/2015/06/26/whitney-cummings/, Rick Rubin https://tim.blog/2015/05/15/rick-rubin/, Dr. Vivek Murthy https://tim.blog/2020/03/26/vivek-murthy/, Darren Aronofsky https://tim.blog/2017/09/09/darren-aronofsky/, Margaret Atwood https://tim.blog/2022/02/22/margaret-atwood/, Mark Zuckerberg https://tim.blog/2022/03/24/mark-zuckerberg/, Peter Thiel https://tim.blog/2014/09/09/peter-thiel/, Dr. Gabor Maté https://tim.blog/2018/02/20/gabor-mate/, Anne Lamott https://tim.blog/2021/07/09/anne-lamott/, Sarah Silverman https://tim.blog/2022/01/12/sarah-silverman/, Dr. Andrew Huberman https://tim.blog/2021/07/06/andrew-huberman/, and many more. See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

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

• 0:00Tim Ferriss?

  This episode is brought to you by Nordic Naturals, the number one selling fish oil brand in the US. More than 80% of Americans, that's probably a lot of you listening, including me, because I do measure my omega-3s, do not get enough omega-3 fats from their diet. That is a problem because the body cannot produce omega-3s, an important nutrient for cell structure and function. Nordic Naturals solves that problem with their doctor recommended, and in fact, this brand was recommended to me by one of my doctors, Ultimate Omega Fish Oil Formula. So the Ultimate Omega Fish Oil Formula for heart health, brain function, immune support, and more. It's incredibly pure and fresh with no fishy aftertaste. So I have been taking Ultimate Omega for the last two months or so,

• 0:45Tim Ferriss?

  and this fishy aftertaste issue has been a problem for me. And it's actually with other brands induced some nausea after a few days. And Ultimate Omega has been as clean as a whistle. I've had no issues whatsoever. And if you are vegetarian or prefer to alternate, I ended up alternating two products. And that is number one, the Ultimate Omega Fish Oil Formula, and also the Algae Omega, which is plant-based EPA and DHA. That's also from Nordic Naturals. So I end up getting both of those products, and it has improved my recovery from workouts. It's improved my sleep. It has improved my mood. And I know that because I pulled out a lot of other variables. In any case, back to the read.

• 1:29Tim Ferriss?

  All Nordic Naturals fish oil products are offered in the triglyceride molecular form, the form naturally found in fish, and the form your body most easily absorbs. Their Ultimate Omega Fish Oil is offered in soft gels, liquid, and zero sugar gummies. Nordic Naturals fish oils are Friend of the Sea certified and sustainably made in a zero-waste facility powered by biofuel. They're also non-GMO and third-party tested, surpassing the strictest international standards for purity and freshness. Want proof? You can visit their website, where they provide certificates of analysis for every one of their products. So go to Nordic.com, N-O-R-D-I-C, Nordic.com, and discover why Nordic Naturals is the number Number one selling omega-3 brand in the U.S.

• 2:12Tim Ferriss?

  And while you're there, use promo code TIM, T-I-M, for 20% off of your order. That's N-O-R-D-I-C dot com and code TIM for 20% off of the fish oil with no fishy aftertaste. All upside, no downside. Try it out.

• 2:27Speaker 01

  These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

• 2:37Tim Ferriss?

  This episode is brought to you by Eight Sleep. Temperature is one of the main causes of poor sleep and heat is my personal nemesis. I've suffered for decades tossing and turning, throwing blankets off, pulling the back on, putting one leg on top and repeating all of that ad nauseam. But now I am falling asleep in record time. Why? Because I'm using a device that was recommended to me by friends called the Pod Cover by Eight Sleep. The Pod Cover fits on any mattress and allows you to adjust the temperature of your sleeping environment, providing the optimal temperature that gets you the best night's sleep. With the Pod Cover's dual-zone temperature control, you and your partner can set your sides of the bed to as cool as 55 degrees or as hot as 110 degrees.

• 3:19Tim Ferriss?

  I think generally in my experience, my partners prefer the high side and I like to sleep very, very cool. So stop fighting. This helps. Based on your biometrics, environment, and sleep stages, the Pod Cover makes temperature adjustments throughout the night that limit wake-ups and increase your percentage of deep sleep. In addition to its best-in-class temperature regulation, the Pod Cover sensors also track your health and sleep metrics without the need to use a wearable. Conquer this winter season with the best in sleep tech and sleep at your perfect temperature. Many of my listeners in colder areas, sometimes that's me, enjoy warming up their bed after a freezing day. And if you have a partner, great, you can split the zones and you can sleep at your own ideal temperatures. It's easy.

• 4:02Tim Ferriss?

  So go to eightsleep.com/Tim, spelled out, eightsleep.com/Tim, and save $250 on the Pod Cover by Eight Sleep this winter. Eight Sleep currently ships within the U.S., Canada, the U.K., select countries in the EU, and Australia.

• 4:19Speaker 02

  At this altitude, I can run flat out for a half mile before my hands start shaking. Can I ask you a personal question?

• 4:26Speaker 03

  No, we're just sitting at the perfect time.

• 4:29Speaker 02

  I'm a cybernetic organism living tissue over metal endoskeleton.

• 4:42Tim Ferriss?

  Hello, boys and girls, ladies and germs. This is Tim Ferriss and welcome to a very special episode of The Tim Ferriss Show. This is an episode that I think might be an example of peeking around corners. So what we are going to talk about, what we discuss in this episode, I think may be a component of the future of mental health treatments in the next, say, five to 10 years. It's at least a sample of it. My guest is Nolan Williams, M.D. You can find him on Twitter @NolanRyWilliams. And Nolan is an associate professor within the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine and director of the Stanford Brain Stimulation Lab.

• 5:23Tim Ferriss?

  And we're going to go deep into a lot related to brain stimulation. He has a broad background in clinical neuroscience and is triple-board certified in general neurology, general psychiatry, and behavioral neurology and neuropsychiatry. Themes of his work include examining spaced learning theory and neurostimulation techniques, development and mechanistic understanding of rapid-acting antidepressants, and identifying objective biomarkers that predict neuromodulation responses in treatment-resistant neuropsychiatric conditions. That is a long way of saying that he specializes in looking at, I would say, and these are

• 6:03Tim Ferriss?

  my words, of course, cutting-edge treatments and new technologies that can be applied to treatment-resistant psychiatric disorders, let's just say. So treatment-resistant depression, things that are notoriously difficult to address like OCD, there are many others. Nolan's work resulted in an FDA clearance for the world's first non-invasive rapid-acting neuromodulation approach for treatment-resistant depression. And I've tested this myself, and we get into this in the conversation. He has published papers in Brain, American Journal of Psychiatry, and Proceedings of the National Academy of Sciences. Results from his studies have gained attention in Science and the New England Journal of Medicine Journal Watch.

• 6:46Tim Ferriss?

  He received two NARSAD Young Investigator Awards, the Earl L. Klerman Award and the National Institute of Mental Health Bio-Behavioral Research Award for Innovative New Scientists. Again, you can find him on Twitter or X @NolanRWilliams. We'll link to this in the show notes as well. And you can find him online at NolanRWilliams.com. I really enjoyed this conversation. I think it is very important, highly tactical, and we also discussed things like ibogaine, which are seemingly unrelated to neuromodulation, and yet Nolan is an expert, very well-versed in multiple disciplines and in multiple toolkits,

• 7:26Tim Ferriss?

  pharmacological and non-invasive neuromodulatory. And it's this combination, this rare Venn diagram, that makes him incredibly interesting to me. So I hope you enjoy this conversation as much as I did. And without further ado, Nolan Williams, M.D.

• 7:46Speaker 04

  Dr. Williams, good to see you there.

• 7:48Tim Ferriss?

  Yeah, thanks, man. Thanks for having me. And I thought we would start with a personal story, not your personal story, but a story of Deirdre Lehman.

• 7:59Speaker 04

  Yeah.

• 7:59Tim Ferriss?

  Could you tell us who this person is, how it fits into your story? But let's begin with just a description of Deirdre.

• 8:07Speaker 04

  So Deirdre is maybe in her 50s, 60s, female in Bay Area who has suffered from bipolar disorder much of her life and pretty successfully treated for the mania side of things over the years, had a psychiatrist taking care of that part in Marin, and happened to slip into this pretty severe depressive episode a couple of years back. I guess it's been maybe like four or five years now. And her psychiatrist had actually gone to see a talk that I gave at this Mood Disorders Day like the year before. We were talking, it was really early on when we were working on a rapid-acting neurostimulation approach. So the psychiatrist had heard the talk, and then her patient kind of fell into this

• 8:50Speaker 04

  really bad suicidal depression. And so she... Reached out to me to treat her and I got on the phone. I'll never forget. It was like a Wednesday and I got on the phone with her psychiatrist and she was telling me symptomatically how bad off she was. And I was like, I don't think we can treat her outpatient. She's like way too ill. I think she needs to go to the inpatient hospital. So essentially gave her some information on how to do that. So I see her the next morning and she's in really bad shape.

• 9:19Tim Ferriss?

  What does that mean? Like, how did that show up?

• 9:21Speaker 04

  When people are at the level where they like kind of definitively need to go into the hospital, they're not really totally communicative anymore and they've got some cognitive issues sometimes. And so in her case, you know, she couldn't look you in the eyes. You look at the ground and she was doing this rocking thing, which you can see in pretty severe depression. It's kind of this catatonia overlap symptoms, you know? I mean, she's like at the kind of the very end of the spectrum, one of the highest severity patients we've ever treated. So she was like a score of 50 on the modus of 60, like very, very severe, right? And just rocking and not really talking and, and husbands were counting everything and she had bipolar one. So she was hypomanic, I think, or manic like two weeks before, and then dropped into this very, very severe depression.

• 10:06Speaker 04

  So it was her daughter and the husband and they're sitting in the room with me and I said, they want me to treat her. And I say, listen, like it's Friday. We go Monday to Friday. Like you have to find a way basically to keep her well from now until Monday. And that means-

• 10:21Tim Ferriss?

  And by well, you mean safe, like preventing self harm?

• 10:23Speaker 04

  Yeah, exactly. So keep her not having a suicide attempt, basically from now until Monday. She's very suicidal. And I said, you're going to have to like take every knife, I don't think any guns, but gun, chemical, like scissors, everything out of the house. The whole, all of it has to go and you guys have to be on like a 24 hour, you know, watch until Monday. And so Monday morning rolls around and we, we bring her in and the craziest thing, we had like a repair on the motor threshold coil, which is a coil you use to kind of get- Calibrated on the intensity and it shorted out the device and blew the capacitor bank up on the first stimulator.

• 11:05Tim Ferriss?

  Blew your flux capacitor.

• 11:07Speaker 04

  Yeah, yeah, at like 7:00 AM. And I mean, you can't imagine how stressful that was. So we had a second machine. I'll tell you about this later. We were running this, you know, trait hypnotizability modulation study and it was over at the scanner. So it was like, pretty far away. And this thing's weigh like 100 pounds. So I had to send my team over there, run over there and grab it, bring it over. And luckily, we were able to kind of get her going and treat her with a second machine. She was in really, really bad shape that morning. And by 5 o'clock that afternoon, she was basically normal. And the next morning, she was like, totally zeroed out and completely normal.

• 11:44Tim Ferriss?

  Meaning no suicidality.

• 11:45Speaker 04

  Meaning no depression, no nothing. I mean, she looked like any person walking the street, like totally normal. And that was in 24 hours. And we've seen this with bipolar patients quicker, right? It'll happen really quick for like a bipolar one patient. You can get it done. And sometimes in a day.

• 12:02Tim Ferriss?

  Just for clarity, by get it done and don't worry people listening, we're going to define terms and get into all this. But you're talking about accelerated TMS.

• 12:09Speaker 04

  Yeah, we're talking about accelerated TMS. Our rapid acting neurostimulation approach, we're able to get people out of these states and in a normal mood, you know, and in short periods of time, generally, like 2.6 days on average for major depression patients, but it's quicker with bipolar. We've seen especially with bipolar one patients. So she was totally out of it in 24 hours. I remember it was like, right around July 4th or something. And so we, you know, the whole team left. I guess we'll tell you about caffeine later too. So, so my wife and I are like big Phil's Coffee fans. And so I'll never forget this either. So we go down to the Phil's Coffee in Palo Alto. After I saw them, I'll never forget it. Clark Lehman, her husband was also went to Phil's. Didn't know I was going to be there. And I look over and this guy's just kind of staring at me.

• 12:55Speaker 04

  And I was like, hey, how are you? Good to see you again. I just saw the guy like 10 minutes ago. And he's like, I still don't understand what happened. And it makes sense, right? Like, to take somebody from the worst you've ever seen them mood wise to like, normal in such a short period of time was remarkable for him. And, you know, it ended up being that, you know, after that period, they actually went out and really were helpful with a lot of the philanthropy that led to the trials being funded and ultimately, the clearance. And Clark and Deirdre really were advocates and have continued to be advocates for this to kind of get it out into the world. And he, it was totally based off of that experience of feeling, him feeling helpless, you know, and going from that to feeling like it was

• 13:37Speaker 04

  all solved. And I think she went maybe a year completely asymptomatic, ended up needing to get retreated again at some point, but gets like these little touch ups here and there and is able to stay well ongoing and depression. As they tell me, depression's not her problem anymore. And so that's good. She's a great illustrative case of what this can do. And I think what the promise of it can be.

• 13:59Tim Ferriss?

  What I'd love to talk about next is not necessarily direct mechanism of action, but I'd love to hear you just explain a snippet that I pulled from your conversation with Andrew Huberman.

• 14:09Speaker 04

  Yeah.

• 14:10Tim Ferriss?

  Which was a very good conversation. Specifically, it was about, and I'm not going to use the right terminology here, so bear with me as a layperson, but the sequencing or abnormal slash pathological sequencing of activation or activity in different parts of the brain. So I don't know if it's the anterior cingulate.

• 14:28Speaker 04

  Yep.

• 14:30Tim Ferriss?

  I think you know what I'm alluding to here. Would you mind just explaining that? Because it was something that I had never been exposed to, and I found it deeply fascinating. And I'll just also mention this context for people who are listening to this, that part of what is deeply interesting to me about a number of the different tools and modalities that you explore in depth is not just the speed of action, but the durability of effect.

• 14:55Speaker 04

  Yep.

• 14:56Tim Ferriss?

  Super.

• 14:58Tim Ferriss?

  Super potent combination and very unusual, from what I can tell, combination of things. All right, so as far as the sequence of activation goes, could you explain what I'm referring to?

• 15:09Speaker 04

  We published a paper in the Proceedings of National Academy of Science, I guess it's been about six months ago now. So, one of the former research track resident post-docs in the psychiatry program at Stanford, Anish Mitra, who's now junior faculty, was working with Carl Deisseroth and I during that training phase. And Anish had this interest in a specific way of looking at brain imaging, particularly this type of brain imaging called resting state functional connectivity MRI. And so resting state functional connectivity MRI has been around for a long time. The resting state part of it is, basically, you tell a person to sit in the scanner and let their mind wander. So that's kind of the resting state, or the default mode, however

• 15:54Speaker 04

  you want to think about it. And functional connectivity, what that means is it's the brain regions that have blood flow that is time-locked with each other, right? And so essentially, these connected brain networks, the blood flow will go up or go down in those areas in a time-lock fashion. And blood flow is really-

• 16:14Tim Ferriss?

  By time-lock, you just mean at the same time?

• 16:15Speaker 04

  At the same time.

• 16:16Tim Ferriss?

  Correlating.

• 16:17Speaker 04

  Yeah, exactly, yeah. And so, blood flow is a surrogate of electrical activity. It's hard to see electrical activity kind of deep in the brain. People see it at the surface with EEG, but with MRI, you use the blood flow as like a surrogate of the electrical activity. And it makes sense, if you're using glucose in a brain region, because you're using that network, then you need to have cerebral autoregulation, so the blood vessels increase and they dilate and more blood goes into that area. So it's just like a response to increased activity. And so you have these increases in blood flow that are supposed to represent electrical activity that are in different, separate nodes in the brain,

• 16:59Speaker 04

  and they come on roughly at the same time. And we've known that for a while. Anish got very interested in this idea that the- Timing of the blood flow is consistently temporally offset between these nodes, so slightly that people ignored it for a long time, but he was able, through using various math, able to show that there's a slight offset of the timing such that one brain region slightly comes on before the other. And that's interesting because that infers some level of causality, right? So instead of the whole network coming on at the same time, maybe it's just one area and it's signaling the whole network on, you know, and it's so quick that you see it as all like this, but really it's more like this, right?

• 17:42Speaker 04

  If that makes sense, like it's coming on all at the same time, but from this network node, kind of turning this one on, turning that one on or something.

• 17:49Tim Ferriss?

  Right, like the lead domino matters.

• 17:50Speaker 04

  Yeah, that's, that's right. The lead domino, exactly. So in the case of mood, it looks like the dorsolateral prefrontal cortex, the area that's involved in control, precedes slightly the cingulate cortex. In our normal, healthy control population, essentially nearly everybody had that directionality. In the depressed cohort, 70% of them had it flipped, where the cingulate was temporally in front of the dorsolateral, but not everybody. And if you just had that information, you wouldn't know what to make of that, like, why, why is it some people and not others? But what was interesting is when he looked at the folks that had it versus the ones

• 18:33Speaker 04

  that didn't, the ones that had it were the ones that were responsive to our, we'll talk about, you know, what SAINT is and the rapid acting neurostimulation approach in detail, I guess, later, but the, the folks that responded to SAINT, responded to this rapid acting TMS approach were the ones that had the biomarker. And the ones that had no change did not have the biomarker and looked like a normal, healthy control. And the signal on the post-scan flipped to look normal. And the folks that responded had the biomarker and then their brain changed after. And so the post-scan looked just like the pre-scan on the folks that didn't clinically change in the normality controls.

• 19:16Speaker 04

  You know, we see this sort of test all the time in medicine. You know, 10 people come into the primary care doctor's office with blurry vision, urinating a lot, drinking a lot, headache. A lot of those folks probably have diabetes, but not all of them. Some of them have migraine headache and need glasses and some other things. And it looks like a diabetes presentation, but when you go and do the blood sugar, the blood sugar is normal. And then you go and in the folks that have elevated blood sugar that look like they have diabetes, you go and you give them diabetic medicine and then it normalizes. So the blood sugar after looks like the blood sugar of a normal healthy and looks like the blood sugar of somebody that symptomatically presented, but didn't have diabetes.

