The Peter Attia Drive

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter In this episode, Peter sits down with Dr. Lisa Feldman Barrett, a psychologist, neuroscientist, author, and distinguished professor at Northeastern University whose research challenges many of the conventional assumptions about emotions and how the brain works. Lisa is best known for her theory of constructed emotion, which challenges the idea that emotions such as fear, anger, and sadness are hardwired responses with universal biological signatures. She begins by explaining how unexpected findings early in her research led her to question traditional theories of emotion. She discusses why studying individual variation, rather than relying on averages, is essential to understanding the brain. Lisa then explores the idea that the brain is fundamentally a predictive system rather than a reactive one. She explains how past experiences and memories shape what we perceive, feel, and do. She also describes how the brain continuously anticipates and regulates metabolism through a process called allostasis. The conversation then turns to the effects of chronic stress, uncertainty, and childhood adversity on physical and emotional health. Lisa explains how our relationships help regulate our nervous systems and why the loss of a loved one can have such a profound physiological impact. She also discusses how deliberate practice and new experiences can reshape the brain's predictions, potentially changing how we think, feel, and respond to the world around us. Throughout the discussion, Peter and Lisa explore how this framework challenges traditional views of emotion and offers a greater sense of agency over our emotional lives. We discuss: How unexpected results in graduate school changed Lisa's understanding of emotion [3:30]; Why variation is the norm for emotion, and the danger in tracking averages instead of characterizing variation [15:30]; Lisa's experience with Hashimoto's disease and the value of modeling individual variation [30:00]; How Lisa's research challenges common views about emotions, and why there is no biomarker for emotions [40:00]; The difficulty of defining emotions and the brain's role in regulating the body [49:15]; Consciousness, interoception, and the limits of subjective experience [54:00]; Defining emotion: fear and anger [1:00:15]; The brain as a predictive system rather than a reactive one [1:13:15]; Baseball as an example of the brain's predictive nature [1:31:00]; How the human brain differs from that of other animals [1:44:00]; The impact of stress on metabolism, and the role of the brain in maintaining allostasis [1:49:45]; Childhood adversity, social regulation of the nervous system, and the effect of chronic stress [1:56:45]; Understanding chronic stress: why some people respond differently, and its impact on metabolism [2:02:15]; How practicing new predictions can change thoughts and feelings [2:10:15]; Lisa's practice of finding awe in everyday experiences and the greater sense of agency it brings [2:13:30]; The impact of grief on nervous system regulation and the metabolic "body budget," as well as practices that reduce sadness [2:22:15]; The connection between memories and predictions, and Peter's closing thoughts [2:29:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter In this "Ask Me Anything" (AMA) episode, Peter looks back on 400 episodes of The Drive with another installment of "strong convictions, loosely held," revisiting some of the positions he has taken over more than eight years of the podcast. He explains why changing one's mind in response to new evidence, conversations with experts, and clinical experience is essential for practicing medicine well. Peter begins with nutrition, describing how his views on ketogenic diets, extended fasting, and the framework of dietary restriction, time restriction, and calorie restriction have evolved. He explains why he no longer takes metformin for longevity and discusses his growing uncertainty around rapamycin despite compelling animal data. Peter also revisits his views on cancer screening, including whole-body MRI and liquid biopsies for early detection. On exercise, Peter explains how his approach to cardiorespiratory training and the 80/20 Zone 2 framework has changed, particularly for people with limited time to train. He also shares why he has moved away from heavy barbell squats and deadlifts and how he now thinks about balancing benefit