Harvard Psychiatrist Treats Refractory Mental Illness via Ketogenic Diets

哈佛精神科医生利用生酮饮食治疗难治性精神疾病 限制碳水化合物摄入可通过恢复线粒体功能并诱导细胞修复通路，逆转严重精神症状。 Chris Palmer 医生分享了他通过低碳水化合物饮食逆转代谢综合征和慢性疲劳的亲身经历，这也促使他探索针对难治性精神障碍的饮食干预措施。讨论详细阐述了生酮饮食如何通过调节大脑化学机制、改善胰岛素敏感性，以及促进线粒体自噬与线粒体生物发生，来治疗从轻度焦虑到严重精神分裂症等多种疾病。此外，对话强调了线粒体作为细胞“主板”在协调神经传递、应激反应和炎症中的核心作用，并明确区分了轻度的日常保健饮食微调与医学监督下的代谢疗法。 长期营养、代谢健康与大脑功能之间存在直接且深层的因果关系。克里斯·帕尔默医生（Dr. Chris Palmer）通过采用阿特金斯低碳水饮食彻底逆转了自身的代谢综合征，并在情绪、日常精力、注意力和睡眠质量上获得了显著提升。 (0:20) 限制碳水化合物摄入可产生强效的抗抑郁作用，甚至对难治性严重精神疾病有效；临床观察显示，达到可测量的血酮水平通常是难治性精神疾病患者获得精神改善的关键。 (5:28) 针对不同程度的心理问题需采取差异化的饮食干预：戒断超加工食品足以改善轻度情绪困扰，而分裂情感性障碍、精神分裂症或双相情感障碍等重度病症则需要深度生酮治疗（血酮浓度 ≥ 1.5 mmol/L）。 (11:01) 生酮饮食最初于1921年在梅奥诊所（Mayo Clinic）开发，用于模拟禁食对癫痫的抗惊厥与代谢保护机制。该状态能调节谷氨酸、GABA及腺苷等关键神经递质，调控离子通道，降低神经炎症，并改善胰岛素敏感性。 (13:55) 线粒体是细胞统筹资源与信号传导的核心“母板”，深度参与神经递质合成、囊泡释放与类固醇激素生成。生酮和禁食能刺激线粒体自噬（mitophagy）以清除受损线粒体，从而提供了一种非药物途径来修复脑细胞代谢机能。 (19:54)

Dr. Chris Palmer argues that mental illnesses are fundamentally driven by metabolic and mitochondrial dysfunction rather than isolated chemical imbalances. Based on historical neurology and his clinical psychiatric practice, Palmer proposes that carbohydrate restriction and ketogenic protocols can structurally remodel brain metabolism to alleviate both subclinical symptoms and treatment-resistant psychiatric disorders. Mitochondria as Cellular Signaling Hubs (19:54) Dr. Palmer challenges the conventional view of mitochondria as passive cellular power plants, characterizing them instead as the cell's coordinating "motherboard." Beyond generating ATP, mitochondria actively direct resource allocation, govern cellular stress pathways, and regulate the synthesis, packaging, and release of primary neurotransmitters such as serotonin, dopamine, glutamate, and acetylcholine. intermediate metabolites from the citric acid cycle serve as precursor building blocks for these transmitters. Crucially, ATP alone is insufficient for synaptic signaling; imaging demonstrates that mitochondria must physically migrate to the presynaptic terminal to enable neurotransmitter vesicle exocytosis. Mitochondria also house key enzymes required to synthesize steroid hormones—including cortisol, estrogen, testosterone, and progesterone—while directing macrophage transitions during tissue repair and using reactive oxygen species signaling to extinguish inflammatory cascades. Neurological Roots in Epilepsy Management (13:55) The clinical use of ketosis originated within mainstream neurology rather than psychiatric dietetics. Building on ancient observations that fasting abruptly halted epileptic seizures, Dr. Russell Wilder developed the ketogenic diet at the Mayo Clinic in 1921 to simulate the biochemical state of fasting without caloric deprivation. Early trials showed that the diet eliminated seizures entirely in 50% of pediatric epilepsy patients and reduced seizure frequency by at least 50% in an additional 35%. Although the rise of anticonvulsant pharmaceuticals in the 1950s led clinicians to favor medication over strict diets, Johns Hopkins revived ketogenic protocols in the 1970s for treatment-resistant epilepsy. Approximately one-third of these refractory patients became seizure-free, and another third saw reductions of 50% or more. This clinical history yielded decades of neuroscience demonstrating that ketosis shifts central neurotransmitter balance (modulating GABA, glutamate, and adenosine), alters calcium channel dynamics, decreases neuroinflammation, and improves systemic insulin sensitivity. Psychiatric Remission and Ketone Thresholds (11:01) Applying metabolic interventions to treatment-resistant psychiatric patients, Dr. Palmer observed sustained clinical remissions after conventional therapies failed. In one pivotal 2016 case, a 33-year-old patient who had suffered from severe schizoaffective disorder for eight years—experiencing daily auditory hallucinations and paranoid delusions despite 17 failed psychiatric medications—achieved complete symptom remission and lost 60 pounds after adopting a ketogenic diet under medical supervision. Palmer emphasizes that therapeutic dietary requirements scale with clinical severity. While eliminating ultra-processed foods can stabilize glucose spikes and resolve mild mood symptoms, managing clinical depression typically requires mild-to-moderate ketosis with blood ketone levels of at least 0.8 mmol/L. Severe psychotic illnesses and bipolar disorder demand deep ketosis, targeting blood ketone concentrations of 1.5 mmol/L or higher to stimulate structural brain remodeling. Mitophagy and Graduated Carbohydrate Interventions (25:44) At the cellular level, fasting, caloric restriction, and ketogenic regimens stimulate autophagy and mitophagy—the targeted lysosomal breakdown and recycling of damaged cellular components and defective mitochondria. Because the body prioritizes degrading impaired organelles during nutrient deprivation, this clearance process stimulates mitochondrial biogenesis, replacing dysfunctional structures with healthy mitochondria and counteracting pathways tied to metabolic decline and aging. For general subclinical concerns such as burnout, chronic fatigue, or anxiety, Dr. Palmer notes that moderate carbohydrate restriction often relieves symptoms within weeks without requiring deep ketosis. However, he warns that severe psychiatric disorders such as schizophrenia or bipolar disorder require strict clinical supervision. Dietary metabolic shifts alter psychiatric medication metabolism and physiological baselines, necessitating careful medical adjustments rather than self-directed interventions. While large-scale randomized controlled trials evaluating ketogenic diets for psychiatric care are still underway, Dr. Palmer stresses that metabolic therapy should be integrated as a mainstream biological tool alongside conventional psychiatry rather than positioned as an alternative lifestyle trend.