• 19:59Speaker 04

  And so it was nice to see this and we're replicating this now. We have money from National Institutes of Health to do that. But this idea that we're able to have a test that would change and the same thing that signals that there's an abnormality is the thing that changes later. And that's more rare in psychiatry, right? To be able to have all of that line up. So we're pretty excited about that and hope to see it. It does replicate in the larger population of patients. But it's a, you know, as a conceptual idea, it's an important conceptual idea, this general idea of being able to use neuroimaging or whatever it is, EEG, whatever it is, to type different people that are presenting with similar symptoms

• 20:42Speaker 04

  and be able to say, okay, you're going to respond to this and not this or vice versa. I think that's part of what we need for psychiatry, right? Because people spend just so much time in their lives trying to find the answer and we don't really have any tests.

• 20:59Tim Ferriss?

  Trial and error.

• 20:59Speaker 04

  Yeah, it's a lot of trial and error.

• 21:01Tim Ferriss?

  It's like pharmaceutical ready fire aim.

• 21:04Speaker 04

  Yep.

• 21:05Tim Ferriss?

  In a sense. And this raises, I guess, just a meta observation slash question. Perhaps you could just discuss this briefly, which is it seems to me like there have been, and this is part of the impetus for us having this conversation. Part of the impetus for me in the last, let's call it half year, paying a lot of attention to accelerated TMS, which is there have been these dominant paradigms in certain types of, let's call it psychiatric treatments for things like depression, treatment resistant depression. And it seems like a very dominant paradigm for a period of perhaps several decades has been these chemical imbalance theory of.

• 21:45Tim Ferriss?

  Psychiatric disorders, so you have a serotonin issue, therefore, we're going to treat it in these following ways. You have such and such an issue, sure, we're going to give you SNRIs. And then, like you said, it's a lot of trial and error to figure out what works. And even if something works, it may often only work for a period of time. So it seems to me, and I want you to absolutely fact check and correct everything that I'm saying, but that part of the reason that the research you're doing and that others are engaging in is so fascinating is that it presents an alternative paradigm through which you could look at certain disorders, right? Like, oh, wait a second. Well, maybe this person's car, when you turn the ignition, is just tripping things in the wrong order.

• 22:27Tim Ferriss?

  And if that's causal, we could try to address that. And then maybe that addresses what we might have otherwise perceived as a chemical disorder. I have a lot of follow up questions, but is that a helpful way to think about this? Or what would you add to that?

• 22:40Speaker 04

  You know, there's been, I would argue, like, three eras in psychiatry, you know, what friends of mine have called psychiatry 1.0, 2.0, 3.0. And, you know, the first era was this era in and around Freud and this idea that it was a content issue and a life experience issue, which is partially true. It's not that that's not true, it's just not complete. And so then the solution is a content solution, ala initially psychoanalysis, all the way through kind of modern forms of psychotherapy. The limitations of that led us to psychiatry 2.0, right? This idea that we serendipitously found the first antipsychotics, first antidepressants, and we were able to deinstitutionalize primarily schizophrenia

• 23:23Speaker 04

  patients out of inpatient asylum stays with these drugs, which kind of flew in the face of this being a content issue.

• 23:31Tim Ferriss?

  What was the first antipsychotic?

• 23:33Speaker 04

  Thorazine.

• 23:35Tim Ferriss?

  I was gonna say Thorazine.

• 23:36Speaker 04

  Yeah, yeah.

• 23:37Tim Ferriss?

  I don't want to take you off track, so keep track of where we are. We're at 2.0. How was it serendipitously discovered?

• 23:43Speaker 04

  If I remember correctly, I think it was, it was like an antibiotic or something like that. And they were trying to develop That drug out for something completely unrelated and happened to give it to some patients with schizophrenia and they had a dramatic improvement.

• 23:57Tim Ferriss?

  Yeah. I would love to read a book that is just a collection of case studies like this. Right?

• 24:01Speaker 04

  Yeah.

• 24:01Tim Ferriss?

  It's like, uh, sildenafil, right? Viagra. It's like for angina or whatever.

• 24:05Speaker 04

  That's right.

• 24:05Tim Ferriss?

  And then the male patients are like, why aren't the male patients sending their meds back? Oh, wait a second.

• 24:09Speaker 04

  That's right.

• 24:10Tim Ferriss?

  Here we, here we go.

• 24:11Speaker 04

  Yeah.

• 24:11Tim Ferriss?

  I'm saying, all right, so Thorazine and the serendipitous discovery of, oh, wait a fucking second. This seems to, not necessarily negate, but certainly render incomplete this pre-existing paradigm.

• 24:27Speaker 04

  Yeah, that's right.

• 24:28Tim Ferriss?

  Then where does it go from there?

• 24:29Speaker 04

  So then I think that, you know, to your point, there was this accumulation of assumptions around, well, if we're moving all of these chemicals around in the brain, then it must be that there's, you know, a deficiency or an imbalance or whatever. And that led us to recent history where there's quite a bit of prescribing of oral antidepressants and all that stuff. And, you know, the third era, this kind of circuit era that I think we're, we're in now, and I'd, I'd argue we kind of were entering in 10 years ago, but I think we're pretty squarely at the, the beginning of now flies in the face of that. Right? If I can take a patient as severe as Deirdre Lehman, get her out of it in a very quick

• 25:09Speaker 04

  timeframe and looking normal and holding that for a long time, and there was no chemical exchange, right? There's nothing that went into her system, then it gets you into this newer way of thinking about it. It's a circuit problem. The useful thing about this framing, one, it's seemingly consistently true in the sense that we're through all the various modalities, seeing these differences, but, you know, more importantly, it lets you integrate past ideas into that concept. Drugs act on circuits, therapy acts on circuits, but focal neuromodulation is a really direct way of acting on those same circuits. And so. From a patient's standpoint, I think it's very empowering because we're not saying to

• 25:54Speaker 04

  the patient, there's something inherently like missing or too much for you in the sense that you're constrained to having to take these exogenous chemicals to kind of stay well, but rather like there's a circuit, you know, there's a miswiring sort of misfiring sort of problem. And if we can reroute that information, then you can feel well. And I think that there's a level of empowerment that comes of that. One of the things that patients always tell me after they get well with some of our stimulation approaches is that they, you know, they kind of look at it and say, well, I may get depressed again, but I don't think I'll ever get suicidal at that same level again, because I know that I've got a way of getting out of it and it's my own volition to choose to do

• 26:39Speaker 04

  that. And it's something I can tolerate and I feel normal.

• 26:41Tim Ferriss?

  So I'd like to highlight that last part because not that I'm the world's foremost expert in suicidal ideation, but as someone who came very close to offing himself in college and really just by a series of lucky events ended up not fulfilling that, it's the hopelessness. I mean, for me and for a lot of people, it's the feeling that nothing can fix this. I am broken. I am permanently broken. There is no option other than trying to silence this voice in my head. And the only way I can think of doing that is by ending my life. But once you see, once you experience even more so, something that alleviates that, especially with any type of durability, doesn't need to be forever, but some type

• 27:24Tim Ferriss?

  of durability, and especially if it's rapid acting, right?

• 27:28Speaker 04

  Yep.

• 27:29Tim Ferriss?

  Then you feel like you have a plan B. And that is incredibly empowering. Let me ask you a few questions. The first is, this type of neuromodulation, is that synonymous with the term that I came across? I don't know who coined it. It's a nice term, electrosedicals? Or are those different?

• 27:48Speaker 04

  Yeah, it's part of that broader term of electroscuticals. Yeah, and so what we had done with what we called SAIN or Stanford Accelerated Intelligent Neuromodulation Therapy is that we came up with a way of reorganizing conventional TMS, which had been around for some time, reorganizing it in time and in space, right? And so with conventional, our TMS that had developed in the mid 80s, first used as a therapeutic within clinical trials by my mentor Mark George when he was at NIH in the mid 90s, and approved by the FDA in the kind of mid to late 2000s, it utilized average scalp positions to find an average spot to stimulate, which, you know, at the time,

• 28:32Speaker 04

  given the technology that was available, that was the right call, right?

• 28:36Tim Ferriss?

  Can I pause for one second just to give some additional context?

• 28:38Speaker 04

  Yeah.

• 28:39Tim Ferriss?

  What does TMS stand for?

• 28:40Speaker 04

  So Transcranial Magnetic Stimulation.

• 28:43Tim Ferriss?

  And it was originally developed for what?

• 28:45Speaker 04

  As a motor probe by Tony Barker in the UK. And the idea is this idea of Faraday's law. So Faraday's law is this idea that if you pulse a magnet, you can generate current in electrically conducting substances. So if I take an electromagnet, if I take a TMS machine to the beach and I try to pulse the sand, nothing's going to happen because sand is not, as you know, electrically conducting at all, it's an insulator. And so if you put a TMS coil or any electromagnet next to a wire, a copper wire, speaker wire, or whatever, you can generate current in that wire. If you put the coil on the head, it will bypass the skin, scalp, skull, and induce

• 29:29Speaker 04

  current in the electrically conducting substance in the brain, the kind of brain tissue, right? And so you're able to selectively turn on cortical neurons without really interacting with much of the rest of the head. People do feel something because of the nerves in the scalp, but you don't, your brain can't feel anything, so that's scalp nerves. And so if you, as they did in the 80s, just kind of send a single pulse, it doesn't really change the brain, but you can probe the brain, right? So I could take that. Coil from the mid 80s and I could put it over my hand representation to make my thumb move, I could put it over my wrist representation of my brain, I could make my wrist move. And it's organized in this stereotyped way such that essentially the head, face area is

• 30:13Speaker 04

  like closer to the ear and you can march up to the midline of the skulls such that when you get to the midline, you're able to actually move the foot and the leg. If you have a certain kind of coil, you can do that. And so you can actually probe the entire motor system and make all of it move without having any volition to it.

• 30:30Tim Ferriss?

  Question, what is the value of this probe?

• 30:33Speaker 04

  So the value of a probe itself is just as they

• 30:37Tim Ferriss?

  Figuring out the mapping?

• 30:38Speaker 04

  Yeah, it's like, it's a mapping exercise initially, right? Like where is everything? Is it the same in everybody? Is it consistent? And they wanted to kind of have a way of doing that non-invasively. Penrose and others had been doing this invasively as neurosurgeons for 100 years, I guess 50 years at that point. And so they wanted to be able to emulate what the surgeons could do in epilepsy patients when they're doing epilepsy surgery, non-invasively. And then what folks realized over the next 10 years is we can send a signal into the brain that's like Morse code and basically send this signal to change the excitability of the brain. And we can measure it if we do it in motor cortex by how much the thumb moves with a

• 31:23Speaker 04

  set amplitude out of the machine. So if I get X movement from stimulating hearing, I make the thumb move X amount. And then I send this Morse code signal into the brain to tell it to tone down or to kind of be less excitable. And then I send that same intensity back in, the thumb will move half as much.

• 31:42Tim Ferriss?

  Hmm.

• 31:43Speaker 04

  And so you've toned down cortical excitability. If instead I get this measurement of X and then instead of putting in what we call inhibitory or deep potentiating stimulation, we put in excitatory potentiating stimulation into the brain and we do that and then we measure again, it'll be 2X.

• 32:00Tim Ferriss?

  Hmm.

• 32:01Speaker 04

  So we knew by the mid 90s that we could actually move around how excitable the brain was in these normal, healthy, control, volunteer motor cortices. And so the aha moment for Mark and his team Was this idea that depression at that time on PET scans, on spec scans was this kind of hypoactivity, hypometabolism.

• 32:23Tim Ferriss?

  Meaning lower.

• 32:24Speaker 04

  Yeah, lower activity, lower metabolism of the prefrontal cortex where the prefrontal cortex just isn't as active, isn't as robust as it is in normal, healthy controls. And so he had this idea, well, could we use this excitatory stimulation to drive up activity? And so that was the aha moment and the kind of first version of this. But they were super careful. There'd been some seizures in the early days from trying to figure out how all this works. And so they wanted to do a stimulation approach that wasn't going to have much in the way of risk. And so they had this once a day, very extended protocol. And because of the, you know, the mid 90s, it was very hard to get cheap brain scans on patients.

• 33:07Speaker 04

  And so this idea that they were going to have to use kind of average coordinates to target it. And so they get average skull measurements and then they would do kind of a low dose approach once a day and do that out for weeks and then it extended out to months. And so the original TMS trials and the original approval was this less efficient version that basically utilized kind of a low efficiency signal into the brain and used kind of average coordinates to place the coil.

• 33:37Tim Ferriss?

  So average coordinates, meaning just by clumsy analogy, like we can't take an x-ray of you, but we do have 100 other x-rays that seem to indicate roughly this is where you have your fractures. So we're going to aim at those coordinates.

• 33:50Speaker 04

  That's right. Yeah, that's right.

• 33:51Tim Ferriss?

  And the once a day protocol, I've heard the number 36 from somewhere, but is it somewhere in generally like the 30 to 40 session range?

• 34:00Speaker 04

  Yeah, that's exactly right.

• 34:01Tim Ferriss?

  So we're looking at, let's just call it for a placeholder, 30 to 40 sessions, one per day. And to perhaps not necessarily conjure an image, but remove an image from the minds of some listeners, they may be thinking, this is a beautiful mind. This is somebody chomping down on a wallet or a piece of wood, getting electroconvulsive therapy.

• 34:19Speaker 04

  Yep, yep.

• 34:20Tim Ferriss?

  These are not the same thing.

• 34:21Speaker 04

  Yeah, it's actually the opposite. So in the goal of electroconvulsive therapy, ECT, which has been around for 100 years. Is to produce a therapeutic seizure. And some people with autobiographical memory troubles, it's pretty underutilized as a treatment in psychiatry because of these issues, because of particularly One Flew Over the Cuckoo's Nest and that story. And that movie culturally has actually had an impact on ECT. And it's one of these things that's kind of, for a lot of patients, a last ditch resort because of the concerns around the side effects. TMS is different. You're not trying to induce a seizure. In fact, you're not trying to have any sort of change in cognition. I always tell patients it's really boring. So we have Netflix running in the background

• 35:07Speaker 04

  and people have their Netflix movie that they keep watching every day. And it's basically just, once folks get used to it, it's just part of a routine where they're sitting there and watching their show or whatever it is, and the stimulator is turning the brain on. And unlike in ECT, there's no anesthesia. There's really no need for anything. You can do this in an outpatient setting. But the old forms of TMS are extremely slow. You can't use that in a psychiatric emergency. And so this is something that happens over a couple of months. And it's tricky for some people. Like if you're a working person and you have to do TMS during, conventional TMS during business hours and you're, you basically have to tell your boss or sneak out of the office or whatever it is,

• 35:52Speaker 04

  and go do an hour and a half during the middle of the day, during like standard banker's hours to be able to do this. And it's hard to do that over a couple of months. And so, and it doesn't address these kind of high acuity emergencies. And so we got very interested in this idea of, can we, like I said earlier, reorganize the stimulation in time and space? Space being, can we personalize it to each person's brain? I can talk about that in greater detail. And then can we compress these six week courses, in this case, into a single day? So that's why Deirdre was able to get well in a day is because we gave her a whole six-week course in a day.

• 36:27Tim Ferriss?

  You gave her how many sessions?

• 36:29Speaker 04

  So that's 10 triple-dose sessions, and so it's like 30, 30 total equivalent sessions in a day. And so the FDA cleared 600 pulses of ITBS once a day, five days a week for six weeks in 2018.

• 36:43Tim Ferriss?

  And that was for a major depressive disorder?

• 36:45Speaker 04

  That was major depressive disorder. We give a triple dose every session, so 1,800 pulses. And so after 10 sessions, you've got the equivalent of 30 sessions worth in that first day, and you do that for five days. And so people are getting the dose equivalent of seven and a half months' worth of TMS in five days. And what we found is, surprising to us, that was this linear, is that, you know, you just pick up remitters as you progress through the days.

• 37:14Tim Ferriss?

  What do you mean by remitters?

• 37:15Speaker 04

  People who completely lose all of their depressive symptoms to a level that is within the normal range. So they're rating at the same level as somebody who's not depressed. And, you know, we can get people there on average at 2.6 days, and we're able to do that by personalizing the target and then being able to deliver treatment into that target, you know, a lot of treatment over a short period of time. And so what's useful about that is, somebody can be in a really pretty bad state on Monday morning, they can take a week off of vacation, or they may end up being on the inpatient unit or whatever it is, but they can go out, get this done, and get back to work in a timeframe that's actually reasonable. And that was really our goal. How do we get people acutely

• 38:00Speaker 04

  out of these high acuity settings and into a state of wellness quick enough that it doesn't make a major impact on their lives?

• 38:12Tim Ferriss?

  Just a quick thanks to one of our sponsors, and we'll be right back to the show. This episode is brought to you by AG1, the daily foundational nutritional supplement that supports whole-body health. I do get asked a lot what I would take if I could only take one supplement, and the true answer is invariably AG1. It simply covers a ton of bases. I usually drink it The mornings and frequently take their travel packs with me on the road. So what is AG1? AG1 is a science driven formulation of vitamins, probiotics, and whole food sourced nutrients. In a single scoop, AG1 gives you support for the brain, gut, and immune system. So take ownership of your health and try AG1 today. You will get a free one year supply of vitamin D and five free AG1 travel packs with your first

• 38:56Tim Ferriss?

  subscription purchase. So learn more, check it out, go to drinkag1.com/tim. That's drink AG1, the number one, drinkag1.com/tim. Last time, drinkag1.com/tim. Check it out.

• 39:16Tim Ferriss?

  I've had a number of friends, and I've certainly heard of many cases where people with certain professions, airline pilots, firefighters, police officers, there are many more, will not report any type of mental health issue because they will be suspended in a lot of cases, or relieved of duty. They'll be forced to take time off. And in a case like this, where you have a compressed protocol, there's the possibility of taking PTO or taking a week off and doing this treatment. Whereas, like you said, doing it during banker's hours over months is going to be highly visible, right? And until the entire system changes, which is going to take time, if it happens at

• 39:56Tim Ferriss?

  all, this would be an incredibly attractive, alternable protocol if it were to work. So please continue.

• 40:03Speaker 04

  Yeah, absolutely. Yeah, and that's the way that we thought about it, right? Is can we take folks who need to get well quickly? I mean, we had people in conventional TMS courses where, you know, they started, they're in really bad shape, they lose their job halfway through, maybe they get better at the end of it, you know, but it took so long, you know? And so it's one of these things, if we can compress that up and get them well in a short period of time and get them out of it, you know, it gets people back to their lives and it has a low impact.

• 40:31Tim Ferriss?

  I know I'm interrupting a lot, but the threading of this, I think, is important. So we can sort of foreshadow something that is going to be on the minds of a lot of people, which is what are the downsides? What are the risks? So my question is, like, was it easy to get the sort of ethics board approval to compress all of this into a much shorter timeframe?

• 40:49Speaker 04

  I was able to make a compelling case to the IRB and then eventually to the FDA around. Safety. And so we give 90% of the resting motor threshold that's depth corrected for atrophy. So if somebody, if it's an older patient, they have more prefrontal atrophy, then you can increase the intensity based off of that difference in depth of the motor cortex. But essentially, what their brain is getting is 90% of the resting motor threshold, which is kind of a calibrated number that's based off of these TMS-induced motor movements. It gives us a sense of how to dose the stimulation.