and injury risk. Throughout the episode, Peter emphasizes the importance of focusing on durable principles, strong foundations, and sustainable practices rather than chasing optimizations that provide marginal gains. If you're not a subscriber and are listening on a podcast player, you'll only be able to hear a preview of the AMA. If you're a subscriber, you can now listen to this full episode on your private RSS feed or our website at the AMA #90 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here. We discuss: Strong convictions, loosely held: changing opinions as evidence, expert conversations, and clinical experience evolve [2:00]; Nutrition: Peter's evolving view of ketogenic diets, energy balance, and dietary dogmatism [5:30]; Extended fasting, autophagy, lean-mass loss, and who may benefit from prolonged fasting [12:00]; The dietary restriction, time restriction, and calorie restriction framework—and why GLP-1 agonists are tipping the balance toward calorie restriction [20:15]; Why Peter no longer views metformin as geroprotective for metabolically healthy people [24:45]; Rapamycin for longevity: compelling animal data, unresolved human dosing, and Peter's growing uncertainty [29:15]; The importance of early cancer detection, declining whole-body magnetic resonance imaging (MRI) quality, and more targeted alternatives [41:30]; Liquid biopsies for cancer screening: the NHS-Galleri trial, why early-stage rather than late-stage detection is what actually matters, and why the technology remains "fuzzy" [53:30]; Evolving exercise goals, the limitations of the 80/20 Zone 2 framework, and programming cardio at lower training volumes [1:00:00]; Exercise prescriptions for limited time, building a training habit, and becoming less dogmatic about forcing workouts [1:05:00]; Moving away from heavy squats and deadlifts, alternative exercises, and deliberate risk management [1:13:00]; Prioritizing principles, foundations, and sustainable practices over marginal optimization [1:21:30]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter Lloyd B. Klickstein is a physician-scientist who has spent more than 20 years at the intersection of drug discovery, healthy aging, and preventive medicine. Drawing on his experience in academic medicine, translational research, and biotechnology, Lloyd walks through the full arc of modern drug development. He explains how scientists identify an unmet medical need and decide which diseases and therapeutic targets are worth pursuing. From there, he takes us through the process of engineering a drug, testing it in animals, and navigating clinical trials and regulatory approval. Using bimagrumab as a case study, Lloyd explains the rationale for targeting myostatin and activin signaling to increase muscle mass and strength and describes how the antibody was engineered and screened. He then walks through what was learned from early clinical trials. Unexpected effects on fat mass and type 2 diabetes helped reshape bimagrumab's development as a potential treatment for obesity, including its use in combination with semaglutide. Along the way, Peter and Lloyd explore the differences among drug modalities, including biologics and small-molecule therapeutics. They discuss the roles of patents and capital allocation in drug development, along with the requirements for IND submission and GMP manufacturing. They also examine why developing a new drug takes so long and costs so much, and why identifying failures early is critical. At the end of the episode, the conversation turns to mTOR inhibition and geroprotection, as well as Lloyd's current work on a novel pharmacologic approach to cancer prevention. This episode provides a rare behind-the-scenes look at how new medicines are actually created and the scientific, regulatory, and economic decisions that determine which ideas ultimately make it to patients. We discuss: Lloyd's path from academic medicine to translational drug development [3:15]; Drug modalities, patents, and the economics of innovation [11:30]; Choosing sarcopenia as a target for drug development, and confronting the problem of measuring falls [23:00]; The rationale for bimagrumab: improving muscle mass and strength by targeting myostatin and activin signaling (and why follistatin failed) [36:45]; Engineering and screening the bimagrumab antibody, and the cost of developing a new drug [43:45]; From candidate antibodies to animal proof of concept (impressive muscle