哈佛医学院精神病学助理教授克里斯·帕尔默（Dr. Chris Palmer）指出，精神疾病与代谢功能障碍之间存在深层因果关联；通过生酮饮食等代谢干预手段改善线粒体健康，能够有效缓解乃至逆转包括难治性精神分裂症和抑郁症在内的严重精神疾患。 个人病史启示与难治性精神病突破 (0:00) 帕尔默博士在20多岁担任哈佛住院医师期间，曾严格遵循低脂饮食与规律运动的标准医疗建议，却仍患上代谢综合征，并面临终身服用降压、降脂和降糖药物的前景。为了避免长期服药，他尝试了阿特金斯低碳水饮食，在三个月内彻底逆转了代谢综合征，同时发现自身长期的慢性疲劳和情绪低落显著改善，晨间精力得到重塑。这一经历促使他认识到自身疲劳具有生物代谢根源，并开始探寻饮食对大脑神经的调控作用。 在后续的临床实践中，帕尔默开始尝试将低碳水化合物及生酮饮食应用于对药物、长期心理治疗乃至电休克疗法（ECT）均无效的难治性患者。2016年，一名患有精神分裂情感性障碍长达八年、尝试过17种精神科药物且体重达340磅的33岁男性患者，在严格执行生酮饮食两周后即出现情绪好转，并在六至八周内使每日出现的幻听和被害妄想完全缓解。该患者最终减重60磅，实现了独立生活并在严密医学监测下逐步递减了精神科药物。 抗癫痫历史沿革与精神分级干预 (11:01) 帕尔默指出，利用生酮状态治疗神经系统疾病拥有上百年的神经医学历史。自古希腊希波克拉底时代起，医学界便发现禁食能遏制癫痫发作。1921年梅奥诊所的拉塞尔·怀尔德博士（Dr. Russell Wilder）设计出生酮饮食，以在不剥夺患者必需热量的前提下模拟禁食的生化状态。早期数据显示，该疗法使50%的儿童癫痫患者完全停止发作，另有35%的患者发作频率降低50%以上；20世纪70年代约翰斯·霍普金斯大学重启该疗法时，同样在难治性癫痫中记录到约三分之一完全无发作、三分之一发作显著减半的治疗反应。 基于这些临床与神经科学基础，帕尔默提出了根据精神状况严重程度分级实施营养干预的框架。对于亚临床的日常疲倦或轻微情绪波动，仅需戒除高糖高脂结合的超加工食品、降低葡萄糖与胰岛素峰值即可带来明显改善；针对抑郁症，他建议将血酮体浓度维持在0.8 mmol/L以上以调节神经递质；而面对精神分裂症、双相情感障碍等重度精神疾病，则需要达到1.5 mmol/L以上的深度生酮状态，以推动大脑深层的代谢与结构重塑。 线粒体：细胞“主板”与神经递质中枢 (19:54) 针对传统生物学教材将线粒体仅视为单纯生产ATP的“细胞能量工厂”或“电源线”的看法，帕尔默提出线粒体实则是细胞的“主板”。线粒体主动负责分配资源、调控复杂的细胞内信号传导，并直接参与血清素、多巴胺、谷氨酸和乙酰胆碱等核心神经递质的合成、包装与释放过程。研究表明，线粒体必须物理性地迁移至突触前膜以驱动囊泡胞吐作用，若从突触中移除线粒体，单纯补充外源性ATP并不能恢复正常的突触传递。 此外，线粒体还主导着多项关键生理轴线：其三羧酸循环的中间代谢产物为神经递质提供基础前体；线粒体内含有合成皮质醇、雌激素、睾酮和孕酮等类固醇激素的关键酶；它们深度参与皮质醇与肾上腺素的应激反应系统，并通过活性氧（ROS）信号指导巨噬细胞阶段转换以关闭炎症反应。帕尔默认为，线粒体功能障碍将神经递质失衡、内分泌紊乱、表观遗传变化及慢性神经炎症等零散的精神病学研究领域统一到了代谢机理之下。 线粒体自噬机制与严格医疗监护界限 (25:44) 生酮饮食与禁食带来的神经获益，很大程度上依赖于细胞自噬及特定降解受损线粒体的“线粒体自噬”（Mitophagy）。在热量限制或营养匮乏状态下，机体能够精准识别老旧、受损的线粒体等细胞器，将其送往溶酶体降解回收为基础构件，随后启动线粒体生物发生（Biogenesis）以构建健康的新线粒体。该机制能显著降低神经炎症、调控钙离子通道、改善胰岛素抵抗并重塑肠道菌群，从而修复大脑神经网络的代谢灵活性。 尽管对于普通人群因轻度焦虑或职业倦怠进行的低碳水调整（如仅限制碳水化合物摄入即可在数周内明显缓解焦虑）可以自行探索，但帕尔默严正警告：针对重度抑郁症、双相情感障碍及精神分裂症等重大精神疾病，代谢干预绝对不可盲目自行实施。深度的代谢转变会直接改变精神药物的代谢速率和生理基准，极易诱发躁狂或药物中毒风险，必须由专业医疗团队在严密监测下协同调整用药和实施饮食治疗。 帕尔默强调，营养与代谢干预并非替代常规精神病学的“伪科学”，而是基于神经生物学机制的主流干预工具。尽管其背后的生物学通路已在癫痫领域积累了长期证据，但针对精神分裂症等重大精神疾患的大规模随机对照临床试验（RCT）目前仍在进行中；患者在面对重大精神疾病时，必须在严密的医疗监护下将其作为综合治疗方案的一部分推进。

[25:44] Chris Palmer: When your body senses that you don't have enough food, it actually hunkers down and starts to recycle dead old parts in this kind of carefully orchestrated way... The body doesn't just destroy the healthiest tissue along with the old dead stuff. It has these processes that identify the old and defective parts first. [30:51] Chris Palmer: If you're using it to treat a serious disorder, I think you need serious help... weight loss, everybody wings it and either you're successful or you aren't... If you're using it to treat a serious disorder, I think you need serious help.