• 41:23Tim Ferriss?

  I'll show a bit of my hand here, which is I've undergone two separate weeks with different hardware, different protocols, because I'd never want to talk about things like this unless I've put myself in the spaceship and been the monkey shot into space, which doesn't mean at this point I am a proselytizer 100% for the treatment, but I find it very compelling, at least for investigation. So to just explain, since I recently went through this, each morning, or certainly on the first morning, but on multiple mornings in my case, they will test your motor threshold.

• 42:01Speaker 04

  Yep.

• 42:01Tim Ferriss?

  Right? And that could be a finger or a hand, it could be a foot, and they'll watch movement really closely. And then based on that, determine the sort of dose that will be delivered throughout the day during these sessions. And in my case, it was, you know, once an hour for 10 hours a day.

• 42:16Speaker 04

  Yeah. So it's just a way of getting the intensity that you need. And so we know that 90%, meaning sub-motor threshold, there's never been a TMS-related seizure for that kind of sub-motor threshold intensity. Even, you know, giving multiple sessions a day or whatever it is, there's never been a, an event like that. It's always been at a higher kind of intensity of the stimulation in the moment, if that makes sense. So the amount of magnetic field that's being put out in proximity to the brain. And so You know, it's much more, it seems to be much more related to that than it does the amount of pulses that you receive in a day.

• 42:58Speaker 04

  And so I was able to lay that out to the various regulatory bodies and show the evidence that that threshold is really the threshold where risk goes up.

• 43:07Tim Ferriss?

  Right. It's sort of the magnitude, like the strength of the pulse, not the frequency or the density.

• 43:13Speaker 04

  Yeah. It's more about the intensity in this case and less about the density or the amount. So laying that out, it was acceptable and various parties deemed it to be non-significant risk and they let us proceed. Now, this is FDA breakthrough status, FDA cleared and all the way through all of the regulatory processes. And so it's kind of an on-label approach these days. But, you know, back then I had to make a lot of those arguments and, you know, knock on wood, we still haven't seen any seizure.

• 43:43Tim Ferriss?

  How many people would you say at this point have gone through well-designed accelerated TMS?

• 43:49Speaker 04

  It's definitely, you know, I'd say more than 400 or 500 between trials. You know, we have trials where they're ongoing and I don't know what the clinical outcome of those trials are because I'm blinded to them. But I do know that AEs, we don't have any serious adverse events since we haven't had anybody have a seizure yet. So that's good. What you do see is headache. People will have a headache. It's usually from the, not everybody, but you know, a fair percentage of people. And it's mainly related to the coil activating scalp nerves and basically kind of turning the facial musculature on. And that actually goes away over time. So in the long term, you actually see a reduction

• 44:30Speaker 04

  in migraine headaches and you see a reduction in pain, all that sort of thing. And people actually have an anti-nosusceptive effect.

• 44:37Tim Ferriss?

  Anti, excuse me?

• 44:38Speaker 04

  Anti-pain effect.

• 44:39Tim Ferriss?

  Ah, pain.

• 44:39Speaker 04

  Yeah.

• 44:40Tim Ferriss?

  What was the word you used?

• 44:41Speaker 04

  Nosusceptive.

• 44:42Tim Ferriss?

  Ooh, new one. All right.

• 44:43Speaker 04

  Yeah. Yeah. Yeah. Yeah. And so you can actually have an anti-pain effect. And the reason why we think that happens is because you actually-

• 44:50Tim Ferriss?

  Anti-pain, meaning it could help with chronic pain or something like this?

• 44:52Speaker 04

  Uh, at least acute experimental pain. There are some chronic pain studies. You can see that you release endogenous opioids from stimulation because you can actually use opioid blockers and block the anti-pain effects of TMS.

• 45:06Tim Ferriss?

  Oh, wow.

• 45:07Speaker 04

  So there's this whole kind of pharmacostimulation thing that people are looking into. A buddy of mine, Joe Taylor, who's at Harvard now, did these studies when he was an MD PhD and he was able to actually show that- There is this release and then you can kind of block it with co-administration of opiate blocking drugs. But yeah, that's the idea is that there is some acute potential headache risk. And people can get a little fatigued from this. It's like fatigue, more like you ran a marathon instead of like depression related fatigue, you know, just from kind of being there all week.

• 45:38Tim Ferriss?

  Look, end of one here, but seems, and I spend a lot of time talking to folks, as you know, kind of my job. My experience was headache for sure. I was hesitant to take any type of Tylenol or medication for that, just because, and this is again, as a naive layperson, but I was like, well, you know, like if you do take NSAIDs, if you're doing, say, weight training, that can inhibit some of the adaptive response. I'm not sure we fully understand what the hell's going on here. So I'm, I'm just going to deal with the headache. It was tolerable. I mean, you could feel it. The fatigue was the fatigue that you might feel if you were cramming for your final exams every day.

• 46:11Speaker 04

  Yep.

• 46:11Tim Ferriss?

  It was not the fatigue of apathy and anhedonia, like the difficulty or impossibility of finding joy and the things you would normally find joy with. Like that type of fatigue is characteristically, it was very different. It's more like, yeah, you just crammed for 20 hours to try to nail your finals because you didn't prepare and you're going to do that every day.

• 46:31Speaker 04

  Yeah.

• 46:31Tim Ferriss?

  That was the feeling. Question for you then. We're going to get to the results. I want you to discuss the sort of results of, of SAINTE. But I think before we do that, it's important to maybe describe this patient population. Is it, is it fair to say that you're seeing, it'd be an exaggeration maybe to say the worst of the worst, but you're dealing with patients who've had multiple failed interventions. So it seems like that's important to kind of keep in mind if that is true.

• 46:56Speaker 04

  Yeah. Yeah. And so our randomized control trial, people had an average of nine years of the current episode. So they were depressed for nine years on average straight before they came into our trial. Had five plus or minus two med failures and they had a A lifetime load of depression of about 25 years. So these were folks who've been depressed with multiple episodes or very long episodes. They tried a lot of meds to get out of those episodes. You know, these are not mild cases, right? These are folks who've kind of been through it for a long time. And interestingly, that's going back to the, the study that we talked about earlier with the flipping of the signal, that flipping of the signal was correlated with higher modus scores. And so the more-

• 47:38Tim Ferriss?

  Modus is the assessment.

• 47:40Speaker 04

  I'm sorry, yeah, higher depression scores. And so the higher your depression rating, the higher likelihood you are to have that signal from the data that we collected. And so, and that's what we've seen, right?

• 47:52Tim Ferriss?

  Got it. And the switching, just to tie it back to what we're talking about, is that sort of having the, the wrong lead domino? Or like-

• 47:58Speaker 04

  Exactly.

• 47:59Tim Ferriss?

  You have a car where you're trying to start the diesel car without heating the coil first?

• 48:02Speaker 04

  Yeah, that's right.

• 48:02Tim Ferriss?

  That's the situation, yeah.

• 48:03Speaker 04

  Yeah. So it's that directionality. And so that's what we've seen. Folks that are at that kind of more end stage sort of depression seem to be more responsive to this. I think that's because in those cases, you're really correcting this pretty dense brain signaling problem if that PNAS work, you know, replicates. And what we've also seen is folks that do really well with dorsolateral at least, or folks who are, have a pretty impaired tension. And so they actually score up on the concentration item of the depression scales. And so that was something we observed earlier on, that if you're, if you're saying you can't read

• 48:44Speaker 04

  a book anymore, you can't really follow a, you know, recipe book to cook your favorite meal or whatever, because you just can't attend to it, then your likelihood of getting better from this is higher. Whereas folks that are more on the kind of obsessive depressive side of things, that don't complain as much about cognitive problems and concentration problems, but more about they're just ruminating and kind of obsessing on things, we've found that inhibiting the right frontal pole or the frontal cortex, so stimulating here, and we have OCD trials to do that. Is pretty effective at shutting that down. So it's more of a shutting down than a turning up sort of intervention. So some of it's actually like where the illness intersects

• 49:29Speaker 04

  with the brain anatomy intersects with like the symptomatic presentation to try to derive the best spot to stimulate for those folks. And we have some early studies now where we're trying to use brain imaging to actually sort folks into buckets neurally to figure out which target makes sense for their symptomatic presentation.

• 49:48Tim Ferriss?

  Based on their personalized fMRI scans?

• 49:51Speaker 04

  Yeah.

• 49:51Tim Ferriss?

  Yeah. So I think this would be a good point, and we'll mention this again at the end, but maybe you could mention any open trials or if people would like to consider enrolling or they know someone who might want to become subject in the study. Is there anything you'd like to mention?

• 50:09Speaker 04

  So we have a number of trials that are ongoing at the Stanford Brain Stimulation Lab. So it's bsl.stanford.edu. And you can go on the website and then there's like a screening portal and people can go on and fill out their information. And essentially, we have trials for anadonic depression. We have trials for standard severe treatment-resistant depression, obsessive compulsive disorder, borderline personality disorder, patients who also have depression, bipolar depression, and other pilots, some addiction work that my collaborators are working on. And so folks have, you know, that range of symptomatology, happy to have folks come through and screen. And it's all free, which is nice. So it's

• 50:50Speaker 04

  all basically funded through these trials. And we're excited to bring people in and see if it makes sense for them to work with us on this. And it's a couple of week commitment.

• 51:01Tim Ferriss?

  What did the results or what have the results looked like with SANT or slight permutations of that? And how do they compare to, let's just say, more conventional treatments for these same conditions?

• 51:14Speaker 04

  So in our original pilot study, 90% of people experienced remission at the post.

• 51:20Tim Ferriss?

  90%.

• 51:20Speaker 04

  90%. Yep. In the randomized control trial, it was 79% of people transited through remission at some point in the four week follow-up. What's interesting is it's not all at the same time point. So if you look at time point by time point, it's like in the 50 to 60% range. The reason for that is because there's this colleagues of mine at Cornell, Connor Liston and others have replicated this finding that there's a subpopulation of patients that actually has a slower time to remission. And we've seen this too, folks will lose their suicidal ideation and actually peak their antidepressant effect at one month. It's usually in older adults. And that's what we've seen is basically it's only in 50 year olds and above. We haven't seen that.

• 52:02Tim Ferriss?

  That that's sort of delayed remission.

• 52:04Speaker 04

  That delayed remission, yeah. But if you're putting together 22 to 80 year olds, you're going to have some of these folks. But what's interesting is TMS is also a probe of the system. You kind of ignore the kind of normal rules of how to define remission. And you just ask the question of who crosses through? 79% of our active group crossed through, 13% of our control group crossed through. And that tells you something, I think, about the neuroanatomy, you know, that probably something in the 70% of folks have this dorsolateral cingulate problem. And then that was a version of that thinking was seen in our PNAS signaling paper too. About 70% of those folks had the flip in the signal.

• 52:46Speaker 04

  And so, you know, my suspicion is, is that there's a subpopulation of people who don't have that, who have some other diagnosis. It probably looks a lot like depression, but it's probably a different neuroanatomy. And we've seen this sort of phenomenon happen in medicine before. We used to cluster all the Parkinsonism together. So there's lots of reasons that Parkinsonism, you know, some of those reasons are idiopathic Parkinson's disease in the classic sense, the way.

• 53:15Tim Ferriss?

  What does idiopathic mean?

• 53:16Speaker 04

  Just that it's kind of this spontaneous happening of Parkinson's disease. That's the core Parkinson syndrome that we think about, Michael J. Fox and others. And then you've got other things that look like it. Progressive supranuclear palsy, Lewy body dementia, drug related Parkinsonism. And so we used to kind of.

• 53:37Tim Ferriss?

  Parallel to your like diabetes presentation earlier.

• 53:40Speaker 04

  Yeah, exactly, exactly. So we forever lumped all these folks together and it really took the UK brain bank and being able to, in that case for Parkinson's link. Parkinson's pathology to symptomatic presentation.

• 53:52Tim Ferriss?

  What is the UK brain bank? And I've never heard of this.

• 53:55Speaker 04

  Yeah, so it's like a brain donor. I mean, there's lots of brain banks or brain donation entities.

• 54:00Tim Ferriss?

  Physical brains, or are we talking about scans?

• 54:03Speaker 04

  Physical brains, after death, postmortem donations. So there's a lot of ways you can donate. If you have a neuropsych disease, you can donate your brain to science. And so a lot of Parkinson's patients donated their brains to this brain bank to try to understand what it is. And what they found was with like a deep clinical phenotyping before death. So then you had this kind of deep phenotyping and then.

• 54:25Tim Ferriss?

  Sorry, what do you mean by deep phenotyping?

• 54:27Speaker 04

  Like a deep kind of understanding of the symptomatology, right? So, so basically, you know, does this person's, does their tremor happen on one side or both sides at the same time?

• 54:40Tim Ferriss?

  How do things present?

• 54:41Speaker 04

  How do things present?

• 54:42Tim Ferriss?

  In an observable way.

• 54:43Speaker 04

  That's right, exactly.

• 54:44Tim Ferriss?

  In the same way, just folks, so you have like genotype, phenotype, right? Like, so this would be similar idea. Okay.

• 54:49Speaker 04

  Yeah. So basically what they found was clinically, people that have the kind of standard Parkinson's disease typically tend to have a presentation of unilateral onset illness, right? Where one side of the body or the other is much worse from a Parkinsonian standpoint than the other. And it's actually very common for people with Parkinson's to present where if it's a leg onset Parkinson's, their foot's dragging or tremor just in one hand. And that's actually what you would expect from normal Parkinson's. If it's like really symmetric, it's less likely to be that. It's more likely to be something else. And they figured that out from essentially the brain biology informing that, being able to link up substantia nigra

• 55:31Speaker 04

  problems, they found on autopsy with symptoms. And so I think we're at the beginning of an era in psychiatry to be able to do the same sort of thing, to take what's lumped together as depression or anxiety or whatnot, and to be able to parse it into a lot of different, what we call biotypes or, you know, people think about as endophenotypes or whatever these. Specific kind of flavors of that symptomatology, some linked with a very specific brain physiology or brain functional neuroanatomy such that you can say that this depression type one needs this treatment, depression type two needs this treatment,

• 56:12Speaker 04

  and so on and so forth. And so that's really, from my vantage point, the future, right, is being able to, to really, at an in of one level, at a single patient level, be able to figure out something about their brain and then help to prescribe what the next step is for them. And, you know, if we can do that, we can also cut time, right? Because we can go straight to the effective treatment for people and cut all the time around diagnosis. I mean, there's-

• 56:39Tim Ferriss?

  And it's not just time, it's risk, right? In a lot of these cases.

• 56:42Speaker 04

  Absolutely. It's risk from potentially the wrong treatment, it's also risk from waiting.

• 56:46Tim Ferriss?

  It's cost, potentially, also, right?

• 56:48Speaker 04

  It's also cost, yeah. So as you know, right, like, there's a period of time where the diagnosis is uncertain, and then there's a period of time where the treatment is uncertain. So for bipolar depression, the average length of time it takes to diagnose somebody with bipolar disorder from a depressive episode onset, so they come in with depression, and depression's their primary, you know, presentation, seven years till you get them-

• 57:16Tim Ferriss?

  Jeez.

• 57:17Speaker 04

  Right?

• 57:18Tim Ferriss?

  That's wild.

• 57:19Speaker 04

  Right? And then, that's just to get to that point. Now you're in the right realm of medications or whatever, now you're talking about, in year seven, you're having to spend whatever it is, like, three, five, seven more years trying to find a solution. So you could go from being 25 years old and, you know, having this be your first depressive episode, and you're still trying to figure out what you're gonna do about it at 40, and you see these patients.

• 57:47Tim Ferriss?

  I'm just imagining you're, like, reaching into a dark closet, and there's a, what you think is a screwhead. And you're just trying different tools where you're not allowed to touch the screwhead.

• 57:56Speaker 04

  That's it.

• 57:56Tim Ferriss?

  Versus like, let's flip on the light, take a photograph. And then go find the appropriate tool for the job. Just a couple of follow-ups. The numbers that you're mentioning, right? The remission rates, the people who pass through, so to speak. How does that compare to like frontline conventional treatments right now?

• 58:13Speaker 04

  You know, oral antidepressants in, so there's a study called STAR-D. It's a little, it's been an interesting year for STAR-D in the sense that some people have reanalyzed that data and there's open questions about what the percentages are as far as what percentage of people make it to, you know, a remitted state after going through this algorithm. But essentially STAR-D started with a pretty low side effect burden, oral antidepressants, cetolopram, and then kind of transited through, you know, higher risks, sort of like SNRIs and.

• 58:44Tim Ferriss?

  What's the trade name for cetolopram? Do you know what people would know that is?

• 58:47Speaker 04

  Lexapro.

• 58:48Tim Ferriss?

  Lexapro, got it.

• 58:49Speaker 04

  Yeah, yeah. And cetolopram, Celexa. So those drugs, you know, and then you go to like Acinorise, like Effexor, venlafaxine, and then into like the tricyclics and the monomino oxidase inhibitors. And so people would go through this algorithm and then they'd pop out on the other end after five or six or seven different treatments. And then they'd ask the question of, after people go through all of this, what's their remission rate? So that number's kind of been called into question. But essentially, when you get into like Med 4, which is roughly where insurance used to start to pay for conventional TMS, conventional TMS would beat that pretty well, like almost double compared to, you know, your time about lithium or thyroid hormone, things like that, when you start getting into that step.

• 59:32Speaker 04

  And conventional TMS would beat that. When you get to those kind of next even more severe steps, you start to lose efficacy with conventional TMS. So you go from like a remission rate of around 30% with conventional TMS down to about 16%. When you get into the higher treatment resistance levels, that's the levels that we ran our trials on, which really that where people normally get about 16% remission with conventional TMS. That's where we were seeing those numbers.

• 1:00:00Tim Ferriss?

  Could you just repeat those numbers? Were you seeing what numbers?

• 1:00:03Speaker 04

  In our open label trial, 90% and our randomized controlled trial, depending upon how you look at it, it's in like the 50, 60% at each time point, or 79% if you're asking, did people transit through remission at any point?

• 1:00:16Tim Ferriss?

  Versus 16%?

• 1:00:17Speaker 04

  Versus 16%.

• 1:00:18Tim Ferriss?

  And this wasn't like a head to head?

• 1:00:19Speaker 04

  It's not a head to head.

• 1:00:20Tim Ferriss?

  But, but, just, just so people have some means of comparison. And in terms of pharmaceutical interventions at that point?