hypertrophy) [54:15]; Toxicology, capital allocation, and the path to an IND [1:02:45]; IND requirements, GMP manufacturing, and gray market peptides [1:14:45]; First in-human study design, patient selection, and protection of healthy volunteers [1:22:00]; Phase 1 dosing, pharmacodynamics, and global trial strategy [1:33:45]; Phase 2 lessons on muscle mass, function, and nutrition [1:43:30]; Bimagrumab's effects on fat mass and type 2 diabetes [1:50:45]; The BELIEVE trial of bimagrumab plus semaglutide [1:59:30]; Selective mTORC1 inhibition and the challenge of testing geroprotection [2:11:45]; A new pharmacologic approach to cancer prevention [2:15:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter Michael Davidson is a world-renowned cardiologist, lipidologist, and the founding CEO of NewAmsterdam Pharma. He begins this episode by sharing how his family history shaped his interest in lipidology and primary prevention. He explains why prevention should focus on causal drivers of disease rather than near-term risk and examines the causal relationship between LDL and atherosclerotic cardiovascular disease. Michael then traces the complicated history of CETP inhibitors—from the original rationale that raising HDL would reduce cardiovascular risk to the failures of torcetrapib, dalcetrapib, and evacetrapib—and explains how lessons from these trials ultimately led to the development of obicetrapib. He reviews the phase 2 and phase 3 trials of obicetrapib, its effects on LDL-C, apoB, LDL particle number, and Lp(a), the ongoing cardiovascular outcomes trial, and where the drug could fit alongside statins and other lipid-lowering therapies. Peter and Michael discuss the relationship between statins and diabetes risk, then turn to the potential role of obicetrapib in Alzheimer's disease prevention, exploring the genetics of APOE4 and CETP, cholesterol metabolism within the brain, and emerging biomarker data. Finally, Peter and Michael explore the benefits of omega-3 fatty acids and the challenge of delivering DHA to the brain, as well as ongoing work on klotho in preparation for clinical trials. They discuss the potential for AI to transform clinical trials and the scientific and financial challenges of developing new therapies for cardiovascular and neurodegenerative disease. We discuss: Michael's path to lipidology, and his passion for primary prevention [3:30]; Reframing prevention around causal drivers rather than time horizon [9:30]; What CETP inhibition does, the evolutionary biology of CETP, the HDL-raising rationale, and Pfizer's torcetrapib failure [15:00]; Why raising HDL is thought to be beneficial, a quick review of the functions of HDL, and how this connects to torcetrapib [24:00]; The graveyard of CETP inhibitors: Roche's dalcetrapib, Lilly's evacetrapib, and Merck's REVEAL trial [27:15]; The causality of LDL in cardiovascular disease [34:30]; Reviving obicetrapib at NewAmsterdam, and confirming the benefit is LDL lowering: the TULIP data, the abandoned statin-intolerance path, and the Mendelian randomization verdict on HDL [37:30]; Phase 2 and phase 3 trials of obicetrapib—ROSE, BROOKLYN, BROADWAY, and TANDEM—and the PREVAIL outcomes trial, with the European and US approval paths [44:45]; Discordance among LDL-C, LDL-P, and apoB with CETP inhibition, and obicetrapib's Lp(a)-lowering effect [50:30]; Where obicetrapib fits in the lipid-lowering toolkit, the case against high-dose statins, and the problem of drug pricing [57:30]; The case for obicetrapib in Alzheimer's: the APOE4 and CETP genetics, the animal models, and funding Alzheimer's research [1:03:45]; Brain cholesterol metabolism and the APOE4 mechanism: the blood-brain barrier, astrocyte cholesterol efflux, the amyloid-tau cascade, the role of HDL, and why statins don't cause Alzheimer's disease [1:08:00]; The biomarker evidence: the CSF pilot study, Alzheimer's as a disease of middle age, the pharma graveyard problem, and the p-tau 217 results from BROADWAY [1:17:45]; Whether obicetrapib translates into clinical benefit for Alzheimer's disease: the risk of fooling yourself, the persistence of the amyloid dogma, ARIA in APOE4 homozygotes, and the next prevention trial [1:28:00]; Fish oil, EPA, and DHA: the cardiovascular trials and the challenge of delivering DHA to the brain [1:32:00]; Two open problems: using AI to reform clinical trials, and the statin–diabetes signal [1:41:15]; What it takes to develop a drug, the biotech investment landscape, and