[0:00] Welcome to Huberman Lab Essentials, [0:02] where we revisit past episodes for the [0:04] most potent and actionable science-based [0:06] tools for mental health, physical [0:08] health, and performance. [0:11] I'm Andrew Huberman and I'm a professor [0:13] of neurobiology and opthalmology at [0:16] Stamford School of Medicine. And now for [0:18] my discussion with Dr. Chris Palmer. [0:21] Chris, Dr. Palmer, thank you for being [0:23] here. [0:23] >> Thank you, Andrew, for having me. I have [0:25] a lot of questions for you and I'm [0:27] really excited about this topic because [0:28] I think most people know what mental [0:32] illness is or they have some idea what [0:33] that is. Most people have some idea what [0:35] nutrition is. Fewer people certainly [0:38] know how closely those things can [0:42] interact. I think everybody is familiar [0:45] with the feeling of a food or the [0:48] ingestion of a food making them feel [0:50] good in the short term. But I believe [0:53] that very few people understand or are [0:56] familiar with the fact that nutrition [0:59] and our mental health interact in this [1:02] very intimate, maybe even causal way. [1:05] And that is something that occurs over [1:07] long periods of time. Meaning what I ate [1:09] yesterday, the day before, maybe even 10 [1:11] years ago could be impacting the way [1:13] that my brain and body are making me [1:15] feel now. So, if you would, I'd love for [1:18] you to just tell us about a little bit [1:20] of the the history, in particular, your [1:22] history with exploring the relationship [1:24] between nutrition and mental health. And [1:27] then we can dive into some of the um [1:29] more particulars of ketogenic diets [1:32] versus other diets and some of the truly [1:34] miraculous findings that you and others [1:37] are coming up with based on real [1:40] patients and real experiences of people [1:42] who suffer and then find relief by [1:44] altering their nutrition. Sure. This [1:47] story really starts with my own personal [1:49] story. I don't need to go into great [1:51] detail, but to set the stage, when I was [1:53] a kid, I definitely had mental illness. [1:57] Started with OCD. I went on to have [2:00] subsequent depression, suicidality, all [2:03] sorts of things. Somehow or another, I [2:05] pulled myself together and got through [2:07] medical school. Actually did quite well [2:09] in medical school and then was doing my [2:12] internship in residency at Harvard. And [2:14] at that point in time, I was diagnosed [2:17] with metabolic syndrome. So, uh, had [2:20] high blood pressure, horrible lipids, [2:23] uh, and pre-diabetes. And I was doing [2:26] everything right. Supposedly, I was on a [2:28] low-fat diet, and I was exercising [2:31] regularly. And year after year, my [2:33] doctor kept telling me diet and [2:35] exercise. I was doing everything he kept [2:37] telling me to do. Everything was getting [2:39] worse. My blood pressure kept going [2:41] higher. And at some point he said, [2:43] "You're going to have to go on [2:44] medication for your pre-diabetes, [2:46] something for your cholesterol, and [2:48] something for your blood pressure." So, [2:50] three pills, basically, you're screwed. [2:52] It's your genes. You're just going to [2:54] have to bite the bullet and take meds. [2:56] As a physician, I knew what that meant. [2:59] I knew that I'm in my 20s. If I'm [3:01] already on three meds for metabolic [3:04] syndrome, I'm going to be screwed by the [3:06] time I'm 40 or 50, and I'm probably [3:08] going to be having heart attacks. I'd [3:10] heard through the rumor mill that the [3:12] Atkins diet could somehow help people [3:17] improve their cholesterol and [3:18] pre-diabetes. I was highly skeptical and [3:21] I, you know, I believed everything I was [3:23] taught in medical school. Why would why [3:26] would my professors lie to me that they [3:28] knew what they were talking about? [3:29] Low-fat diet was the thing to do. Um, [3:32] and the Atkins diet was clearly [3:34] dangerous and reckless. And I had been [3:36] trying the medical dogma for years and [3:39] it wasn't working for me. And so for [3:41] whatever reason, I decided this is going [3:43] to be my last attempt at at something [3:47] different and then I'll just bite the [3:49] bullet and go on meds. So I tried the [3:51] Atkins diet. Within 3 months, my [3:54] metabolic syndrome was completely gone. [3:56] I probably lost about, you know, 10 [3:58] pounds through this process. But [4:01] everything got normal. And when I went [4:03] back to my doctor, he was shocked. The [4:05] thing that was the most striking to me [4:08] after doing the diet for 3 months was [4:11] not the fact that my metabolic syndrome [4:13] was gone. That was my goal. And it was [4:16] a, you know, seemingly miraculous [4:19] uh achievement because I got rid of [4:21] everything with one dietary change. But [4:25] the thing that I noticed was dramatic [4:27] improvement in my mood, energy, [4:30] concentration, and sleep. For the first [4:33] time in my life, I started waking up [4:35] before my alarm went off and feeling [4:37] rested. That never happened to me [4:40] before. I was meticulous about planning [4:43] when my alarm went off and how many [4:45] times I could push the snooze button in [4:48] order to be on time for wherever I [4:51] needed to be, whether it was school or [4:53] the hospital or whatever. Prior to the [4:56] diet, I always felt like there are two [4:58] types of people in the world. There are [4:59] these happy, peppy people who just are [5:02] so positive and they've got energy and [5:05] they have these this saying, they like [5:07] to work hard and play hard. But I never [5:10] understood who the hell wants to play [5:13] hard. Like who's got energy for that? [5:15] Like aren't you tired from working so [5:17] hard? I assumed that they were just [5:19] lucky and privileged. They either had [5:22] good genetics or maybe they had good [5:24] childhoods or good parents or something [5:27] something that I didn't have. [5:28] >> What was the journey forward into the [5:31] work that you're doing now? [5:32] >> So within a few years I'm you know an [5:36] attending physician. I've got all these [5:38] patients in my clinical practice with [5:40] treatment resistant mental illness. I'm [5:41] in a