• 1:00:27Speaker 04

  Very low. I mean, you're talking about sub 10% efficacy. You know, this is around where electroconvulsive therapy is thought about, right? This kind of therapeutic seizure thing we were talking about earlier. That's got about a 48% remission rate, but it's not fast either. And you definitely can't work the day you get it. And there's this autobiographical memory things. You're talking about a, like conventional TMS, like a one to two month commitment. And then quite a bit of risk for side effects there. You know, you've got ketamine, which produces about a 30% spot remission rate with a single infusion. And that goes up as you administer more ketamine treatments, you know, with the IV ketamine forms.

• 1:01:10Speaker 04

  But as you go from a single infusion to, you know, what they did in this New England Journal paper that was published a couple of months ago, like, you know, six treatments over a couple of weeks, it starts to accumulate more time. And so we're able to, from my standpoint, we're able to get the most bang for your buck the quickest. And with the least kind of interruption and I think people's ability to do stuff during that time. But there, you know, there are other things, ketamine, psilocybin, other psychedelic drugs that I think you've thought about and talked about on this show before that are also coming over the next couple of years.

• 1:01:46Tim Ferriss?

  A few follow up comments and questions. So you mentioned a number of things, borderline personality disorder, bipolar as, as two examples. Part of the reason that I'm so interested in neuromodulation right now, accelerated TMS in particular, although I'm also interested in other things that I know less about, like focused ultrasound and so on, which we might get into if we have time, is that many of the conditions that would be screened out, there would be exclusionary criteria in say a psychedelic assisted psychotherapy trial.

• 1:02:15Tim Ferriss?

  Are eligible for this type of treatment, which is incredibly interesting. There are people also who might have something that is more common, extreme hypertension, some type of like ocular issue where physiologically psilocybin shouldn't technically pose a risk. But if they have a lot of panic, rapid heart rate, et cetera, there might be complications, right? Elderly patients, et cetera. So part of the reason this entire realm of treatment possibilities with neuromodulation is interesting is because these tools could be available to people who would not be good candidates for some of these other things that you're mentioning. What I'd love to ask you about, because this has been one of the questions that's just stuck in my head, is the topic of delayed remission. So having these patients,

• 1:03:00Tim Ferriss?

  I can't remember the number. I was looking at some of the charts, maybe it was three or four people out of NF16. I can't recall. That's right. Okay, there we go. Who had this remission at like week four? Yeah. Or something like that. How do you explain this? And why is it older patients? Or does it seem to be older patients? And how do you relate it to a few things, right? So in the case of, say, SSRIs, some folks also have this, like, a lot of people, like, delayed onset of benefits, right? And then you have ketamine. This is going to be a bit of a sloppy question, but I'm sure you can clean it up for me. Then you have ketamine, which is very rapid acting. And I have heard, I do not have the credibility or the means

• 1:03:39Tim Ferriss?

  of parsing all of this. Like, okay, well, ketamine acts directly on NMDA receptors. Seems like maybe SSRIs do that, but in a very indirect way. And that explains the delayed benefits in some patients. Don't know if that's true or not. Don't know if I'm even wording that correctly. How do you kind of tie this to, or not, the delayed remission? Because I'm just like, how does that even work, right? I'm like, okay, if you put a drug in someone's head and it triggers a cascade, or maybe it triggers some type of... Exceptional neuroplasticity that then shows the fruits of that at weeks, whatever, two, three, four, okay. But I just cannot figure out, I haven't been able to figure

• 1:04:22Tim Ferriss?

  out like a plausible mechanism for the accelerated TMS and that delayed remission. How do you think about that? Like even if it's speculation?

• 1:04:29Speaker 04

  Yeah, it's, and it would be, yeah, it would be speculation. But I think, you know, so we've only seen in older adults, you know, and we know that the brain plasticity in older adults goes down as a generality. And there were lots of metrics about why folks think that. And you're, you know, you're, as you talked about earlier, really, it's, it's cramming for a test. You're actually sending a memory signal into the brain. So the stimulation pattern that you're sending into the brain is kind of Morris code is really a turn on, stay on, remember to stay on memory signal that's going into the brain. And you're just basically taking the hippocampus, the part of the brain that's involved in memory and like that signaling that comes out of there and you're playing that back through the prefrontal cortex in a way to try to tell the prefrontal cortex to turn

• 1:05:10Speaker 04

  on or remember to stay on. And I think part of what's going on is because that older brain is a little less likely to have flexibility, plasticity, it takes some time for the signal to kind of fully lay its tracks into the brain. We don't have any sort of biology to kind of back that up yet. But what we're doing right now, and we haven't analyzed this data yet, is we're actually scanning people every single day. And we're scanning people multiple times out to the month. And I each fund

• 1:05:42Tim Ferriss?

  And by scanning, you mean FMRI?

• 1:05:43Speaker 04

  FMRI scanning. Yeah, yeah. So we're actually getting like 10 scans spread out over

• 1:05:47Tim Ferriss?

  It's a lot of coffin time.

• 1:05:49Speaker 04

  It's a lot. Yeah. Yeah. You know, people have been very cool about this. And so with that, we think that we're going to be able to potentially spell some of this out, right? Like, why are these delayed remitters happening? But my suspicion is, is that it's probably a plasticity related issue. Interestingly, you know, ketamine and TMS may have more in common with each other than one would initially think, right? Like, you know, a lot of the TMS effects are probably in part glutamate related is ketamine. And then, as we talked about earlier, there's endogenous opioid release from TMS. We've done some work with opioid related mechanisms and ketamine. And so there's probably a confluence of not one neurotransmitter system, but like an orchestra.

• 1:06:36Speaker 04

  Of neurotransmitter systems that are being affected across these interventions. And it's my suspicion that that's probably what needs to happen in order for these treatments to be effective. And our old views on, you know, this kind of chemical imbalance, sort of 1990s view of like one neurotransmitter, one neurotransmitter receptor, sort of problem in the brain is way too simplistic and that it's probably a lot more complicated, as one would imagine, a lot more complicated than that.

• 1:07:06Tim Ferriss?

  Outside of accelerated TMS, if you're looking out, say, over the next five years for rapid acting, potentially durable antidepressant effects, what other tools or molecules or treatments are most interesting to you?

• 1:07:22Speaker 04

  We have a paper coming out soon in Nature Medicine on looking at IBN as a potential treatment for, in this case, for military traumatic brain injury, but a lot of these folks had depression, generalized anxiety disorder, and PTSD. And so it was a interesting, that was another interesting story. So I was approached back in 2018 by a professor, a senior professor at Stanford, who was tapped by some folks to kind of find somebody who'd be willing to partner with a nonprofit called Vets at the time, who were sending, and I think you've interacted with Amber Marcus Capone a little bit.

• 1:07:58Tim Ferriss?

  Yeah, I interviewed Rick Perry and Rick Doblin two years ago at their Veterans Day fundraiser.

• 1:08:03Speaker 04

  Yeah, I was there. I remember, it was an interesting one. You know, we partnered up with them and I had to, again, go to the Stanford IRB and ask them for another edgy, and you know, you have to give the Stanford IRB credit.

• 1:08:16Tim Ferriss?

  Could you just spell out IRB?

• 1:08:18Speaker 04

  Oh, sorry. Institutional Review Board. It's the entity that reviews all research protocols at institutions. And so this is the kind of governing body that's in place, that's been around for about 100 years, that essentially is a non-conflicted, uninvolved group of senior professors that look at your proposed research and then determine if it's ethical and safe and answering the questions that you think you're going to answer. And so. Just like going to them to talk through doing accelerated TMS and saying we were able to talk to them about doing a study where people would come to Stanford knowing in the IRB knowingly agrees to them then going down to Mexico to take an illegal in the US root

• 1:09:01Speaker 04

  bark extract that's been utilized for millennia in the country of Gabon and related areas in Central West Africa. And as you can imagine, this was not a quick turnaround, nor should it have been for the IRB in the sense that I had to convince them this was science worth doing.

• 1:09:18Tim Ferriss?

  At that time, though, is it fair to say you're the TMS guy? Or was it like in the air that you also had an interest in exploring something like an ibogar and ibogaine?

• 1:09:28Speaker 04

  People knew that I was very open minded to things. I'm a pragmatist, right? I mean, for me, like, patient's the most important thing. I have this view of psychiatry that it's going to look like inpatient cardiology in 20 years where we're going to use drugs, we're going to use devices, we're going to be able to figure out what the best thing is for that patient. To your point, you know, some of these things are good for different problems. And so I think that was known, that I was open to that. We'd just been running this ketamine mechanism trial. And so I was tapped to look at this and a couple other people too. And I found out later, they'd gone to like, a lot of people. And apparently I was like, the only person that was willing to do this trial. Like, I felt kind of special

• 1:10:12Speaker 04

  back then. And then like later realized that like,

• 1:10:15Tim Ferriss?

  Oh, wait a second. I was on The Bachelorette and I didn't even realize.

• 1:10:18Speaker 04

  Yeah, I was on The Bachelorette and I didn't realize it. So essentially, yeah. And The Bachelorette was a tricky one. And so we, we ended up reluctantly agreeing to this. And admittedly, like, I almost pulled out a couple of times because ibogaine has this street knowledge and academic knowledge that it has a death risk, right? It has a one, roughly one in 300 risk of death from Torsasde point, this fatal arrhythmia that can happen with certain cardiac acting drugs. And it works through this. What they call HRG potassium channel. Other things do this or like FDA cleared cancer drugs and arrhythmia drugs that'll do it too.

• 1:10:59Speaker 04

  So it's not in context, it's like something that happens with lots of different drugs that we use. But I think there was a somewhat of a stigma, a bias around particularly an addiction drug. And so folks had been trying to get this through the FDA and NIH and whatnot in the nineties. Howard Lotzoff and others, and it was a very complicated drug. And I'd known about it since residency. I'd read about it. I thought that, you know, it's like, wow, this is like the most promising anti-addiction drug on the planet. But I'd thought it was completely unstudiable and I kind of like kept doing my other stuff.

• 1:11:36Tim Ferriss?

  And then At that point, how did you come across IVEG? Where did you find it?

• 1:11:40Speaker 04

  In 2012, 2010, I think.

• 1:11:43Tim Ferriss?

  Would this been like early Debra Mash stuff or?

• 1:11:46Speaker 04

  No, no, I come across this book, Breaking Up in the Head by Daniel

• 1:11:50Tim Ferriss?

  Pinchback?

• 1:11:50Speaker 04

  Yeah. And he, you know, he's a big, I think he wrote for the New Yorker or something. And, uh, and I was stuck. I was like going kite surfing in South America and I was stuck in the San Salvador airport. And there was like five English speaking books or something. And I picked this book up in the airport, like stuck.

• 1:12:10Tim Ferriss?

  That was in the San Salvador airport?

• 1:12:12Speaker 04

  Yeah.

• 1:12:13Tim Ferriss?

  Wow.

• 1:12:14Speaker 04

  And so I got ahold of this book and read it waiting on my flight, which was like eight hours delayed to get to Peru. And so essentially he just like lays the whole thing out. It was very interesting. He talks about his own personal experience of it. And I read a lot about it. And there was some work that folks like Ken Alper and others had published on the kind of case report level outcomes. But then also cardiac problems. So then I figured it was kind of unstudiable. And then in 2018, I was approached and was asked to do this trial. And so we went to the IRB, spent a year back and forth. And like right when they were about to, they approved it, COVID hit. So we were actually supposed to start right when COVID happened and it paused the whole thing.

• 1:12:59Speaker 04

  And then, uh, it took a while to get it back online, but it was actually the quickest recruiting study I've ever run. We got 30 people done in like eight months.

• 1:13:08Tim Ferriss?

  Now, is that because of the? Sort of category of like potential death of despair. I mean, is it because of the patient population? Were you dealing with addicts?

• 1:13:16Speaker 04

  So the patient population was, and that was the unique part about this. It was veterans with traumatic brain injury, some of which were alcohol use disorders. So, you know, we used to call alcoholism more than a third, like 13 or 14 people out of the 30. But everybody had TBI, a lot of them, most of them had depression, most of them had PTSD. And so, you know, we're running this trial. I was put like my best neuropsychology postdoc on it and a couple other superstars. And it was running in the background and I was like, you know, we'll get this into a pretty good journal or whatever, thinking we'd see some people get better, some not, whatever.

• 1:13:56Speaker 04

  And I remember I was, I was asked to give a talk about it at a very prestigious university and asked the postdocs, we just wrapped up the immediate post and asked the postdocs to put the data together and we'd have data to present for them. And they showed me like the clinical outcomes and I was like completely blown away. It was way better than I think we anticipated, like very consistent improvements in like basically everybody, some people would lose it, you know, before the month, but most people held it and they're holding it out to a year now. And I was floored, I actually told them to delete all the code and start the analysis over because they had to have done something wrong in the math, which is always fun. The postdoc always, they kind of say yes and look at you. You just ruined my weekend.

• 1:14:40Speaker 04

  And so, so we, we did it again and it was the same exact findings. So they, I was wrong, they're right, they had done it right the first time. Yeah. And essentially really, really striking. And by the time this will come out, you know, Nature Medicine will have published this.

• 1:14:56Tim Ferriss?

  Somewhat prestigious.

• 1:14:58Speaker 04

  Yeah, somewhat, you know, top five biomedical journals in the world and they.

• 1:15:01Tim Ferriss?

  It's like being nominated for best picture at the Academy Awards. I mean, scientifically speaking, right? It's up there.

• 1:15:06Speaker 04

  It's up there. It's a nice deal and it's, it was very surprising that for me that they were going to be open to publishing an open label. Paper which, you know, historically, you're going to publish in that kind of a journal, like a randomized trial.

• 1:15:19Tim Ferriss?

  So just for clarity's sake, for folks listening, so open label means no placebo control. And also, to just rewind for a second, I want to mention to people that for accelerated TMS, how do you know it's not placebo effect? You mentioned the control group, but that's a sham treatment, right? Like, you're basically, people feel like they're getting a treatment, but they're not actually getting the proper treatment.

• 1:15:39Speaker 04

  Yeah, in that case, you want to ask a blind guess, and that's actually been a big, so I was going to get into here, a big problem with, with a lot of the psychedelic trials, and why there's a lot of criticism for a lot of the psychedelic trials, is that they kind of know that the blind guess is going to be highly skewed. So there's one trial where they did psilocybin for alcohol use disorder, I think it was like 99% correct blind guess rating, so the p-value is highly significant. In our same studies, to my, like, great surprise, our blind guess was chance.

• 1:16:08Tim Ferriss?

  Could you explain what, what do you mean by blind guess? These are the experimenters trying to guess who is in which group.

• 1:16:15Speaker 04

  This is the patients trying to guess what they got.

• 1:16:17Tim Ferriss?

  I see.

• 1:16:18Speaker 04

  Yeah, so Mr. Smith, you know, you just wrapped up your treatment. Which treatment did you get, active or sham? What's your confidence?

• 1:16:23Tim Ferriss?

  Got it.

• 1:16:24Speaker 04

  In what you got? And so, what we found, which is really interesting for St, was that, I didn't know what people got, but I talked to some of these people, and I heard some of this, so it was really interesting. You know, patients who'd gotten totally better, and they'd say things like, "Yeah, you know, I just got lucky with placebo this time," and they ended up getting active, and then the folks that didn't get any better, that they got sham, would say things like, "You know, I'm not even good enough to respond to, like, the active treatments," so they, so, so it was confusing enough for them, where they were making the wrong guess 50% of the time, which is what you, what you're looking for, is about 50% error rate, and it's a coin toss.

• 1:16:58Tim Ferriss?

  Sidebar on that, I know this is kind of staccato, the way that I'm trying to hold this conversation, but... Having gone through two weeks, different hardware, different practitioners, et cetera, and having had a lot of conversations with technicians and so on, it also seems like for some people, it takes a while for their narrative to catch up with like the hardware upgrade, right? In this sense that they, they say, well, maybe I got lucky, or maybe I don't really feel that much. And yet their assessments are improving and/or their significant others see dramatic changes, right?

• 1:17:31Speaker 04

  And that's true. That's not specifically a TMS effect, or extended effect, or accelerated TMS effect. That's true. I think for a lot of treatments, you see that. I mean, I've even, I've had calls and since our data's been out on Ibogaine, where I've had people call me and say, hey, Mr. Or Mrs. So-and-so, they look amazing and they're not, they don't think they're, they're any better, you know? And so I think you can see it across the board psychedelics, you know, Neuromod. There's a certain problem called alexithymia in about 25% of people with treatment-resistant depression.

• 1:18:02Tim Ferriss?

  Lexithymia?

• 1:18:03Speaker 04

  Yeah. And so A, meaning without lex, meaning the ability to describe thymia mood. And so they can't really describe their mood, right? And so they have a, an inability to accurately rate their mood. And the way you know that is-

• 1:18:17Tim Ferriss?

  Alexithymia. I'm gonna use that at a fancy cocktail party. So, Tim, how you doing? Sorry. Got alex, alexithymia. Oh, sorry. You may better know that as difficulty to describe mood.

• 1:18:31Speaker 04

  So I'll, I'll, I'll try to back up on the medical, medical-

• 1:18:35Tim Ferriss?

  No, I like it. I'm learning all sorts of words.

• 1:18:37Speaker 04

  Yeah. It's an interesting term and it's an interesting phenomenon. And you see this in psychiatric conditions. Like if you ask them very specific questions, like, well, when's the last time you've been sad or thought about anything negative? Oh, it's like been a week or two. Are you depressed? Yes. Well, why do you know that? I don't know. You know, they just don't know.

• 1:18:54Tim Ferriss?

  It's also like a self-reporting problem too, I think, in some cases, right? It's like if you ask someone like, how many calories did you eat yesterday? Like most people would be off by like 30 to- Like 60% or something, right?

• 1:19:04Speaker 04

  Yeah, that's right. And I think what the remedy for that is that you have a clinician raider and the clinician raider asks these really, really pointed, very detailed questions. And then the patient's able to answer. And then it's like a formula to calculate what that mood rating is in that case. And sometimes it's just off from what their perception is. Their kind of meta perception of the whole thing. But when you get down to the brass tacks they're answering, right? And so we've seen that. And that's been true across these problems. And there's ways of constructing trials to deal with that. But yeah, we've seen that with psychedelics as well. So we went after military TBI.

• 1:19:45Tim Ferriss?

  And these were all special operations?

• 1:19:47Speaker 04

  Mm hmm. Yeah, they were basically all Army Rangers, Navy SEAL, former Army Rangers, former Navy SEALs. And there's been a big cohort of these folks that have gone down. I mean, some people in Congress have gone down and done this and have spoken about it publicly. I mean, it's this National Defense Authorization Act, the NDA, I think is just, you know, went through the Senate and the House, both approved it, I think, yesterday, and it's going to Biden. And so, you know, to earmark money for for IBG for trials, you know, which is pretty cool. So the military community and some of the government is pretty aware that this is a possibility. There's been a lot of advocacy that Amber and Marcus have been involved in. And my hope is that coming out of a journal like Nature Medicine that

• 1:20:31Speaker 04

  really kind of validates what we were seeing and put some context to what we observed and what we found in our study will help to spur more funding and more focus. And I think the the kind of veteran psychedelic angle is is an important one, you know, for like a lot of ethical moral reasons, you know, and a lot of

• 1:20:51Tim Ferriss?