the klotho program [1:48:15]; Closing reflections: what to do if you carry APOE4, balancing motivation against over-testing, and the need for multiple therapies [1:55:15]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter Brian Grosberg is a world-renowned headache specialist who joins Peter to provide a master class on the diagnosis and treatment of headache disorders. In this episode, Brian explains the distinction between primary and secondary headaches and breaks down the defining features of the "big three" primary headache types (migraine, cluster, and tension headache)—highlighting how often they are misdiagnosed and how they are treated. He explores the epidemiology of headaches, describing migraine as an invisible disease affecting about 12% of the population, disproportionately affecting women, while cluster headaches more often affect men. He discusses the major gap between demand for headache care and available specialists, and he offers advice on when to see a physician. Brian dives into the multifactorial nature and pathophysiology of migraine, including genetic and hormonal influences, neurovascular changes, and inflammatory signaling, and connects these mechanisms to modern therapies. Throughout the conversation, he emphasizes the individualized nature of headache disorders and the importance of a detailed headache diary. Brian shares practical strategies for treating headaches including lifestyle changes, medications, and neuromodulation devices. We discuss: Brian's interest in headaches and how Peter met Brian [2:15]; Differentiating the types of headaches: primary versus secondary headache and tension versus migraine headache [7:30]; The epidemiology and burden of migraine, its disproportionate affect on women, and the shortage of headache specialists [20:00]; Genetic susceptibility to migraine and the role of hormones [24:45]; Migraine triggers, the impact of hormones, and the importance of a headache diary [31:15]; The phases of a migraine: premonitory symptoms, aura, the headache itself, and the postdrome [38:15]; Tension headaches: symptoms, causes, and prevalence [41:45]; Cluster headaches: extreme pain, distinctive symptoms, and frequent misdiagnosis as a sinus infection or allergies [43:15]; Lifestyle interventions to prevent headaches [51:15]; Pharmacological treatments to prevent headaches [1:05:00]; What's known about the pathophysiology of migraines: neurovascular changes, release of neuropeptides, and inflammatory response [1:14:45]; CGRP antagonists for the treatment of migraines: large monoclonal antibodies and gepants [1:20:15]; Use of calcium channel blockers and Botox to treat cluster headache and migraine [1:28:30]; Drugs for the acute treatment of migraines [1:32:30]; Treatment of migraines with electrical stimulation devices [1:40:00]; Use of THC or cannabis to treat headaches [1:44:00]; What Brian wants people to know about headaches [1:45:45]; Brian's advice on when to see a doctor about headaches and how to prepare for that visit [1:49:15]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter In this episode, Peter sits down with Dr. Linus Abrams, a psychiatrist with nearly 35 years of clinical experience specializing in mood disorders and psychopharmacology, to explore how our understanding of mental health is evolving beyond the traditional neurotransmitter model. After decades in practice, Linus began questioning many of the assumptions underlying modern psychiatry, leading him to investigate how hormones, metabolism, inflammation, circadian biology, and the endocrine system shape mood and cognition. Together, Peter and Linus examine why psychiatric care should aim not only to reduce symptoms but also to restore the full human experience. They discuss how psychiatric medications work, where they fall short, and why distinguishing bipolar disorder from unipolar depression is essential for effective treatment. The conversation also explores the growing mental health burden of social isolationn associated with digital devices and social media, along with the biological factors—nutrition, exercise, sleep, and chronic stress—that influence resilience and distress tolerance. Linus explains the powerful roles of estrogen, progesterone, testosterone, and thyroid hormone in regulating mood and cognition across the lifespan. Finally, Peter and Linus review the promise and limitations of ketamine and psychedelic therapies, and why the future of psychiatry may lie in