tertiary care hospital. So, I [5:44] almost never get somebody off the street [5:47] with their first episode of depression. [5:50] Out of the gate as part of my career, I [5:52] get treatment resistant mental [5:54] disorders. So, I get people who've [5:56] already been to six plus psychiatrists, [5:58] therapists. They've usually tried dozens [6:01] of different medications. They've been [6:03] in decades of psychotherapy. They've [6:05] often had ECT and other things and [6:08] nothing's working. And I'm thinking, you [6:11] know, well, we're kind of out of options [6:12] for these other people and this diet is [6:15] having this really powerful [6:16] anti-depressant effect. I think I'm [6:18] going to try it and just see if any of [6:20] my patients are game to try it to see if [6:22] it might help them. Sure enough, it did. [6:26] didn't help everyone and not everybody [6:28] was interested and or able to do it. But [6:31] some of the ones who were able to do it [6:33] ended up having a remarkable and [6:36] powerful anti-depressant effect. One [6:38] woman actually became hypomomanic within [6:40] a month. And she had been depressed [6:43] pretty much nonstop for over 5 years, [6:46] chronically depressed, suicidal, in and [6:48] out of hospitals. And I saw her become [6:51] hypomomanic. And I'm thinking, wow, this [6:52] really is a powerful anti-depressant [6:54] effect. like this is amazing. This is [6:57] like a medication but better because it [7:00] actually is working for her. At that [7:02] point, we didn't have many clinical [7:04] trials of the safety or efficacy of the [7:07] Atkins diet for even weight loss or [7:10] diabetes, let alone any mental [7:12] disorders. And so, I really actually [7:14] felt like I'm on the fringe here and [7:16] this is not going to be met with with [7:19] praise by anyone. So, I'm just going to [7:22] lay low. I'm going to offer it to [7:24] patients and uh and I I went along that [7:28] way up until [7:31] 2016. [7:32] >> So, low carbohydrate diet, certainly low [7:34] sugar. [7:35] >> Yeah. [7:35] >> I'm assuming you're not a nutritionist. [7:37] So, how did you prescribe a nutrition [7:40] plan for your patients? [7:42] >> The first few patients it was try this [7:44] Atkins diet. I want to see ketosis. So, [7:47] I was strongly recommending that [7:49] patients achieve urinary ketosis. And [7:53] the interesting thing is I noticed a [7:55] pattern that when they were trying the [7:57] diet and not getting ketones, they often [8:00] did not get a clinical benefit. It was [8:02] once they got into ketosis that I began [8:04] to notice the clinical benefit. The [8:06] thing that completely upended everything [8:09] that I knew as a psychiatrist though was [8:11] when I helped the patient in 2016, [8:14] 33-year-old man with schizoeffective [8:16] disorder. He had been my patient for 8 [8:18] years now. He had daily auditory [8:21] hallucinations. He had paranoid [8:22] delusions. He could not go out in public [8:25] without being terrified. This man was [8:28] tormented by his illness. It ruined his [8:31] life. He had already tried 17 different [8:33] medications and none of them stopped his [8:36] symptoms. He weighs 340 lbs and for [8:39] whatever reason he gets it in his head. [8:41] I'm never going to get a girlfriend if I [8:43] don't lose some weight. He also [8:45] recognizes I'm never going to get a [8:47] girlfriend cuz I'm a loser. I'm [8:48] schizophrenic. I live with my father. I, [8:51] you know, I have nothing going for me. [8:53] For a variety of reasons, we ended up [8:54] deciding to try the ketogenic diet. He [8:57] decides to give it a try. Within two [8:59] weeks, not only does he start losing [9:01] weight, but I begin to notice this [9:03] dramatic anti-depressant effect. He's [9:06] making better eye contact. He's smiling [9:08] more. He's talking a lot more. I'm [9:11] thinking like, what's gotten into you? [9:12] Like, you're coming to life. Like, [9:13] you're I've never heard you talk this [9:15] much. I've never seen you so excited or [9:19] present or alive. I haven't changed his [9:21] meds at all. The thing that upended [9:25] everything that I knew as a psychiatrist [9:27] was 6 to 8 weeks in, he spontaneously [9:30] starts reporting, you know those voices [9:32] that I hear all the time, they're going [9:34] away. And he says, you know, you know [9:37] how I always thought that there were all [9:38] these families who were controlling my [9:40] thoughts and out to get me and they had [9:42] targeted me. And I'm thinking, oh yeah, [9:45] we've been talking about that for years. [9:46] We could talk about that again. He says, [9:48] now that I think about it, I don't think [9:50] that's true. [9:52] And now that I say it, it sounds kind of [9:53] crazy. It probably never was. I've [9:56] probably had schizophrenia all along [9:58] like everybody's been trying to tell me, [10:00] and I think it's going away. He's now [10:03] lost60 pounds and kept it off to this [10:05] day. [10:06] >> Wow. [10:06] >> He was able to do things he had not been [10:09] able to do since the time of his [10:10] diagnosis. He was able to complete a [10:12] certificate program. He's able to go out [10:14] in public and not be paranoid. He [10:16] performed improv in front of a live [10:18] audience. At one point he was able to [10:22] move out of his father's home and live [10:24] independently. [10:25] >> Did he stay on any kind of antiscychotic [10:28] or other medication? [10:29] >> We have slowly but surely tried to taper [10:31] him off his meds. He has been on meds [10:34] for decades. He started medications when [10:37] he was a young child. His brain is [10:41] developed in response to all sorts of [10:45] psychiatric medications. And it has not [10:47] been easy to try to get him off. And I [10:49] just want to say for any listeners, [10:51] getting off your meds is very difficult [10:53] and dangerous and you need to do it with [10:56] supervision with a a mental health [10:59] professional or a prescriber to stay in [11:02] ketosis. Uh what sort of blood levels of [11:05] ketones do you like to see in your [11:07] patients? Uh what is the range that you [11:10] think most people could uh aspire to? [11:12] >> So it really depends on the patient and [11:15] what I'm treating quite honestly. And I [11:17] don't