  They also have like a political immunity bracelet, right?

• 1:20:54Speaker 04

  That's right.

• 1:20:55Tim Ferriss?

  It's a very

• 1:20:56Speaker 04

  That one.

• 1:20:56Tim Ferriss?

  important subpopulation. And it's very fortunate that it aligns with sort of driving forward the Research around these therapeutic tools.

• 1:21:07Speaker 04

  Yeah, it's super cool to work with those guys.

• 1:21:09Tim Ferriss?

  And this was a monotherapy in the sense that it was just ibogaine. I know that at least in many places in Mexico, they sometimes combine it. Well, they don't combine it, but they sequence it with 5-MEO DMT at the tail end. Was this ibogaine alone?

• 1:21:23Speaker 04

  Yeah, so it was ibogaine alone. And then we had folks come back later to do the 5-MEO outside of this kind of month follow-up period. But the data that we're publishing in Nature Medicine is just the ibogaine effect. It was tricky because that kind of divorced those two together because that's what's been going on, as you know, in Mexico quite a bit. So all the acued out to the one month effects are all direct ibogaine effects. And it's, you know, super cool. And the thing that I found really interesting about this drug is that it produces what I think is probably the most stereotyped trip, if you want to call it, or the psychological phenomenon that happens alongside the drug effects.

• 1:22:04Speaker 04

  And so people will describe this earlier life autobiographical replaying of emotionally salient memories that are epoch in time.

• 1:22:16Tim Ferriss?

  Some people would go life review, right?

• 1:22:17Speaker 04

  Life review or slideshow. Yeah, exactly. And so, you know, it's interesting. Everybody's kind of got a different version of what the slideshow ends up playing out to be like for them. And so some people would say, I found myself in this room and it was like my TV from childhood. And all of a sudden it was playing all these things. Or I found myself in a hall of mirrors and it was playing all these things. So like the context can be very different and the mind seems to shape that. But the actual replay seems to be pretty stereotyped.

• 1:22:43Tim Ferriss?

  Stereotype meaning like it's a pattern that repeats or it's just like a common characteristic?

• 1:22:48Speaker 04

  It's a common characteristic and it's closed eye only. It's not open eyes. It's not, for a lot of people, the ibogaine experience is kind of really around this part, this kind of replay part that happens. And, you know, from what I have heard, there's kind of a cathartic. Reevaluation of these memories and interestingly, an ability to not only have insights into your own reasons, which may have been good or bad for feeling or behaving or doing whatever it was, but also reasons for they have some insight in the reasons for the other, which to me is like the hardest thing to explain.

• 1:23:27Tim Ferriss?

  You say it one more time.

• 1:23:28Speaker 04

  When people have this slideshow or life review, they seem to have it as a third party person in the experience, you know, like, what is this Christmas Carol Scrooge or whatever, when they go back and they go back in life and you see like-

• 1:23:42Tim Ferriss?

  You become the observer of your own past experience.

• 1:23:44Speaker 04

  Right. It's kind of like that. Like Scrooge goes back and sees himself as a kid. He sees himself as like when he broke up with his significant, you know, all that stuff. It's almost like that. Like you're having a similar sort of thing where you're, I've used the analogy of Tom Cruise in The Minority Report where you're able to go back and see these events. And what's so fascinating and why I've, why I've said, and I'll continue to say, I think this is the most sophisticated drug on the planet, is that I think that there's nothing else that can seem to do this, right? Where you have these experiences where you're able to hold this neutral place and you're able to have this sense of where you were and why you did what you did, and you have this sense of the other and you're

• 1:24:25Speaker 04

  able to, I don't know, intuit, I don't know what that is. You somehow stored it at the time and you weren't able to fully access it and you're able to access it, whatever that is, being able to forgive or to forget or to understand this person's position as well as your own, and then seemingly like unlock the lock on both sides and then dissolve the problem. And people say they'll, they kind of would work through all of this and you know, there's one veteran, you know, would say, well, I went through all this military stuff and at the back of the room, it was my early childhood trauma, you know? And so this idea that at the core of it, for a lot of this ends up being a childhood trauma

• 1:25:10Speaker 04

  thing that's kind of buried below all of it and really being able to actually both access that in a way that you can understand. Understand that in many cases, the traumatizer was themselves traumatized and that it's a pattern of trauma and the ability to kind of resolve it by understanding at this kind of, you know, more meta empathic viewpoint. And so that's why I think the tool is really going to be important is this ability to have what seems to be a pretty profound or atrophic effect. You know, we were able to see disability improvements from traumatic brain injury, but also this pretty pronounced kind of cathartic reevaluation, reconsolidation of past life problematic memories.

• 1:25:56Tim Ferriss?

  All right. As I want to do, let me hop in with just a few comments that we can bounce around if we want, and then a whole bunch of questions. So the first comment is with the special operations vets who are friends of mine, what I've observed, maybe similar to what you're describing, that is, part of what has contributed to them being extremely high performers in these high stress environments is their ability to tightly compartmentalize, which they developed when they were traumatized as kids. Super high overlap, like incredibly high overlap. Of course, there are many other factors that contribute to them being like the one person out of 10,000 who doesn't get washed out of training, being that unbreakable

• 1:26:41Tim Ferriss?

  in a sense. But I, with those friends, and look, it's a tiny sample size, but of those friends, like I wouldn't say any of them would claim to have PTSD or moral injury, like a feeling of having done the wrong thing. But the TBI, and this is where I want to lead into a question, which is not to negate the fact that a lot of people could have, of course, meet the diagnoses for complex PTSD and so on. With the TBI, what makes Ibogaine different from some of these other psychedelics? And I want to say, One maybe place to explore would be glial cells. Am I making this up?

• 1:27:14Speaker 04

  Glial-derived neurotrophic factor, yeah.

• 1:27:16Tim Ferriss?

  Glial-derived neurotrophic factor, there we go. What makes it different in terms of mechanisms of action, therapeutic effect compared to some molecules? People might be more familiar with psilocybin or otherwise.

• 1:27:27Speaker 04

  The classic psychedelics like psilocybin, as you know, primarily affect the 5-HT2A receptors, right? So they're 5-HT2A agonists. They produce these kind of classic psychedelic experiences from largely from that receptor. You can selectively knock out 5-HT2A receptors. You can knock out the psychedelic effect. So we've largely thought about kind of this class of psychedelics in that way. Ibogaine is a known neurogen, so it produces a dreamlike state. Some people call it an atypical psychedelic. You know, we've elected to kind of use this neurogen term because I think it more accurately reflects what's going on in the trip and in the way of kind of perceiving what it is. It does have some 5-HT2A action, but that's probably the minority of the effect.

• 1:28:12Speaker 04

  It affects a broad range of other receptor systems. So like salvia, for instance, is a kappa agonist, right? You know, and so there's kappa mu effects, there's NMDA effects with ibogaine. There's SERT effects, serotonin effects. And then there's this upregulation of BDNF, brain-derived neurotrophic factor, and GDNF, glial-derived neurotrophic factor. And so, and both of those are, you know, profound neurotrophic factors for plasticity in the brain. The problem is, is this has been psychedelics were thought of as relatively obscure 15, 20 years ago to study. Obviously, that's changed now, but ibogaine is extremely obscure, right?

• 1:28:53Speaker 04

  So there were a handful of studies that were performed in publishing journals over time, but it's very limited in the data that we have so far. So it's hard to like, give you some sort of definitive answer. What I can tell you is that it was a paper published, you know, I think 15 or 20 years ago where they Took mice and they got them to self administer alcohol. So that's kind of like a way of like an addiction model or whatever alcohol self administration or sucrose self administration, sugar self administration. It's like a way of kind of getting, you can put cocaine in the water and get mice to-

• 1:29:23Tim Ferriss?

  Modeling addiction.

• 1:29:24Speaker 04

  Yeah, exactly. And so if you give a mouse IBN, you can get them to stop self administering alcohol. It's interesting, we saw that in humans that stopped drinking as well in our study. Or you can, in this case, you could actually drill a small hole in the mouse's brain, you can inject GDNF directly into the ventral tegmental area, the area that produces dopamine for the, kind of more of the pleasure seeking part of the brain. And it emulated the same effects as the IBN, right? So this GDNF effect in the dopamine system at least. And GDNF is thought to regulate dopamine neurons. And so, you know, I think that that's probably at least a pretty strong part of it and what makes it so unique. But I always tell people, like when I'm talking about this IBN stuff, like if we gave one

• 1:30:07Speaker 04

  of the big pharma companies $100 billion and said, "Don't just resynthesize IBN, but make a drug that works like IBN." I think even some of the classic psychedelics, but really specifically IBN, I think they'd have a hard time doing it because we don't have the neuroscience to understand what's going on there. And I think it's because it's not a one receptor.

• 1:30:29Tim Ferriss?

  It's not super clean in that way, right?

• 1:30:31Speaker 04

  Yeah.

• 1:30:32Tim Ferriss?

  It's like promiscuous.

• 1:30:33Speaker 04

  People use that term dirty drug. I think it's-

• 1:30:35Tim Ferriss?

  It has the wrong connotation, but-

• 1:30:37Speaker 04

  Yeah, yeah. I mean-

• 1:30:38Tim Ferriss?

  Like LSD is pretty kind of promiscuous on their-

• 1:30:41Speaker 04

  Yeah, I think promiscuous, I like to think about it like a-

• 1:30:44Tim Ferriss?

  Complex, sophisticated?

• 1:30:45Speaker 04

  I like to think about it like a symphony.

• 1:30:47Tim Ferriss?

  There we go.

• 1:30:47Speaker 04

  Right? Like you're interacting with these neurotransmitter systems in proportions in such a way that it produces this effect. My suspicion is that it's probably more sophisticated than we want to attribute to, I mean, maybe not you, but like the scientific community wants to attribute to nature being able to pull off, you know? But it's this idea that maybe somehow we have this drug that just happens to work the way it works because it's able to interact with these systems in pretty important ratios or pretty important kind of- Simultaneous effects and that's really what's driving it and that's the part I'm saying it's going to be hard to reproduce. I mean, obviously Sasha Sholga and others were able

• 1:31:27Speaker 04

  to take emulate similar sort of 5-HT2 effects, but I don't even think he was able to produce an ibogaine-like multi-receptor sort of symphony like this. There hasn't really been another drug like it in this way. And so trying to think about what that is and how to really how to study it, it's going to take a new wave of neuroscience tools to be able to capture all the effects, you know, in real time.

• 1:31:54Tim Ferriss?

  I have a symphony of follow-up questions.

• 1:31:56Speaker 04

  Okay.

• 1:31:58Tim Ferriss?

  And so I'll give you, you can choose. This is dealer's choice. You're the dealer.

• 1:32:02Speaker 04

  Okay.

• 1:32:03Tim Ferriss?

  So we could go with, and we will get to all these, but improving the safety profile of ibogaine, which I should also say, like, I've had people reach out to me, which is always can be very uncomfortable for me, but like friend of a very close friend. And in this particular case, someone's sister was a heroin addict who is now homeless, acting as a prostitute, like living under an overpass. And the reason I bring up that level of detail is that for a lot of interventions, in this case, ibogaine, at that point, the cardiac risk or some of the risks were known. And there's a question of, is this risky? And the follow-up is compared to what? And in this particular conversation was, well, she could die tomorrow.

• 1:32:43Speaker 04

  Yeah.

• 1:32:43Tim Ferriss?

  From an OD or this and the other thing. So, so I'm just kind of setting the table with that. But improving the safety profile, right, is one question. Another, because you mentioned the cessation of, or the minimizing of the AUD, right? So like people stopping drinking.

• 1:32:58Speaker 04

  Yep.

• 1:32:58Tim Ferriss?

  We were also talking before recording, people stopping drinking caffeine, I guess, or coffee.

• 1:33:03Speaker 04

  Yeah.

• 1:33:03Tim Ferriss?

  Right?

• 1:33:04Speaker 04

  Okay.

• 1:33:04Tim Ferriss?

  Unexpected, presumably.

• 1:33:06Speaker 04

  Yeah.

• 1:33:06Tim Ferriss?

  And so my question there, which I sort of seeded, I've mentioned I would want to talk about this, it's like, any overlap in terms of mechanism or how does this? Compared to something like semaglutide, right? Like an Ozempic or some of the newer gen, I think it's Monjaro, maybe getting that wrong. And then the last one, and I've been wanting to ask somebody about this. You mentioned 5-HT2A. It seems like some psychedelics exert effects also on 5-HT2B receptors. And if I'm not mistaken, there's some data to suggest that that can continued stimulation, like agonism of that B can lead to some type of cardiac complication as well, like some type of like ventricular hypertrophy.

• 1:33:46Speaker 04

  Heart valves.

• 1:33:46Tim Ferriss?

  Valves, exactly. So the question there is, do you think that microdosing, for instance, which has become all the rage, could that potentially have long-term negative cardiac effects?

• 1:33:59Speaker 04

  The FDA guidance document for psychedelics that they released, actually like on the last day of the psychedelic science meeting, which was really interesting, is specifically has a section about this issue of cardiac valve problems, particularly from these more classic psychedelics. The problem with ibogaine is different, right? The problem with ibogaine is that it interacts with Herg potassium channel. There are a number of groups, folks at Columbia, folks at UC Davis, who have looked at this and their solution is to modify the molecule and to affect it in such a way that it no longer interacts with Herg.

• 1:34:37Tim Ferriss?

  So do you mean like noribogaine or something like that? Or is it more of a?

• 1:34:41Speaker 04

  Noribogaine, the primary metabolite of ibogaine that goes after 2D6 is a normal part of the ibogaine process, has a similar cardiac risk.

• 1:34:49Tim Ferriss?

  It does.

• 1:34:50Speaker 04

  Profile. So it's drugs that are, I think they call them like tabernathologues or something, but ibogologues or something, I think is what was coined at Davis. But essentially, these are drugs where they like try to engineer off that interaction, which may or may not have an effect on its brain effects. And so I want to answer the question I'm trying to ask. And the question I'm trying to ask is, does ibogaine? Help with certain, you know, human illness by modifying the molecule. It's not Ibegan anymore. It's something else. And then you're asking the question is, does something else help? The view is maybe, maybe it's close enough to Ibegan to do something similar.

• 1:35:33Speaker 04

  And I've taken like a different stance on this where I've basically taken the frame of, how do you preserve the molecule and really lean in on the cardiac risk?

• 1:35:44Tim Ferriss?

  How do you put an airbag in the car instead of redesigning the whole car?

• 1:35:47Speaker 04

  Yeah, instead of making it a, you know, an airborne shuttle or something. I don't know, whatever. So it's putting an airbag in with a, you know, with a high likelihood of, of saving the person. And so we talked about this in the article, but essentially all the patients that were treated received torsades like IV magnesium at the start, right?

• 1:36:07Tim Ferriss?

  What type of magnesium?

• 1:36:08Speaker 04

  So it's like magnesium sulfate. So it's basically just like IV bag magnesium. And so what's really interesting about this arrhythmia torsades that everybody's worried about is that the treatment for it, per the American Heart Association guidelines is to give IV magnesium, which is incredibly safe. And I've given many times for various things in the ER and you can just give it to people and you'll eventually urinate it out or whatever. And so you can give it, get people through this risk period. They may be slightly hypermagnesemic or a little high on their magnesium in their blood and it'll go out and everything's all good. And, you know, there've been about a thousand operators that have gone down to Mexico so far and to my knowledge, and we looked into this pretty significantly, there hasn't been a single case of torsades.

• 1:36:53Speaker 04

  Conversely, like the New Zealand study that was published a couple of years ago, they had a death out of 10 people. And so we're not doing head to head. I can't tell you for sure what the deal is there, but my suspicion is, is that if you give, what is the treatment for the problem you're worried about before you give the, the thing that can cause that problem, then it's much more likely that you can knock out the risk or significantly reduce the risk. It's also about doing it in a monitored bed setting. So Tikosyn, T I K O S Y N is a drug that is approved for atrial fibrillation and it's an anti arrhythmic. That can be proarrhythmic in the same way as Ibogaine and actually has more risk than Ibogaine.

• 1:37:35Speaker 04

  The rates of torsades are higher with ticosin, it's approved and it's totally safe. You just do it in a monitored cardiac bed. And so I think that we have to, my suspicion is if we're going to do a study in the US with Ibogaine, we're just going to need to do it in a monitored cardiac bed with cardiologists involved. And I think if you do that, you're good, right? I think the trick is between now and when, you know, in theory, one could see an approval eventually from the FDA for this, you're going to have to think about, well, not just can this place in wherever, Mexico, wherever it is, provide, you know, a good pure form of Ibogaine, but what's kind of the wraparound risk reduction there?

• 1:38:16Speaker 04

  And I think that's what people have to think about as they kind of think about, you know, that taking on that level of risk. It's not trivial risk though. It's a real risk. I think the reason why the veterans that we studied were so interested in going is because, as you point out, there's a lot of risks from not doing things too.

• 1:38:34Tim Ferriss?

  There's also a lot of social proof in that community now.

• 1:38:37Speaker 04

  Oh, yeah.

• 1:38:37Tim Ferriss?

  Right? And like a friend will go down with their friends to like sit in the same room. And it's a tight group, right?

• 1:38:44Speaker 04

  It's a super tight group and it's pretty cool, right? And I think it's, the reason why I did the trial ultimately, my view was there's no way that all of these special, these very high performing special operators are all going down to Mexico and taking this thing, which is not recreational at all, and spending a week down there dealing with this and then they're not really getting benefit, they're getting some pure placebo effect. It just seemed unlikely to me, given how treatment resistant, how many things that these folks had done, how much time they'd spent in the VA hospital and all that good stuff. And so, you know, that's why we did it. And what we found was enough of a consistent finding and this reversal of disability such that the, well, I can't tell you this works because I don't have like that level of evidence

• 1:39:29Speaker 04

  on it, that the signal that this could work is really high. It's the highest of any kind of brain acting drug I've been involved in, in looking at.

• 1:39:38Tim Ferriss?

  Okay, let's talk about the alcohol and the caffeine.

• 1:39:41Speaker 04

  Yeah.

• 1:39:42Tim Ferriss?

  So mechanism of action, I mean, you sort of mentioned the GDNF in the animal models, like the direct kind of injection. How do you think about this and does it in any way tie into what we're seeing with some of these? Drugs that are, I guess, designed for type 2 diabetics like semaglutide and Ozempic like drugs, but they're having such an effect on various types of cravings that large box retailers are having to revise, sort of in a panic, their sales projections and inventory planning around like snack foods and stuff. I mean, it's wild to see like the societal ripple effects.

• 1:40:20Speaker 04

  Walmart apparently has

• 1:40:22Tim Ferriss?

  Sure.

• 1:40:22Speaker 04

  Yeah.

• 1:40:23Tim Ferriss?

  Yeah, and I have friends

• 1:40:24Speaker 04

  Sold less food.

• 1:40:24Tim Ferriss?

  Yeah, and I have friends who have been obese effectively their entire lives, never had an exercise habit, and now they're doing pull-ups for the first time, which is, again, not an endorsement because I don't understand, and maybe nobody really quite understands exactly how these things work, but I certainly don't. So I'm not yet there. But how do you think about this? Are there any overlaps with these? Are they completely different mechanisms just presenting similarly?

• 1:40:49Speaker 04

  There's no evidence that there's a direct overlap in mechanism, just because the kind of CNS, kind of psych addiction side of things, people are still in the like, is this doing something? Yeah, it looks like it's doing something there, but not any deeper than that. I think we'll learn about that on the kind of Ozempic drug side of things. And then Ibain's been relatively underexplored from a basic science standpoint. But my suspicion is, is that it is probably similar enough and maybe some of the same mechanisms are being enacted because what you're finding is a similar phenomenon across both instances. We thought these were diabetes drugs, and then there was a significant weight loss observed. And then we thought these were weight loss drugs, and then everybody's quitting

• 1:41:31Speaker 04

  all their other habits. And placebo works by a phenomenon called expectancy. And as you can expect from the term, it's expecting something, right?

• 1:41:43Tim Ferriss?

  [laughing]

• 1:41:44Speaker 04

  So you're primed to think that this thing's going to help for this reason.

• 1:41:50Speaker 04

  I'm always really clued in when you have really obscure off-target, non-expectancy phenomenon happening. So in our Ibogaine trial, as you mentioned a minute ago, basically, everybody quit drinking coffee for a period of time and like, none of them really went into it, as most of us don't. Our coffee habit is maybe a concern. It looks like coffee is protective against Parkinson's and some other things, you know, so it's kind of a mixed bag about that. But it's generally the thing we're the least worried about trying to deal with, right? It's a generality. People are much more focused on dealing with being overweight, or focused on their alcohol use problem, or they're, in this case, PTSD and depression and TBI and all these other things that folks were worried

• 1:42:34Speaker 04

  about. And so when we started seeing like, consistent reports of people stopping their caffeine intake, it was really a signal for me. I was like, you know what? That's really interesting. I mean, there's probably a bigger systemic change that's happening. And what people will tell you phenomenologically about this is it puts a pause in between stimulus and response. And a phenomenal, and I can't like, prove this, this is just what everybody seems to come back and say, it puts a period of time between when you normally have a trigger to do something and go do it, and it was a habitual action, and really kind of gets into this question of free will and all this stuff that people think about,

• 1:43:18Speaker 04

  where there's a moment where instead of making the habitual action, the person finds himself in a purely unbiased choice phenomenon. And what people who have opiate use disorder would say in those scenarios, when they would relapse after Ibogaine, is they'd say, you know what? I just, I had something about it. I didn't crave it. I just wanted to do it, or something, wanted to remember, or whatever, but it wasn't this habitual action, right? And they go back and they do Ibogaine again, after they'd gone back into the addiction, and then they had all the negative consequences, and they'd say, you know what? And they got back to that choice again, and they're like, it's not worth it anymore. I'm gonna go this

• 1:43:59Speaker 04

  way. But they're able to pause and make those decisions. And it sounds like, from talking to the various veterans that have gone through our study, is that they'd approach things like coffee, and they'd be like, you know, I do this, but do I need to do it? Which is really striking, actually. It's not something that people... Typically tend to do, right? You get into all these habitual actions and your life is just made up of a lot of habitual actions and they they were able to reevaluate all those habitual actions and then establish new patterns. The drug eventually is going to wear off, you know, as all drugs eventually do. And you probably do lay down a level of habituating again. But if you could during the period of time when your brain seems to be pretty plastic,

• 1:44:43Speaker 04

  you know, shift and lay down new patterns that when the drug wears off, assumably you kind of lock into that new set of patterns. And I think that's what's really interesting and probably a little bit different than the Ozimbics in the sense that the Ozimbics seem to kind of take away from what folks will say, a lot of the like seeking or rewarding aspects of things like food or whatever.

• 1:45:07Tim Ferriss?

  Yeah, cravings.

• 1:45:08Speaker 04

  Yeah, cravings, whereas this seems to introduce a level of choice. What would be very interesting, you know, so you know, kind of alluded to this earlier is, you know, you take somebody who has a pretty significant addiction like this. You give them an Ibogaine sort of drug and then you think about how do you use something like an Ozimbic to kind of follow on with that, right? Where you're able to kind of gate some of it and it's way out there and probably not anything anybody's going to do anytime soon. But it's an interesting idea, right? Of these are essentially habit affecting drugs that we haven't had tools to really use before, which I think is pretty cool.

• 1:45:43Tim Ferriss?

  Yeah, and folks who want to dive deeper into this sort of reopening of, let's call it critical windows, I mean, barring the terminology from Professor Ghul Dolan, but pretty fun stuff to dig into as well. If you want to sort of scientifically, at least for the time being, reinforce what a lot of experienced facilitators have been saying for a long time, which is like the post period matters a lot. If you're going to have knee surgery, make sure you do your. Your rehab. All right, let's hop to a few other questions. One is coming back to ibogaine specifically. The two things that have been of greatest interest to me with respect to ibogaine are TBI.

• 1:46:24Tim Ferriss?

  Right? So if someone has no addiction, no PTSD, the only issue they have is some form of TBI. Do you think there is a role for ibogaine? So we can placeholder that there's part two to this question, which is I have heard reports, and I haven't gone into the literature on this side. I don't know. Maybe this has been explained somewhere, but I've certainly heard reports of opiate addicts who have seemed to indicate that ibogaine or iboga opens a window after treatment, during which they do not seem to experience much in terms of withdrawal symptoms. And I want to know what the hell is going on there if that seems to be observed. Right? So those are the two questions. Somebody who just has TBI, do you think there might be a role for an ibogaine

• 1:47:07Tim Ferriss?

  or something like it compared to other options? And then the seeming diminishing or disappearance of for a period of time, physical withdrawal symptoms.

• 1:47:17Speaker 04

  It's a little tough with the cohort that we studied because they were, you know, it was military TBI. While I understand that the PTSD diagnosis is pretty ubiquitous in the system. It's probably true in a fair amount of folks, especially folks who've been exposed to a lot of combat-related trauma and earlier life trauma. And in our group, it seemed to be there and most of the participants, it was depression and anxiety. And so we haven't studied a pure TBI group. And so the confound is without studying a pure TBI group that somehow had, maybe it was a competitor in martial arts, you know, or something like that.

• 1:47:56Tim Ferriss?

  Multiple concussions or whatever.

• 1:47:58Speaker 04

  Yeah, something like that where they like intended to potentially get hit in the head.

• 1:48:03Tim Ferriss?

  Probably intended to hit other people in the head.

• 1:48:04Speaker 04

  Well, for sure, but intended, intended to go into the ring knowing that you were probably going to get hit. Because the problem, right, is in a lot of these cases. Motor vehicle accidents, there's really high rates of PTSD in those because there's not an expectation you're about to get hit in the head. But there's probably a population you could study that's pure traumatic brain injury where

• 1:48:27Tim Ferriss?

  I'd have like football players, right? I mean, a lot of reported depression. Who knows? There could be a lot of other factors involved, but

• 1:48:34Speaker 04

  Yeah, football players is another great example.

• 1:48:36Tim Ferriss?

  Highly correlated, yeah.

• 1:48:37Speaker 04

  Yeah, and those guys know they're going to hit their head in the game probably at some point. And so that population where it's more of a pure TBI population, you know, you could ask that same question that we asked in this more, you know, mixed population, which is, does TBI disability improve? We saw a dramatic improvement in TBI disability at the one month mark. Less actually, right after it really took a while for it to work.

• 1:49:02Tim Ferriss?

  If you had to guess, right, we're two drinks in and I'm like, no one. Just give me your wild ass guess, like mechanistically, what's going on here?

• 1:49:09Speaker 04

  It's the symphony, right? Which is, sounds kind of like maybe even hokey or like a little like less direct. But I just think that there's something about interacting somehow with multiple different neurotransmitter systems at the same time that must produce this. I mean, maybe the GDNF, BDNF alone could do this. I'm not saying it can't, but I suspect that it's a more complex process. And the problem is we don't have great tools to evaluate that. But sometimes nature is, trumps our human scientific abilities. And I think that IBA certainly is there in 2023. It's like the story of scurvy, right? Like we associated eventually after like a bunch of weird stuff, we eventually associated eating oranges with improvement in scurvy,

• 1:49:53Speaker 04

  but it took us another 100 years to synthesize vitamin C.

• 1:49:56Tim Ferriss?

  Yeah.

• 1:49:57Speaker 04

  You know, and so that's, I think, what's so hard about this scientifically and to get the kind of scientific community fully on board with these ideas is that we're likely going to figure out this works before we have any idea on how it works. Your second question, which is, I'm going to answer it the same way, but it's very unique to IBA. And you can take somebody who's going through fluoride opioid withdrawals and you can have them not only have a cessation or stopping of Of a desire to go take more heroin or prescription opiates or whatever it is, but you can have them basically blunt or completely attenuate the physical withdrawal symptoms of withdrawing from opiates, which is diarrhea, like headache, sweating, all the stuff that people will go through when they're going into opiate withdrawals.

• 1:50:42Speaker 04

  And this seems to really kind of like knock that out. It's likely, again, that because it's interacting with the opioid receptors, it's interacting with the glutamate system, but it is, to my knowledge, none of the other psychedelics can do that, ketamine can't really do that. So this is a pretty unique thing to Ibogaine that it can pull this off. And why I think it's such an important drug to understand. I mean, I would argue that because of how broad Ibogaine seems to work across now most of the major psychiatric diagnoses with the absence of something like schizophrenia, but anxiety, depression, PTSD, this traumatic brain injury, you know, multiple different addiction types, it's going to behoove scientific community to really kind of break down why

• 1:51:27Speaker 04

  it does what it does over the next couple of decades, I think, and try to really kind of back engineer what it is. But yeah, we have no idea.

• 1:51:34Tim Ferriss?

  Outside of the lab and more in the wild, what are some of the more interesting things happening related to Ibogaine and Iboga? I believe there's something happening in Kentucky.

• 1:51:43Speaker 04

  Yes, I've been down to Kentucky to testify in front of the Opiate Abatement Commission of Kentucky. It was myself along with Shreeni Rao, Mattai, Deborah Mash, who's CEO of Demorex, was at the University of Miami for a while, and Ken Alper, who was at NYU and is kind of an academic private practice psychiatrist. And there's a guy by the name of Brian Hubbard, which he's a very interesting guy, he's an attorney by training, who has worked in a bunch of different domains within Kentucky state government and whatnot. And he, for one reason or another, has become completely convinced that the money that ended up being some of the lawsuit money for some of the opiate over prescription

• 1:52:27Speaker 04

  that happened, particularly in Kentucky and West Virginia, but all over the country, should be utilized for novel therapeutics and not just for more of the same sort of treatments that we have available. The conventional treatments that are available for opiate use disorder fall under the realm of what we think about as replacement therapy. You're replacing a higher risk opiate with a lower risk opiate. So that's Suboxone and... Which contains buprenorphine and methadone, or opiate blocking drugs like naltrexone. There's a fairly high fail rate on those drugs. Part of it is psychosocial. You know, we put people in the right environment. You could probably drive up the rates of that. There's also a prescription issue. You used to have to have like a special FDA license to prescribe it. I used to have this thing.

• 1:53:12Speaker 04

  And then recently that was knocked out. So everybody with a medical license can prescribe Suboxone. And so there's kind of a group of drugs that can do some work on this. But there's certainly folks that we would think about as treatment resistant opiate use disorder patients. And the numbers I'm not going to get into because there's, you know, they're debated or whatever. But whatever those numbers are, it's a good chunk of folks and they don't really have much to offer. And so people have thought about lots of different options for them. And one of the options is brain surgery. So in West Virginia, a group of neurosurgeons are actually doing full on, there's a surgical form of neuromodulation called deep brain stimulation, where you can actually put an implanted device into the reward system. And also kind of similar to, to some of these Wegovy's kind of drugs,

• 1:53:57Speaker 04

  you can drive down some of the pleasure around. And this is more theoretical at this point. But opiate, opiates, as well as there's some data out of, you know, a couple of different studies with even like weight loss for stimulating in the reward circuitry. What's interesting is that there's a one in 100 risk of a head bleed from that treatment. And about a third of them, it ends up being a pretty significant head bleed. Right?

• 1:54:22Tim Ferriss?

  Yeah.

• 1:54:22Speaker 04

  And so what's really interesting is you, you have no one in West Virginia organizing all of these hearings about it. It's just happening. They're letting people do the science and all that stuff. And I don't disagree with doing that, by the way. I think it's a useful thing to explore and it may be a solution for this. And this is, as we described earlier, such a high risk phenomenon that a one in 300 risk is not bad.

• 1:54:44Tim Ferriss?

  Is it one in 300 or one in 100?

• 1:54:46Speaker 04

  One in 100 risk of a, for the BBS. It can be a trivial, just blood on the tip of the electrode, which is asymptomatic. About a third of those people are going to be, you know, in a more

• 1:54:57Tim Ferriss?

  Have a complication.

• 1:54:57Speaker 04

  Yeah, have a real complication. So, and then you've got about a one in 300 risk of a Torsades risk with Ibogaine. Right. And so next door in Kentucky.

• 1:55:08Tim Ferriss?

  Similar odds. Yeah.

• 1:55:09Speaker 04

  Yeah, you got a similar odd concern, you know, both of which can be kind of dealt with in the hospital. I'd argue that the IBN risk is probably a little less actually than the DBS risk if you just kind of look at everything. And they're having these significant hearings. There's a lot of opinions about this and a lot of.

• 1:55:27Tim Ferriss?

  Shocker.

• 1:55:27Speaker 04

  Right. And I'm, you know, I'm one of the few people that does all this stuff. So I can kind of, and you juxtapose.

• 1:55:32Tim Ferriss?

  Well, it's part of the reason we're having this conversation because you like, you bridge a bunch of interesting, often separate worlds. So anyway.

• 1:55:38Speaker 04

  Yeah, thanks, Ben. Yeah. So I went down there and there were a million questions about the cardiac risk and about whether or not this should be done. And particularly, should state funds be funding this? And there are various opinions about that. My opinion and the reason why I was willing to go down there and support the effort is there are a subpopulation of people in which Suboxone, Naltrexone, and Methadone don't work. And we, we need to spend some money on trying to help those people.

• 1:56:03Tim Ferriss?

  Also, working is, you know, quote unquote, working has different outcomes, right? If you're talking about like substitution therapies as well, right?

• 1:56:10Speaker 04

  Yeah, no, I think you're totally right. I think is living on opiates, if you're having to do this your whole life. I mean, it's tricky. You lose your prescription in a flight to wherever and then yeah, you're in a really bad place. And so this idea of instead of replacement, substitution, or whatever, interruption, which is what IBN is going to do, and I think at some level what DBS is going to do too, right, is going to interrupt that system, that circuit that's driving the seeking behavior and be able to kind of reorganize the brain such the person approaches the problem in a different way, is a promise that I think everybody wants to see. I think that the interesting part about this whole phenomenon down there is, you know, from the folks that are opposed

• 1:56:52Speaker 04

  to this, is this view that, one, that the current treatments are fine or whatever, and then two, that how could it be? That this extract from a root in an African country somehow be something that can do what modern humans in pharma can't do. And it goes back to what I think is a pretty hubristic part of the human psyche, which is that I need to start the fire. I need to hammer the wheel. I need to, you know, and I think at some level.

• 1:57:22Tim Ferriss?

  The sort of not invented here kind of thing.

• 1:57:24Speaker 04

  Yeah, yeah, right. And I think the idea that somehow, somehow this just exists, it goes around the psyche in a way that doesn't really work. And we saw this with scurvy too, right? I've spent a lot of time like studying scurvy because I'm very interested in this human phenomenon. There were people called anti-fruders.

• 1:57:43Tim Ferriss?

  What?

• 1:57:43Speaker 04

  I'm not kidding you. It's a real term.

• 1:57:45Tim Ferriss?

  Wow.

• 1:57:46Speaker 04

  And they were in the royal societies in the 1750s. And so we knew from 1498 that folks that were going around the horn of Africa and going to Asia that way, they'd plant like citrus trees all the way there. So we were doing this. And at some point, scurvy got worse and all that. And people said, there's like literally no way that these fruits could be the solution for this. Humans have to solve this. And actually, the fruits are probably what's making it worse.

• 1:58:15Tim Ferriss?

  Ah.

• 1:58:16Speaker 04

  Yeah. So James Lind ran the first clinical trial in the history of humans on scurvy and citrus fruit, where he gave all these like various weird concoctions, like poisons and they were trying to get people cyanide. They were trying to get people alcohol mixed with acid. This is what they thought.

• 1:58:31Tim Ferriss?

  Yeah.

• 1:58:32Speaker 04

  And so he gave people, he randomized people on a ship with scurvy to these various things and citrus fruit. And what happened was the citrus fruit receiving people at the end of the week were taking care of everybody else. But it took another 100 years. I think this is this meta phenomenon of people need to feel like they made it in that culture within that context, that this is the latest and greatest thing. It needs to be kind of like very proximal in time. It needs to be new, you know, it's got to be the new thing to be the solution. And I think that's part of what's going on. In Kentucky, from my view of it, because if you look at West Virginia and you just look at like the actual information of what's going on, you'd probably be more likely to

• 1:59:14Speaker 04

  cause, and I don't think that people should, but question the brain surgery thing, if you really get down to it, over the Ibogaine thing, just on the risk portfolio and having to have an implanted device for the rest of your life. But nobody said, there was like nothing there. And it's because we're making this. Western society is making this really innovative new treatment that requires a brain surgery and da, da, da, da. And that's totally cool from their perspective. And I think that we've got as a culture and as a scientific community, really changed the way that we think about evaluating tests and particularly therapies and look at the inherent scientific complexity and not the temporal proximity and the fact that we made it or whatever, you know, those sorts of

• 1:59:58Speaker 04

  things that I think drive people to have these misconceptions. And so, so yeah, so Kentucky's really interesting. It's really an argument about whether or not some of this money should be earmarked and whether or not it should be studied. And I think both of those things are a yes, you know, we should be. It's the best candidate that we know about. And the risks are mitigatable and similar to DBS.

• 2:00:21Tim Ferriss?