think every patient needs the [11:18] ketogenic diet. For some patients, [11:20] simply getting rid of junk food can make [11:22] a huge difference in a mood disorder, [11:24] for instance. [11:25] >> So, a junk food meaning highly processed [11:27] food, food that could last on the shelf [11:29] a very long time. [11:30] >> Highly processed foods that are usually [11:32] high in both sugar, carbohydrate, and [11:36] carbs and fats. Those seem to be the [11:40] worst foods. that combination, high [11:43] sugar, high fat, um, seems to be the [11:47] worst combination for metabolic health [11:50] and lo and behold, we've got emerging [11:52] data that suggests that strongly [11:54] suggests it's also bad for mental [11:56] health. So to step back from that, so [11:58] for some patients, I might just want to [12:01] decrease glucose and insulin levels and [12:03] I can do that by getting rid of sweets. [12:05] for other patients like patients with [12:07] schizopeeffective disorder or [12:09] schizophrenia or bipolar disorder [12:10] especially if it's chronic if I'm using [12:13] it as a brain treatment then I do want a [12:16] ketogenic diet and I usually want [12:19] reasonably high levels of blood ketones [12:22] for depression I want to see at least [12:24] greater than probably 0.8 8 mill mole. [12:27] For psychotic disorders and bipolar [12:29] disorder, I usually want to see levels [12:32] greater than 1.5. That's what I'm [12:35] shooting for if at all possible. I think [12:37] that for a lot of listeners and people [12:41] out there who are familiar with how [12:44] changing your diet or changing your [12:46] exercise can positively impact sleep and [12:48] weight and all these things and it [12:50] cascades into feeling better. That makes [12:52] perfect sense. But for a lot of the [12:54] world still, [12:56] the idea that changing or using [12:58] nutrition as a dissection tool or as a [13:03] treatment tool to understand and treat [13:05] mental illness is still a kind of [13:08] heretical idea that to them it kind of [13:10] falls in the okay well that's like a woo [13:13] science or something like that. They [13:15] immediately think, "Didn't Atkins die of [13:17] a heart attack?" You know, I hear that a [13:19] lot, you know, which I do think is [13:20] throwing the baby out with the bath [13:21] water, but it's an interesting thing [13:23] nonetheless. And then I think that the [13:24] majority of people sit in the middle and [13:27] just want to see science and medicine [13:29] come up with treatments that work. And I [13:31] have to say I'm very uh relieved to hear [13:34] what you said earlier, which was you [13:35] never said that people should come off [13:37] their medication and just become go on a [13:39] ketogenic diet and everything will be [13:40] cured. You're certainly not saying that. [13:42] >> No. and rather you're saying if I [13:46] understand correctly that nutrition [13:48] needs to be considered one of the major [13:50] tools in the landscape of effective [13:52] tools and that it can be very effective. [13:54] Let's talk about epilepsy and how the [13:56] ketogenic diet is not just used for [13:59] epilepsy but is one of the oldest if not [14:02] the oldest examples of the use of [14:05] nutrition to treat a condition of the [14:08] nervous system that can be incredibly [14:10] debilitating even deadly. [14:11] >> Yeah. The reality is that this [14:13] literature and this clinical history and [14:16] all of the research we have was the [14:18] godsend that I needed to do the work [14:21] that I'm doing. Otherwise, I would have [14:23] been discredited on day one. The [14:25] ketogenic diet, unbeknownst to most [14:28] people, was actually developed a 100 [14:30] years ago 1921 [14:33] by a physician for one and only one [14:36] purpose, to treat epilepsy. It wasn't [14:39] developed as a weight loss diet. It [14:41] wasn't developed as the the diet that [14:43] all human beings should follow. And the [14:45] reason it was developed is because of [14:47] this long-standing observation since the [14:51] time of Hypocrates [14:53] that fasting can stop seizures. Most [14:56] people think going without food is bad [15:00] and they equate it with starvation. But [15:03] in fact when we go without food it [15:06] causes tremendous shifts in metabolism [15:09] both brain and body metabolism [15:12] and it puts the body into a mode of [15:16] autophagy and conservation of resources [15:18] and all sorts of things that are [15:20] beneficial to human health. And this is [15:23] why fasting has been used as a [15:25] therapeutic intervention in almost every [15:27] culture and almost every religion for [15:30] millennia. But for the most part, that [15:31] was all thought to be religious [15:33] folklore. In 1921, [15:36] one physician used intermittent fasting [15:39] on a child with seizures and found that, [15:41] oh, lo and behold, this religious [15:43] folklore stuff has something to it. It [15:45] actually worked. The problem with [15:47] fasting is that you can only fast for so [15:49] long before you starve to death. And [15:50] that's not a very effective treatment. [15:52] As soon as people start eating a normal [15:54] diet again, their seizures usually come [15:56] right back, often times with a [15:57] vengeance. And so it can be a good [15:59] short-term intervention. The fasting can [16:01] take a few days because it can take a [16:03] few days to get ketosis and then you can [16:05] get some relief from chronic seizures, [16:08] but it's not a good long-term treatment [16:11] because again, people will starve to [16:13] death. As soon as they start eating, [16:15] seizures come back. So it was actually [16:18] Dr. Russell Wilder at the Mayo Clinic [16:20] who developed the ketogenic diet with [16:23] one and only one purpose. He wanted to [16:25] see, can we mimic the fasting state [16:29] using this special diet to see if it [16:33] might stop seizures long term? And lo [16:36] and behold, it worked. Early results [16:39] were extraordinarily positive. 