  So many facets to this, like insurance reimbursement, scaling, therapist availability, or I should say more medical availability for like the duration of stay that would be required with Ibogaine versus like, there's so many facets to all of this. In terms of, say, getting to patient 10,000, right, for whether it's this DBS implant surgery or Ibogaine, right, there's so many levels of nuance. But at the basic science level and the further research, who am I to say, but it seems like the cost and severity and prevalence of the problem is such that the answer is of course, yes.

• 2:00:56Speaker 04

  Yeah.

• 2:00:57Tim Ferriss?

  Of course, it's yes. I do want to ask you about synthesis, specifically, really Ibogaine, because I'm always fascinated by rate limiting steps and also unintended consequences

• 2:01:09Tim Ferriss?

  Using different compounds that occur in nature. Before we get there, I want to very selfishly throw in a wild card question around IRBs and funding studies and getting ethical approvals, because I would love to see more studies on extended fasts in humans. But to my knowledge, those basically got taken off of the table. If I wanted to try to make the case and fund some science related to extended fasts in humans, any suggestions?

• 2:01:38Speaker 04

  I think everything's studyable if the risk benefit ratio is on the right side of things. At least at Stanford, I think that's the evaluation is extended fasts in normal, healthy controls. But I think if you can make an argument for some sort of medical psychiatric, whatever it is, condition that you think that the benefit of doing that significantly outweighs the risk.

• 2:02:04Tim Ferriss?

  I think I can make that case.

• 2:02:05Speaker 04

  Then I think you can do it. Yeah. And so it's really is just that, right? It's this ethical, and I think it's, I agree with it, right? It's this ethical justification that we're going to be able to do more good by trying to do something like this than to do harm. I mean, if people, a study that would never go through any IRB is we're going to randomize people to no motorcycle helmet or motorcycle helmet and have them do laps around the university. You know, like, we pretty much know the answer to that question. And the benefit of knowing in a randomized controlled trial way, the benefit of the answer to that question, you know, does not outweigh the risk at the individual patient or participant level of participating in a trial like that. So that trial would never get done, right? And so I think that's the way that we, that we have to kind of look at it.

• 2:02:49Speaker 04

  So if you've got a reason, your reason is you think that there's going to be some effect on coronary artery disease or something like that.

• 2:02:57Tim Ferriss?

  I think there are a couple of different approaches I could take, just in case there's anyone listening who, who wants to do this. And there are extended, people study fasting in animals all the time, but it's for whatever set of reasons, at some point, it seems to have been taken off the table for human subjects. I mean, there was research done on something like that up until maybe the 40s and 50s, but then it kind of vanished. And I'm very interested in, if I had to make the case, I would probably make some type of case around. What Chris Palmer at Harvard and other people have called metabolic psychiatry. So to look at this almost like the accelerated TMS equivalent of a ketogenic diet for certain psychiatric conditions, because you see some incredible results and Chris has been on the podcast with,

• 2:03:42Tim Ferriss?

  say ketogenic diet as applied to conditions like schizophrenia, for instance. I mean remarkable transformations where people get off of half a dozen or dozen medications. And like you, I am interested in practical solutions and especially things that are uncrowded from the perspective of scientific support, which for a while has been psychedelics, but certainly accelerated TMS, I'm agnostic when it comes to the tools. And I think I'd probably make the metabolic psychiatry argument, but the fact of the matter is, I also feel like it's been so long since we applied modern tools and tracking of biomarkers and so on, everything that we have at hand now to human fasting.

• 2:04:27Tim Ferriss?

  That may not be the argument that I would use, but certainly there is that. Okay. So synthesis, there's a great piece that came out in National Geographic not too long ago by journalist named Rachel Nuer, I think I'm getting the last name right, N U W E R. She also has a great book on MDMA and MDMA assisted psychotherapy, the history and implications that recently came out. And she traveled to, I think it was Gabon, although I think there is also, I think you can also find iboga in Cameroon, if I'm not mistaken. And she went on the ground to look at all the implications of global demand for ibogaine and iboga. And it's very, very nuanced, but it seems clear, and I wrote a piece a long time ago

• 2:05:08Tim Ferriss?

  on my blog, which was a letter to users of psychedelics, like a plea for a more ethical menu of options, something like that, to just point out some of the diminishing natural supplies for, say, peyote, almost certainly going to go extinct. Use something else, use San Pedro cactus, look at the growth cycles. Just don't touch it unless you're part of a culture that has this as an integral part of tradition and healing, as would be the case for, say, people who are in the Native American church and so on. But ibogaine can be had in, I guess, a number of different ways. Maybe you could speak to like the known options and then looking forward what some of the most interesting options are for whether it's like extraction or synthesis.

• 2:05:51Speaker 04

  There's kind of the straight extract out of the iboga tree, as you're pointing out, and that's, that one's probably a pretty big ethical issue because what's happening, and I think that National Geographic article really reflect this, is that there's such a global demand that it drives the prices up in the Boiti, the peoples that take ibogaine and Gabon and surrounding countries no longer can access it because of the high cost, which is the last thing that you want to have happen, right? That's the thing that you're, that everybody, I think, should be trying to avoid first. And so what else can you do? So another way to do this is that there's another tree in Ghana and other places in

• 2:06:30Speaker 04

  Africa that has voicangene. This is voicang, Africanist tree, and has voicangene, which is a very similar, but not identical alkaloid to ibogaine. It's actually not even a controlled substance, so voicangene is not on the controlled substances list. And it's not as much of an issue because there's not really a current medicinal usage of voicangene or utilization of that within those cultures that have these trees.

• 2:06:58Tim Ferriss?

  It's also more commercially cultivated, if I'm not mistaken, right, for maybe fragrances or something? I can't recall the commercial use.

• 2:07:05Speaker 04

  Yeah, and it's pretty ubiquitous, too. I mean, I've heard that it's not just in Africa, it's in some of Central and South America. And so you can, you can extract the voicangene and then you can do this simple chemical step to get it to ibogaine, you know, to so just do a synthesis pathway of ibogaine from de novo. It's like 26 plus steps or something like that. But this is like the last step before it's ibogaine from voicangene. And so it's really pretty straightforward to do that. But you're still talking about a botanical. You're still talking about essentially growing a plant to derive a chemical out of the plant. So the other... Way to think about it is, because you do a full chemical synthesis and people have looked at that and tried to do it. It's very hard though, because Ibogaine has two chiral

• 2:07:49Speaker 04

  centers, so it has the potential for four stereonantromers and that chemistry is complicated. And so, full synthesis is a tricky process. My suspicion is that whether it be biosynthesis or straight full synthesis, but there's gotta be a way to make this that avoids trees eventually. I think it's better for the environment. It's gonna be more scalable. It's gonna be something that standard pharma is gonna wanna see happen to really be able to use it. But there's still some time to get from A to B, as far as that goes. So I think it's not a done deal. It's not completely figured out yet.

• 2:08:25Tim Ferriss?

  So bridging from that, I mean, this is actually a completely separate question, but also raises some sustainability ethical questions. Five MEO DMT, so five methoxy DMT. So first of all, I really implore people, I'll link to this in the show notes as well, read the blog post that I put together. So the five MEO DMT, it's present in quite a few different plants, different nuts. Most people who have heard it in the zeitgeist know it within the context of Bufo alvarius. There are other scientific names for this toad, this Sonoran Desert toad. And that has turned into a huge mess in terms of like cartel harvesting and over harvesting from these poor toads. It can be synthesized. There are ways to synthesize it. Hamilton Morris has beat the drum about this, to his credit.

• 2:09:10Tim Ferriss?

  People are not gonna like this, but there is no documented indigenous use of the Sonoran Desert toad. Ken Nelson, look it up, in the eighties, produced a pamphlet after testing god knows how many things. Brilliant amateur biochemist. But nonetheless, it is very, very, it is interesting and appealing on a whole number of levels. A lot of people are trying to commercialize it because, at least in earth time, it is a short experience, right? So, well, it's gonna 10 to 20 minutes, 10 to 15 minutes. So from a business model perspective, I understand the appeal, much like I understand the appeal of the newly branded psychoplastogens, right?

• 2:09:46Speaker 04

  Yeah.

• 2:09:47Tim Ferriss?

  Psychedelics with the content slash mind altering aspects as removed as possible. We might come back to that. But my question related to this is not so much on the production side, because people can read about that separately and I think it's important for people to read about. It's more of practical use following Ibogaine administration.

• 2:10:06Tim Ferriss?

  I believe I've heard people describe its use on what some people call the gray day following administration. Could you speak to this because I'm trying to discern for myself how important or critical it is from a therapeutic outcomes perspective versus being a business differentiator. Does that make sense?

• 2:10:24Speaker 04

  Yeah.

• 2:10:25Tim Ferriss?

  This is something we kind of, you know, we put a nice set of icing on top of the cake and that includes this, what can often be a sublime experience, not always for people, can be destabilizing for some folks in the form of 5-MEO DMT. So what's your take on this?

• 2:10:40Speaker 04

  So we specifically made sure that folks weren't getting a second kind of confounding drug on top of the ibogaine to figure out what the ibogaine effects were in isolation. And as I described earlier, you know, we had extremely remarkable effects in the absence of doing the 5-MEO. I think what people say about this, the 5-MEO is that it just takes the edge, at minimum, it just seems to take the edge off the gray day, which is a day that happens for not everybody that takes ibogaine, but a fair percentage of people, such that there's a name for it, where people for some reason end up having kind of a bad day in and around day two, three, where they, they really have a hard time and then it goes away the next day.

• 2:11:25Tim Ferriss?

  Hard time meaning depressive symptoms?

• 2:11:28Speaker 04

  For some people.

• 2:11:28Tim Ferriss?

  What is hard? Okay, yeah. What makes it hard? Anxiety, anxiety.

• 2:11:31Speaker 04

  Yeah. Anhedonia, low motivation, sadness. I think probably what's going on is there was like a serious kind of flooding of your CNS with a whole host of effects from this drug and then, and the brains then kind of reacting to that. And then it seems to kind of rebound out on its own without the 5-MEO. But it sounds like from what I've heard, 5-MEO kind of bridges people out of that so they don't have to really have to experience that feeling. Now, the question would be, does it do something else beyond that that's useful? We have no idea. What we, I suppose what we could have done, or maybe what we could do in a subsequent study is to just randomize people to getting.

• 2:12:15Speaker 04

  No 5-MEO after a 5-MEO and we could actually answer that question, does it have an effect in the long term? It's hard because there's like a floor effect of just like the profound improvements that we saw just from Ibogaine. So you'd have to, my guess is that the statistics would tell you that you have to do a pretty large sample to be able to see something if it's there with 5-MEO, just because, you know, everybody's flooring out just with Ibogaine.

• 2:12:38Tim Ferriss?

  When you say flooring out, does that mean that the amplitude of the effect is so great that you would need to, in terms of like seeing a large percentage improvement over the Ibogaine, you'd need to see something great? Or what do you mean by flooring out?

• 2:12:53Speaker 04

  Yeah, yeah. So I mean, essentially, we're seeing people drop down within that normal range.

• 2:12:57Tim Ferriss?

  Oh, flooring out on the assessments?

• 2:12:58Speaker 04

  On the assessments. You'd need to see, and you know, people are going into the range of like a score of five, six, something like that on various scales, PTSD scales, depression scales, which are in the normal range. And so you'd have to zero people out with a 5-MEO essentially. Or the other thing that it may do, which nobody knows probably, is whether or not it makes some of these folks who were, and you'll see in the paper, there were a couple of people that relapsed at the month mark, maybe it helps the durability on some people. It could do those things. So I'm not saying that it doesn't have a benefit. It's just, it would be a hard study to deal with. And I think from like a purist, I want to see this go through the FDA and kind of do the FDA things and see if we can get, you know, the first drug kind of through the process.

• 2:13:43Speaker 04

  And I don't want to say it's a distraction from a US kind of scientific regulatory strategy standpoint, but it's definitely something that would add complexity. So I think at the level of clinics that are doing this in Mexico and they have free range to use these substances, I don't think it's, on the face of it, like a terrible thing to do. I think it makes sense why they're doing it.

• 2:14:05Tim Ferriss?

  Do you really think that? I just, I guess, just to push on that a little bit, I'm like, okay, so people have a hard day, but it's known that this is a phenomenon, so they could prep people for the possibility that they would experience this hard day. If they're not somehow edging into dangerous territory where they're likely to self-harm them, I mean, 5-MEO DMT, I have some experience with it. I understand the appeal is like sachinandana, et cetera, but it's not risk-free.

• 2:14:30Speaker 04

  Well, you're strapping yourself to a rocket.

• 2:14:32Tim Ferriss?

  Yeah, I mean, that is a big, big gun, right?

• 2:14:35Speaker 04

  Yeah, yeah.

• 2:14:35Tim Ferriss?

  Which is not to malign anyone who's using this in a clinical setting, but it's not risk free. I mean, I have friends who are very experienced psychonauts. We're talking like 100 plus reps with things like ayahuasca who have been pretty much even keel with their various experiments and been knocked pretty sideways for non-trivial periods of time by 5-MeO DMT. Maybe that's just the sample set that I'm dealing with, but.

• 2:15:00Speaker 04

  Yeah, and I totally agree with you. You know, medicine is a discipline and a profession of risk mitigation and risk benefit ratios and everything. And anybody that would proclaim themselves to be a physician scientist that doesn't believe that, isn't seeing it as it is. Everything that I do is some sort of risk mitigation exercise where I'm looking at this thing has these risks, but this person has these inherent risks and how do you square all that? I think to your point, it would totally make sense if the person was in such a bad place in the gray day that you were worried about them. I think there's a justification there. If you really, it seems that they do have some general experience that this was helpful to kind of getting folks out.

• 2:15:45Speaker 04

  The reality is, is that we're really not going to know much of anything and a lot of this is going to be in the realm of anecdote until we do, do the trials in the US and really thoroughly document everything that happens with this drug, with Ibogaine, with 5-MeO, which as you know, people are trying to put through trials and commercialize that. And so I think there's a moment where we'll be able to kind of rectify all of this and figure it out. I agree with you too, that I think that where MDMA may be a substance that certainly not everybody could use, but like a decently broad population-based drug that a fair amount of the population that had PTSD could go after.

• 2:16:25Speaker 04

  I think that these substances are more constrained to a smaller population where the risk benefit is right for them. And so absolutely, it's a tricky moment. I think we know just enough to be dangerous in some places and we got to get through this just enough to be dangerous moment to the like, we know how to not be dangerous moment as a culture and do that with kind of the scientific process.

• 2:16:48Tim Ferriss?

  So much earlier, you were laying out psychiatry 1.0, 2.0, 3.0. I'd love for you to. Feel free to speculate, right? It's gonna be speculation, but putting aside like the, I know it's hard to do, but like shepherding stuff in its simplest form, cleanest form through the FDA, et cetera, but like, what might psychiatry 4.0 look like?

• 2:17:09Speaker 04

  That's right.

• 2:17:10Tim Ferriss?

  Right? In the sense that, for instance, something that's on my mind, and I'll keep it short, is, as I understand it, very, at a very primitive level, the way that some of the accelerated TMS protocols work from a hardware perspective is you're kind of hitting nodes at the exterior of the hub and kind of triangulating in a way to hit what you're trying to hit. But perhaps you could use, for instance, in my conversation with Nora Volkoff of NIDA, she's talking about focused ultrasound. So maybe you use that to hit the deeper structures directly, you hit the nucleus accumbens or whatever it might be. And then, related to that, if we're talking about like Freud and so on, focusing on content, and then you've got this sort of neurotransmitter focus, oh, it's a serotonin issue, and then

• 2:17:55Tim Ferriss?

  now you have the electrocutical, kind of structural nuance and experimentation. But it seems like these things aren't necessarily wrong, they're just, at least if we're looking at the content, the molecules, incomplete.

• 2:18:07Speaker 04

  Incomplete.

• 2:18:08Tim Ferriss?

  But if you talk to a lot of these guys who go through, say, the, and gals, but a lot of these operators, men, who go through the I began experience, I mean, they will, and maybe there's a visibility bias, because they can't see what the hell's going on in their head, but from a chemical perspective, but they can remember the content, but like a lot of people attribute the therapeutic effects to much of the content, right? This reconciliation and so on. So what might psychiatry 4.0 look like?

• 2:18:31Speaker 04

  We have a paper coming out soon where we're actually trying to use neurostimulation to change trait hypnotizability, to make people more suggestible transiently. And it's probably an ability to zero in on specific content and manipulate that content through circuit-based intervention, you know? And that's like a pure speculation, but I'll give you an anecdotal kind of case report example. And so there was a patient who got similar sort of deep brain stimulation approach that I was describing earlier, that they were looking at in West Virginia for addiction, and that individual received deep brain stimulation, I think in Europe, I think for OCD, and he

• 2:19:12Speaker 04

  was, had a normal musical taste, he listened to whatever, all the range of standard artists. And then he got his deep brain stimulation and he became obsessed with Johnny Cash. Like totally sold all of his.

• 2:19:25Tim Ferriss?

  Didn't see that coming. All right.

• 2:19:26Speaker 04

  Yeah, totally sold all of his other albums and listened to Johnny Cash. And the batteries for these deep brain simulators will wear out after time and you need a new one. And it's decently common that if the person's doing pretty well, then they will forget to come in. And then all of a sudden their battery is dead and then they'll have a reemergence of symptoms. And so this gentleman did. So I think it was his OCD and his OCD got worse again. And he fell out of favor with Johnny Cash and threw away all of his Johnny Cash albums and started listening to whatever he was listening to before, went in, got a battery changed. The battery was put back in.

• 2:20:00Tim Ferriss?

  And he's like, for fuck's sake, I gotta go back to the shop and buy my Johnny Cash.

• 2:20:04Speaker 04

  And that's what he did. Yeah. And so just like, we don't really understand how the game works. We really don't understand what happened there, right? It was a very illustrative case and I love talking about that case because it gets into this area that I think people are really worried about right now about specific content manipulation. I don't think we can do that, you know? We don't have the tools to do that. We have these like broad tools that basically change the lens of the world that you look through. Like I can change your brain in such a way that you're like, for some people, they're going to see rose colored glasses where they saw blue before or whatever.

• 2:20:37Tim Ferriss?

  It's like, I can give you a different set of glasses to watch the movie, but I can't change the movie directly.

• 2:20:42Speaker 04

  Yeah, they can't change the movie directly. My suspicion is, is that we're going to edge into a world where maybe we can change the movie. And that's where it starts to get both very interesting and very ethically complicated. And that story about Johnny Cash, that doctor had no intention of doing that because nobody knows how to do that. And maybe they played Johnny Cash in the OR, maybe not. They didn't report that in the case report, but there's no clear sense of why that happened either. Is this the first song that was playing in the hospital when he woke up and his brain, the reward system just kind of like attached to it or whatever. But it's one of these things where. We're going to get to a place of sophistication. I think we're going to be able to do that.

• 2:21:23Speaker 04

  And what happens in medicine is I see it is we're always redefining what's illness. It used to be that high blood pressure was like 150 over 100 or something, and it was 140 over 90, and then it's 130 over 80, and now it's 125 over like 75 or whatever it is. It's not that the illness has changed, it's our definition of illness changed. And so, you know, my suspicion is, is that as we have enough tools to be able to knock out these major mental illnesses, which are effectively like in states, right? At the end of the day, we let the system go all the way to like this kind of completely semi-functional in-state where people have semi-volition and they're kind of stuck in these mindsets and these behaviors.

• 2:22:03Speaker 04

  If we can figure out what that is, and we have ways of intervening sooner in that process, and we have emerging tools that can help you with this sort of content targeting, manipulation sort of thing, then I think you're going to be talking about much more specific sort of interventions. That's like very sci-fi though, you know? It's not something that I think there's even like a hint of. I wouldn't even know how to tell you how to do that now. Our like one-shot-on-goal is just to move around this brain trait. We do have a study with Rogaron where we're actually packaging ketamine into nanoparticles, infusing them into, through an IV into the bloodstream, and then using ultrasound to

• 2:22:45Speaker 04

  kind of open the nanoparticle ketamine and drop ketamine just in the cingulate, in the area that we were talking about earlier. In this case, in pain patients, because it's easy to measure pain scales and pain reactivity, but what I think will be really interesting with that is if you could take that same technology and start to drop various psychedelics into specific brain regions, and you can do a behavior mapping exercise. What's necessary and sufficient to produce the clinical improvement? What's necessary and sufficient to produce the TRIP? And I think that's going to be way more important than modifying the molecules. Because it's like a confound. We're not really answering the question of, does TRIPless ibogaine work? Because it's not ibogaine, you know? It's just some other thing, right?

• 2:23:30Speaker 04

  But what we really want to know is, does TRIPless ibogaine work? Because we just put it in the amygdala or just into the... Singulate or something like that and that in isolation isn't sufficient to produce the trip, but it's sufficient to produce the therapeutic effect. If we can pull that off, we're going to start next year on that. That's going to be super cool because it's going to give us the ability to have more of these questions. And you could even think about it like if you had a long acting anesthetic, right? Where you had somebody with pretty pronounced psychosis, schizophrenia symptoms coming in and you were able to shut down their amygdala for a couple of days with an anesthetic just in the amygdala and nowhere else. They're totally awake, they're still with you, but their fear response or into the

• 2:24:12Speaker 04

  singulate, their kind of salience of the environment response goes down because you're able to kind of temporarily shut it off, but you're not having to give like a whole body, whole brain anesthetic where you're putting somebody into a medical coma or something. You're just shutting down this one area.

• 2:24:26Tim Ferriss?

  Which you could potentially do through neuromodulation and not pharmaceutical, right?

• 2:24:31Speaker 04

  You can. So people have tried to do that with deep brain stimulation. You can actually do a jamming signal in certain areas and shut it down too. And that may be the long-term solution, right? Using drugs like focal drugs to test it. It's a commitment. It's not something you do in an emergency.

• 2:24:47Tim Ferriss?

  Yeah, right.

• 2:24:48Speaker 04

  But you could in theory do this in the ER. You could take somebody that was acutely psychotic. You could put an anesthetic that could kind of shut down that system for transiently for a couple of days and you could kind of get them more on board with thinking about what the long-term solution is when the fear system isn't in place as much. All total speculation. It's not something I have any direct data to support, but it's definitely interesting.

• 2:25:11Tim Ferriss?

  Let's push into a little bit more sci-fi because it's, it's fun. And also a lot of things that start in sci-fi end up in sci, right? So to speak, right? I mean, you look at Snow Crash by Neal Stephenson and there are many examples, but do you think you could change handedness, hand dominance?

• 2:25:31Speaker 04

  That would be hard. I think it's possible to do that at childhood and we do do this in stroke, right? We do this constraint therapy sort of stuff where you actually constrain the, if you have a big stroke where you have on one side of the brain, you have a pretty devastating stroke where people can't move their arm and all that good stuff or have minimal movement of their arm. And then they have an intact side that's totally fine, right? You actually constrain the intact side and force the person to use the affected side to drink water or to write or whatever. And when what you're trying to do is to kind of reorganize the neural system in such a way where there's more cross-functional attribution of that side. And so we have some evidence, there's ways to do that.

• 2:26:13Speaker 04

  There's kids who need corpus callosumies and various different, like, pretty significant, like, say epilepsy surgeries when they're really, really young, like one years old, two years old, three years old, whatever. And when you look at those cases, it can lose like a pretty substantial part of their brain from whatever surgery they needed to deal with their problem, or if they had a trauma or whatever. And they can reorganize the system to be able to reallocate resources to be able to do bilateral sort of functions. And so it's mostly that the brain gets fixed. You know, the interesting thing about this idea of critical periods and maybe what IBN is doing and whether or not you can make a more plastic brain is this idea that if you could bring the brain to a more juvenile state, then you could probably neurorehab

• 2:26:58Speaker 04

  it better. And that's going to be, I think, one of the questions that'll come out of the data that we're going to present is, how far can this go? I mean, we saw like, people go from mild to moderate TBI disability to none on average, which is awesome and like, never heard of. But if you keep pushing on that, how far could you go with something like that? And that's going to be a question that I don't have an answer for, but at least there's like a signal there to look. That's kind of part of what I like about the general work that I try to do is I like to be relatively disrupting and I like to be in spaces where nobody else is working. I start to not like it when everybody's doing it. So I'm like, always now, like, where am I going?

• 2:27:40Speaker 04

  I'm always looking for the thing, or nobody's really in that space studying it. I always like it when people think it's, if people think it's like really weird, it's like a positive signal that I need to do it kind of thing. And so I think this area of, certainly this area of using psychedelic drugs to try to treat neuro deficits is not something that a whole lot of people are really like looking into right now. So it's pretty curious and hopefully we can ask some of those questions.

• 2:28:08Tim Ferriss?

  One aspect of the accelerated TMS, in terms of case reports, maybe too strong word, anecdotal reports that I found interesting is it seems like some folks report Increased visual acuity or like color contrast.

• 2:28:24Speaker 04

  Yeah.

• 2:28:24Tim Ferriss?

  And I found that very interesting for a few reasons. Number one is that it's very commonly reported. Say if you're on lower doses or higher doses, but let's just say low to moderate doses of certain psychedelics.

• 2:28:34Speaker 04

  Yep.

• 2:28:34Tim Ferriss?

  It's sort of like the dial on your HD visual perception is set forward a few clicks. Right? The flowers sparkle just a little bit more. I mean, you notice details you would otherwise not noticed. And the reason I'm bringing this up, I mean, that raises a lot of questions, but I'm bringing that up specifically because there are athletes who have talked about the performance enhancing benefits of some types of psychedelic use.

• 2:28:57Speaker 04

  Yeah.

• 2:28:57Tim Ferriss?

  And I think Aaron Rodgers would be one example of this, although I don't want to say it's sort of in session use. It's I think more longer term implications. However, there are people, certainly I know athletes who have used these things to enhance their perceptual faculties, which then leads me to wonder and almost assume that neuromodulation will be used as a very hard to detect means of performance enhancement in sports. It's hard for me to see how that would not be the case with people who are willing to. I think there was some type of poll done at one point and say, would you be willing to take a drug that would guarantee you to get a gold medal, but it would reduce your lifespan by like five or 10 years? And the answer for this thing that I'm, it could be all made up, who knows?

• 2:29:38Tim Ferriss?

  But I remember the report supposedly indicating that the yes answer was very, very high percentage of respondents. Right? So if they're looking at something that has a lower risk profile and is basically going to be impossible for like the world anti doping association to

• 2:29:56Speaker 04

  Yep.

• 2:29:57Tim Ferriss?

  track. Why wouldn't they try it?

• 2:29:59Speaker 04

  Absolutely. I'll tell you, we've had a number of patients who've gone through and they remitted really early. So they lost all their symptoms really early in the week. So like day one or two, and then by day three, they've like zeroed out. And then like Thursday, like day four or five, they're coming in and they're saying, you know what? You know, I remember this one guy who's like, I was driving by the beach and I saw the sun setting or whatever it was, and I wanted to stop and for whatever reason, just like sit on the beach. And I don't normally do that. And then he described how he was like completely present in the present moment and able to just be there. And present was like watching the water for an hour. And he said, I've never been able to do that before, but I used to do these mindfulness courses that I couldn't understand.

• 2:30:42Speaker 04

  And it felt a lot like that. And I went and found my book and it sounded like I was having this kind of like totally present mindful moment. And I've had a ton of folks come back and tell me this. So if they remit really early and we keep treating them, we treat them through. It looks now that, you know, we've had folks come through for this and folks come through for psychedelic treatments. It looks like day three, four, five out of a psilocybin experiment where you've got the person's no longer having any trip, you know, but they're just calm and peaceful and kind of pretty relaxed and present. And it's very similar to that. And so I think that you're probably getting a similar or the same state there. And I would assume a state where a lot of good performance can

• 2:31:25Speaker 04

  happen from, right? Because you really are truly in this moment, not thinking about the present or the future. You know, I've had a lot of folks actually offer, and at some point, we need to do this, but offer various philanthropic gifts for me to run trials on athlete performance.

• 2:31:40Tim Ferriss?

  I knew it. I knew it. Of course.

• 2:31:43Speaker 04

  So I had, yeah, one of our donors said to me, I will give you the money if you will take me and all of my group of friends.

• 2:31:51Tim Ferriss?

  All my post-finance guy triathlete friends.

• 2:31:53Speaker 04

  It is basically that. Yeah. And we cycle every morning and randomize us to sham or active stimulation before we get on the bikes. And he's like, the reason why this is good is because we make the same exact times and everybody knows their times and da, da, da, da. And can you change this? There's a little bit of evidence for this. It was a paper that was published a couple of years ago where they took people and taught them to do like complex motor tasks, like hand tasks where it's like tap digit 135, 135, 135, and then intersperse it with 24, 135, 24, like that. It's like a complex kind of multi-step finger task. And if you prime the motor learning area before you do that, you can cut the

• 2:32:37Speaker 04

  speed of acquisition in half compared to the people that had sham.

• 2:32:40Tim Ferriss?

  That's non-trivial.

• 2:32:41Speaker 04

  Right?

• 2:32:41Tim Ferriss?

  Seems non-trivial.

• 2:32:42Speaker 04

  Yeah, and so it's interesting, right? Like, there's some really early, like, preliminary data to suggest that you could potentially improve performance with neurostem. The thing about it is, is that if you could have something, something that, you know, people have been thinking about TMS as a treatment for insomnia, others for acute anxiety, if you could come up with something that could put the brakes on a couple of different symptomatologies, you could make, maybe it's a TMS device, maybe it's another technology, you can make it something you could bring home, then you'd have the ability to have this kind of full-service sort of process for dealing with things. I think trying to treat depression and isolation or something like that, you're, you're never going to be able to scale one treatment alone, but if we get to a place where we can use

• 2:33:27Speaker 04

  this for a lot of different functions and actually, you know, the hypnotizability stuff drive people up to be able to receive information better, or study better, or whatever, do motor tasks better, and then turn it off and flip it on to like, sleep mode, you know, and you had a level of more control over your brain than just your own volition. It's your volition plus your volition to do these things. Now, I think it's very interesting. It's also very sci-fi, though. I mean, we're not anywhere close to knowing we can do that yet.

• 2:33:55Tim Ferriss?

  Yeah, not anywhere close yet, but fun food for thought, at the very least. Nolan, one more time, where can people find your lab online?

• 2:34:06Speaker 04

  So it's bsl.stanford.edu. It's the Stanford Brain Stimulation Lab.

• 2:34:11Tim Ferriss?

  Great. And any other websites you'd like to point people to?

• 2:34:15Speaker 04

  No, I think, I think that one's, that's the place to go.

• 2:34:17Tim Ferriss?

  That's home base. Anything else you'd like to say before we wind to a close? Any comments, public complaints?

• 2:34:27Speaker 04

  It's been super fun. I mean, I think you're, you've definitely gotten yourself quite up to speed and kind of right in the center of a lot of the pulse of this, both on the neurostim side and the psychedelic side.

• 2:34:40Tim Ferriss?

  The pulse.

• 2:34:40Speaker 04

  Yeah.

• 2:34:41Tim Ferriss?

  Yeah.

• 2:34:41Speaker 04

  And so appreciate the kind of the knowledge coming in and your interests and, you know, appreciate the ability to have a conversation around these topics. So.

• 2:34:51Tim Ferriss?

  Thank you for saying that. I really have enjoyed delving into this field. You've been incredibly helpful as a resource and a sanity check since I get all excited about things and sometimes can fly off the rails, but it's been so much fun to engage with this burgeoning, hopefully soon to be dramatically expanded, the field of experimentation, especially given the remission rates and the durability. I mean, I've seen, and the reason I first began exploring this was I saw a friend's family completely transformed. And the before and after was just one of the most unbelievable transformations I have ever seen in my life. And it happened quickly. I think it was about day three, many, many failed interventions, really critical situation,

• 2:35:35Tim Ferriss?

  lots of self harm. And it was just like Ctrl Z, undo, and back to the person they used to be. And it's been durable with, I want to say, let's call them single day boosters, maybe once a quarter or once every six months. And I think it's now been durable, I want to say probably a year and a half, which is just phenomenal. So I appreciate the work you do. I appreciate you being the last man standing on the scientific bachelorette. And I suspect that'll happen again. And thanks for taking the time for the conversation, man. Look forward to watching what you do in the future. And for everybody listening, we will link to everything we discussed in the show notes, including Nolan's lab at tim.blog/podcast.

• 2:36:16Tim Ferriss?

  Until next time, be a little bit kinder than is necessary to others and to yourself. And thanks for tuning in.

• 2:36:24Tim Ferriss?

  Hey guys, this is Tim again. Just one more thing before you take off, and that is Five Bullet Friday. Would you enjoy getting a short email from me every Friday that provides a little fun before the weekend? Between 1.5 and 2 million people subscribe to my free newsletter, my super short newsletter called Five Bullet Friday. Easy to sign up, easy to cancel. It is basically a half-page that I send out every Friday to share the coolest things I've found or discovered, or have started exploring over that week. It's kind of like my diary of cool things. It often includes articles I'm reading, books I'm reading, albums perhaps, gadgets, gizmos, all sorts of tech tricks and so on that get sent to me by my friends, including a lot of podcast guests.

• 2:37:06Tim Ferriss?

  And these strange esoteric things end up in my field, and then I test them, and then I share them with you. So if that sounds fun, again, it's very short, a little tiny bite of goodness before you head off for the weekend, something to think about. If you'd like to try it out, just go to tim.blog/friday. Type that into your browser, tim.blog/friday. Drop in your email and you'll get the very next one. Thanks for listening. This episode is brought to you by Eight Sleep. Temperature is one of the main causes of poor sleep, and heat is my personal nemesis. I've suffered for decades tossing and turning, throwing blankets off, pulling the back on, putting one leg on top, and repeating all of that ad nauseam. But now I am falling asleep in record time.

• 2:37:51Tim Ferriss?

  Why? Because I'm using a device that was recommended to me by friends called the Pod Cover by Eight Sleep. The Pod Cover fits on any mattress and allows you to adjust the temperature of your sleeping environment, providing the optimal temperature that gets you the best night's sleep. With the Pod Cover's dual-zone temperature control, you and your partner can set your sides of the bed to as cool as 55 degrees, or as hot as 110 degrees. I think generally in my experience, my partners prefer the high side, and I like to sleep very, very cool. So stop fighting, this helps. Based on your biometrics, environment, and sleep stages, the Pod Cover makes temperature adjustments throughout the night that limit wake-ups and increase your percentage of deep sleep. In addition to its best-in-class temperature

• 2:38:33Tim Ferriss?

  ...regulation, the pod cover sensors also track your health and sleep metrics without the need to use a wearable. Conquer this winter season with the best in sleep tech and sleep at your perfect temperature. Many of my listeners in colder areas, sometimes that's me, enjoy warming up their bed after a freezing day. And if you have a partner, great, you can split the zones and you can sleep at your own ideal temperatures. It's easy. So go to eightsleep.com/tim, spelled out, eightsleep.com/tim, and save $250 on the pod cover by Eight Sleep this winter. Eight Sleep currently ships within the US, Canada, the UK, select countries in the EU, and Australia. This episode is brought to you by Nordic Naturals, the number one selling fish

• 2:39:17Tim Ferriss?

  oil brand in the US. More than 80% of Americans, that's probably a lot of you listening, including me, because I do measure my omega-3s, do not get enough omega-3 fats from their diet. That is a problem because the body cannot produce omega-3s, an important nutrient for cell structure and function. Nordic Naturals solves that problem with their doctor recommended, and in fact, this brand was recommended to me by one of my doctors, Ultimate Omega Fish Oil Formula. So the Ultimate Omega Fish Oil Formula for heart health, brain function, immune support, and more. It's incredibly pure and fresh with no fishy aftertaste. So I have been taking Ultimate Omega for the last two months or so, and this fishy aftertaste issue has been

• 2:40:01Tim Ferriss?

  a problem for me. And this actually with other brands induced some nausea after a few days. And Ultimate Omega has been as clean as a whistle. I've had no issues whatsoever. And if you are vegetarian or prefer to alternate, I ended up alternating two products. And that is number one, the Ultimate Omega Fish Oil Formula, and also the Algae Omega, which is plant-based EPA and DHA. That's also from Nordic Naturals. So I ended up getting both of those products, and it has improved my recovery from workouts. It's improved my sleep. It has improved my mood. And I know that because I pulled out a lot of other variables. In any case, back to the read.

• 2:40:43Tim Ferriss?

  Nordic Naturals fish oil products are offered in the triglyceride molecular form, the form naturally found in fish, and the form your body most easily absorbs. Their Ultimate Omega Fish Oil is offered in soft gels, liquid, and zero-sugar gummies. Nordic Naturals fish oils are Friend of the Sea certified and sustainably made in a zero-waste facility powered by biofuel. They're also non-GMO and third-party tested, surpassing the strictest international standards for purity and freshness. Want proof? You can visit their website, where they provide certificates of analysis for every one of their products. So go to Nordic.com, N-O-R-D-I-C, Nordic.com, and discover why Nordic Naturals is the number one selling omega-3 brand in the U.S.

• 2:41:26Tim Ferriss?

  And while you're there, use promo code TIM, T-I-M, for 20% off of your order. That's N-O-R-D-I-C.com and code TIM for 20% off of the fish oil with no fishy aftertaste. All upside, no downside. Try it out.

• 2:41:40Speaker 01

  These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.