50% of [16:41] patients who used the ketogenic diet [16:44] became seizure-free and another 35% had [16:48] a 50% or greater reduction in their [16:50] seizure frequency. So about 85% efficacy [16:53] rate. By the 1950s, [16:56] pharmaceuticals were coming out and we [16:58] had many more anti-vulsant treatments [17:00] and there's no question they work for a [17:03] lot of people. That's great. And taking [17:06] a pill is so much easier than doing this [17:08] diet. But lo and behold, even to this [17:11] day, people with epilepsy, about 30% [17:14] don't respond to the current treatments [17:16] that we have available. 30% will have [17:19] treatment resistant epilepsy, which [17:21] means they continue to have seizures no [17:23] matter how many anti-combulsants they're [17:25] taking, even if they've had brain [17:27] surgery. It just doesn't stop their [17:29] seizures. And so, in the 1970s, the [17:31] ketogenic diet was resurrected at John's [17:33] Hopkins for these treatment resistant [17:36] cases. And lo and behold, it works. Not [17:39] for all of them, but it works. And about [17:42] onethird become seizure free. And these [17:44] are people who've tried everything and [17:46] nothing's working. So one/3 becomes [17:48] seizure-free, another third get a [17:50] clinical benefit, meaning a 50% or [17:52] greater reduction in their seizure [17:53] frequency and the other third it doesn't [17:56] seem to work. And so the reality, the [17:58] godsend for me is that we have decades [18:00] of neuroscience research on the [18:02] ketogenic diet and what it is doing to [18:04] the brain. We know that the ketogenic [18:07] diet is influencing neurotransmitter [18:09] levels in particular glutamate, GABA, [18:12] adenosine. It changes calcium channel [18:15] regulation uh and calcium levels which [18:17] is really important in the function of [18:19] cells. It changes gene expression. It [18:22] reduces brain inflammation. It changes [18:25] the gut microbiome. And there are, you [18:27] know, gut microbiome is a huge topic [18:28] right now. And there are some [18:29] researchers who argue that is the [18:31] primary benefit of the ketogenic diet. [18:33] It's changing the gut microbiome in [18:35] beneficial ways. Um so it's doing a lot [18:38] of things. It obviously improves insulin [18:41] resistance. uh it lowers glucose levels, [18:44] lowers insulin levels, which improves [18:46] insulin signaling. The key for [18:50] my research that I've outlined, [18:54] the real magic is that this diet [18:57] stimulates two processes that relate to [19:00] mitochondria. It stimulates a process [19:03] called mphagy, [19:04] which is getting rid of old and [19:06] defective mitochondria and replacing [19:08] them with new ones. And it also [19:10] stimulates a process called [19:12] mitochondrial biogenesis. [19:14] Which means that after people have done [19:16] the ketogenic diet for a while, months [19:19] or years, many of their cells in their [19:23] bodies and brains will have more [19:26] mitochondria and those mitochondria will [19:29] be healthier. And I believe that is the [19:33] reason the ketogenic diet is such a [19:36] powerful treatment not only for epilepsy [19:39] but also for people with chronic mental [19:41] disorders. If you're looking for [19:42] randomized controlled trials documenting [19:45] efficacy in large numbers of patients [19:48] with these disorders, we don't have [19:50] them. They're underway now, but we don't [19:53] have them yet. Maybe we could just talk [19:55] about mitochondria for a moment and then [19:57] talk about these two major effects. What [19:59] are some of the other things that [20:00] mitochondria are important for uh in [20:03] neurons and um and maybe other cells of [20:05] the brain? [20:06] >> If you think of the cell as a computer, [20:09] a lot of people think of mitochondria as [20:11] the power cord to that computer because [20:13] they're providing the power and they are [20:15] in fact the power cord to that computer. [20:17] But actually their real function is the [20:19] motherboard of that computer. So [20:21] mitochondria are directing and [20:23] allocating resources throughout a cell. [20:26] that is their primary function and then [20:28] they happen to be powerhouses as well. [20:31] To give some clear examples, [20:32] mitochondria play a direct role in the [20:35] production and release and regulation of [20:39] some really key neurotransmitters [20:41] including serotonin, dopamine, [20:44] glutamate, ailchine. [20:47] Those are pretty powerful [20:48] neurotransmitters. Yeah, I would call [20:50] those I would consider those the I know [20:51] you listed more than three, but uh the [20:54] sort of primary colors of [20:55] neurotransmission, [20:57] you know, any one of those [20:59] >> in excess or deficiency is going to have [21:02] profound negative effects on a nervous [21:04] system. [21:04] >> Mitochondria are providing both some of [21:07] the building blocks, if you will, for [21:10] some of those molecules. They're part of [21:12] the KB citric acid cycle. some of the [21:15] some of the intermediate products [21:17] actually go into making those [21:19] neurotransmitters. Much more [21:20] importantly, mitochondria provide the [21:23] energy for the production of those [21:24] neurotransmitters. And fascinatingly, [21:28] mitochondria are directly related to the [21:30] release of neurotransmitters. [21:33] ATP alone is not enough. There have been [21:36] some research studies that have actually [21:38] found that mitochondria move along the [21:42] membrane of the syninnapse to release [21:46] batches of vesicles of [21:48] neurotransmitters. [21:50] And that if the mitochondria are removed [21:52] from the syninnapse and researchers [21:54] flood that cell with ATP, [21:58] neurotransmitters usually are not [22:00] getting released. Mitochondria are doing [22:04] other things. We don't entirely even [22:06] understand what all they're doing or how [22:08] they're doing it, but they're doing [22:11] other things than just providing the [22:13] power. Mitochondria at least play a role [22:17] in all of the aspects of the human [22:20] stress response. So, um when humans are [22:23] stressed either physically or [22:24] psychologically, [22:26] there are several things that happen. [22:28] increased cortisol, increased [22:30] adrenaline, nor adrenaline, uh [22:33] inflammation and gene expression in [22:35] particular in the hippocampus occur with [22:38] the stress response. And one group of [22:41] researchers actually genetically [22:42] modified mitochondria in four different [22:44] ways and found that all those four [22:46] buckets of stress response were impacted [22:49] in one way or another, [22:52] implying that mitochondria are somehow [22:54] playing a role in those. In terms of it, [22:58] their role in cortisol, we know that [23:01] mitochondria actually have the enzyme [23:03] required for the synthesis of steroid [23:06] hormones. So that includes cortisol, [23:10] estrogen, testosterone, and [23:11] progesterone. Some names that maybe [23:13] everybody's heard of. So that means that [23:16] if mitochondria [23:18] are in short supply or dysfunctional, [23:21] the production of those hormones may [23:24] become disregulated. [23:27] Mitochondria play a direct role in [23:30] inflammation and they turn the [23:33] inflammatory [23:35] system both on or they at least play a [23:38] role in turning the inflammatory system [23:40] both on and off. One paper in cell [23:43] actually identified mitochondria as the [23:46] key regulator in turning certain [23:48] inflammatory cells off and that when you [23:51] inhibit mitochondrial function those [23:53] cells don't turn off. That mitochondrial [23:56] levels of reactive oxygen species are a [23:58] key signaling process to turn the [24:02] inflammatory cell process off. Another [24:06] study found that macrofasages so [24:08] macrofasages are an important immune [24:10] cell that play a role in healing. So if [24:13] you cut yourself your your body will get [24:16] you know send inflammation that way and [24:19] uh and send immune cells that way to try [24:22] to heal your skin and macrofasages play [24:25] an important role in that healing. One [24:27] group of researchers tried to figure out [24:30] how do macrofasages know to switch [24:33] between the different phases of wound [24:35] healing because the macrofasages do [24:37] different things in the different phases [24:39] of wound healing. And the conclusion of [24:42] all of their research was that it's [24:44] mitochondria. Mitochondria are sending [24:47] the essential signals that change the [24:50] state of the macrofasages to induce [24:54] these different phases of wound healing. [24:56] So, I've just talked about [24:58] neurotransmitters, hormones, epigenetic [25:01] expression, inflammation. [25:04] For anybody familiar with the mental [25:05] health field, [25:07] they know these are like some of the key [25:12] variables that researchers have been [25:14] struggling with for decades trying to [25:16] figure out how do these fit together. We [25:19] know that all of the those buckets [25:22] can be disrupted in people with mental [25:26] disorders and our field has struggled to [25:29] understand but how do they fit together? [25:31] How can we make sense of this [25:33] disruption? I believe once you [25:36] understand the science of mitochondria, [25:40] you can actually connect all of the dots [25:43] of the mental illness puzzle. What I'm [25:45] hearing is that mitochondria in addition [25:49] to being important sources of energy [25:51] production and output in cells which of [25:54] course they are um probably have other [25:58] roles and that maybe maybe someday what [26:01] we call mitochondria will actually be [26:03] two or three different little subscellar [26:05] organel in the landscape of science [26:07] education. Uh often times people think [26:09] okay energy production there'll be a [26:11] picture or a cartoon of mitochondria [26:12] like flexing its muscles. People go okay [26:14] energy mitochondria mighty mitochondria [26:16] and then they'll think oh you know [26:17] they're just sort of like a dumb jock [26:19] portion of the cell right they're not [26:21] doing anything sophisticated and [26:23] everything you listed off is that they [26:24] are doing many sophisticated intricate [26:28] things within cells so now that um [26:30] everyone is well aware that mitochondria [26:33] are doing a large number of very [26:35] important things in a very regulated way [26:38] let's talk about mphagy which I have to [26:40] presume is the um intention [26:44] or not gobbling up of mitochondria [26:47] presumably to replace them with newer [26:49] healthier mitochondria. Is that right? [26:50] >> It is. So in and in many ways mphagy is [26:53] a subset of autophagy but it's got its [26:57] own name because it is specific to [26:58] mitochondria. [27:00] There do appear to be [27:03] some unique regulators of mphagy [27:06] compared to autophagy more broadly. [27:09] mitochondria actually are playing a a [27:11] role in autophagy itself. Um, and this [27:15] makes sense because one of so the global [27:18] picture of autophagy is stimulated by [27:21] fasting states or fasting mimicking [27:24] states. So when your body senses that [27:28] you don't have enough food, it actually [27:32] hunkers down and starts to recycle [27:38] dead old parts in this kind of carefully [27:41] orchestrated way and it takes them to [27:44] loos. They get degraded and then those [27:48] degradation products get used for either [27:51] energy or to build new things. Autophagy [27:54] is always occurring [27:56] um at a low level, but you can really [27:59] hyper stimulate the process through [28:01] fasting, calorie restriction, fasting [28:04] mimicking diets, other things. And this [28:06] is why fasting and fast, you know, [28:08] calorie restriction is so kind of such [28:10] hot topics in the medical field now is [28:13] because we they've been shown to induce [28:15] longevity and we think it's probably [28:18] through that process that you're you're [28:20] stimulating the body to become lean and [28:25] conservative in terms of its allocation [28:27] of resources. [28:30] And the body doesn't just destroy the [28:32] healthiest tissue along with the old [28:34] dead stuff. It has these processes that [28:37] identify the old and defective parts [28:39] first and they go first and that's [28:41] what's beautiful about the whole thing [28:43] and that's why fasting is so important. [28:46] So mphagy we know plays a really [28:49] important role because there's this term [28:52] called mitochondrial dysfunction which [28:54] some researchers are actually wanting to [28:56] get rid of and move away from because as [28:58] you just said mitochondria do so many [29:00] different things and different [29:02] mitochondria even within the same cell [29:04] may very well be specializing in [29:05] different tasks and mitochondria from [29:07] one cell to another are sometimes doing [29:09] very different things like not all [29:11] mitochondria can produce cortisol that's [29:14] specific to specific cells [29:16] where those genes are getting turned on. [29:18] So it's not like all mitochondria are [29:20] producing cortisol. Just the ones in [29:22] your adrenal gland, for instance, are [29:24] producing cortisol. And it has long been [29:28] known for decades [29:30] that mitochondrial dysfunction is [29:33] associated with everything that ails us [29:36] essentially. So David Sinclair [29:40] uh published a p paper in one of the [29:42] cell journals I think saying that oh [29:44] mitochondria are actually the unifying [29:47] link of everything that we know about [29:48] aging. Defective mitochondria or [29:51] defective mitochondrial function [29:53] mitochondrial dysfunction is possibly [29:56] the unifying cause of aging in all of [29:59] the aging related disorders. So mphagy [30:04] is trying to address all that is trying [30:06] to say okay this is bad we don't want [30:08] defective mitochondria and how can we [30:11] get rid of old ones or defective ones [30:13] and and replace them with new ones and I [30:17] think the most powerful signal [30:20] and tool that we have right now is in [30:24] fact related to diet it's calorie [30:27] restriction that is the oldest truest [30:30] best proven way to prevent aging in a [30:34] wide variety of animal species. [30:37] Fasting and intermittent fasting and [30:40] again you can only do those things for [30:42] so long and then fasting mimicking diets [30:46] um can also stimulate this process of [30:49] mphagy. [30:51] So what about the the typical person [30:53] who's an omnivore eating um you know [30:56] some rice, some pasta? Do you think that [30:59] those people might feel far better or [31:02] even a little bit better if they were in [31:05] a lower glucose state? I asked this [31:08] because I think there are a lot of [31:09] people out there who suffer from [31:10] full-blown depression, but there are [31:12] also a lot of people who suffer from [31:14] like moodiness and feeling not so great. [31:17] Subclinical depression. [31:18] >> Yes. Burnout is what I would call it. [31:20] >> Yeah. And and just feeling like some [31:22] days are great and then other days they [31:23] feel lousy for reasons they don't [31:25] understand. I kind of break this field [31:28] and I'm probably getting too nerdy right [31:30] now, but I kind of break this field into [31:32] cause. What's the actual root cause and [31:36] what are effective treatments? And I [31:38] really see them as two separate things. [31:41] Calorie restriction, ketogenic diet, [31:44] carbohydrate restriction [31:47] are inducing metabolic changes in the [31:50] brain and body. [31:52] And regardless of what the person was [31:55] eating, [31:57] they are inducing metabolic changes that [31:59] can be really beneficial to brain [32:01] health. So going to your broader [32:03] question about adults modern day, if [32:06] it's an average person who is not [32:09] currently under psychiatric care, not [32:12] taking prescription medicines, but is [32:14] saying, "I'm burned out. I'm exhausted. [32:17] I want some of that brain energy that [32:19] Andrew Huberman's talking about. I I he [32:22] he talks about feeling good. I want some [32:23] of that. I'm probably actually going to [32:25] recommend let's see if we can just carb [32:27] restrict for a while. Um and see if that [32:30] produces clinical benefit. I have one, [32:33] he's not even a patient, just a somebody [32:36] who read my book, had chronic anxiety, [32:39] was trying meditation, was trying all [32:40] sorts of things. He was ready to go on [32:42] prescription medicine. He read an early [32:44] copy of the book. He took it upon [32:46] himself without consulting with me to [32:48] restrict carbohydrates alone. He did not [32:50] go ketogenic. He is a vegetarian. He [32:53] restricted carbs. Within 3 weeks said, [32:56] "I don't need prescription medicine. I [32:59] can't believe how much better I feel." [33:01] And all I did was cut out some of the [33:04] high carb foods in my diet. So, I think [33:06] for some people, it can be that simple. [33:09] for people with serious mental [33:11] disorders, if they are chronically [33:13] depressed, if they're on lots of [33:15] prescription meds, if they're disabled [33:16] by their symptoms, and certainly if [33:19] you're bipolar or have schizophrenia or [33:22] something, those are the people I really [33:23] do want them to work with, a medical [33:25] professional, because meds may need to [33:27] be adjusted. They really need a they [33:30] need a real shot at this diet. It's not [33:34] like weight loss. weight loss, everybody [33:36] wings it and either you're successful or [33:39] you aren't. You you look on the internet [33:40] or you read a book and seeing whether it [33:43] works or not. If you're using it to [33:45] treat a serious disorder, I think you [33:48] need serious help. On behalf of myself [33:50] and the listeners and and certainly just [33:52] on behalf of everybody out there, [33:54] because everyone does need to be [33:57] concerned about mental health issues, [33:59] whether or not they have them and in [34:00] their family, themselves, or otherwise, [34:02] because they impact everybody. just [34:04] really want to thank you for doing the [34:05] work that you're doing. You've given us [34:06] a lot of hints into the underlying [34:07] mechanisms that suggest as to why it [34:09] would work and you've g us given us [34:11] examples as to how it has worked in [34:14] patients that you've worked with. So, [34:16] thank you for being brave and for taking [34:19] this on and doing it in such a [34:20] structured way and for communicating it [34:22] here today and with the general public [34:24] through your book and your online [34:26] presence. We will certainly point people [34:27] in the direction of those valuable [34:29] resources. Thanks so much. Really [34:32] appreciate it. Thank you, Andrew, for [34:33] being brave and having me on your show [34:36] and uh pleasure and for uh for a great [34:39] conversation.