integrating neuroscience, endocrinology, and whole-body physiology to better understand, diagnose, and treat mental illness. We discuss: Linus's passion for understanding his patients and going beyond traditional psychiatry [2:45]; A short primer on the different classes of drugs used in psychiatry [12:45]; Evaluation of a patient with bipolar disorder [26:00]; An evolutionary perspective on depression [33:30]; Changes in the modern world triggering mental health problems [41:00]; An evolutionary perspective on insomnia [48:15]; Peter's window analogy to understand distress tolerance and irritability [49:45]; The impact of foundational biological factors on psychiatry: nutrition, exercise, sleep, and endocrinology [52:30]; The effect of estradiol on neurotransmitters in the brain [58:15]; Options for increasing testosterone in men, and why clomiphene is inferior to exogenous testosterone [1:11:00]; The rapid drop in progesterone is linked to both premenstrual dysphoric disorder (PMDD) and postpartum depression [1:14:30]; Treatment of postpartum depression [1:18:00]; Hypothyroidism presenting as depression: how Linus makes the diagnosis and what he uses for treatment [1:26:00]; The link between hyperarousal and chronically elevated cortisol [1:39:30]; A case where the menopause transition uncovers bipolar disorder [1:44:15]; Ketamine as a tool to treat recalcitrant depression, and concerns about its recreational use [1:49:15]; Case study: an Alzheimer's patient who improved after psilocybin, and why Linus is cautious about drawing conclusions from it [1:55:15]; Peter's experience with psychedelics, and the myth that estrogen is bad for men [2:00:30]; The therapeutic potential of psychedelics in psychiatry [2:11:00]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter Jim Otvos is a biophysical chemist who pioneered the use of nuclear magnetic resonance (NMR) spectroscopy to measure lipoprotein particles and developed the first FDA-cleared method for directly quantifying LDL particle number (LDL-P), a technology that has since expanded to provide broader insights into metabolic health, inflammation, insulin resistance, and mortality risk. In this episode, Jim recounts the unlikely story of transforming a flawed cancer test into a new way of measuring lipoproteins, explains what standard cholesterol tests can miss and why LDL-P and apoB can inform treatment decisions beyond LDL cholesterol alone, and dispels the misconception that large, "fluffy" LDL particles are benign. He also explores how NMR can reveal insulin resistance before blood sugar rises, GlycA as a marker of chronic low-grade inflammation, and the metabolic vulnerability index (MVX) as a potential measure of frailty, resilience, and mortality risk across the lifespan. Finally, Jim explains why NMR diagnostics remain underused despite the wealth of information they can extract from a single blood test. We discuss: How investigating a flawed 1986 cancer test led to the development of NMR (nuclear magnetic resonance) lipoprotein testing [3:30]; How standard lipid panels measure cholesterol and triglycerides, and why LDL cholesterol is estimated rather than directly measured [15:15]; How NMR spectroscopy measures lipoprotein particle size and concentration [20:30]; Why LDL particle number matters more than particle size, and why large, "fluffy" LDL is not benign [28:45]; Discordance between LDL cholesterol and LDL particle number: which measure better reflects cardiovascular risk? [36:30]; How metabolic syndrome and lipid-lowering treatment contribute to the discordance between LDL-C and LDL-P, and the value of particle number for managing risk [45:30]; Using the NMR-derived LP-IR score to detect insulin resistance and predict type 2 diabetes before glucose rises [51:15]; The development, commercialization, and uncertain future of the Vantera NMR Analyzer and NMR-based diagnostics [1:04:45]; The analytical efficiency of NMR testing and the data-driven development of the Metabolic Vulnerability Index (MVX) [1:16:00]; GlycA as an NMR-derived marker of systemic inflammation: its discovery, biological basis, and advantages over hs-CRP [1:25:45]; Developing the Metabolic Vulnerability Index (MVX): biomarkers of inflammation, malnutrition, muscle wasting, and mortality risk [1:34:00]; What MVX can tell us about longevity and mortality [1:44:15]; How MVX may reveal metabolic frailty and predict premature mortality decades in advance in young, healthy adults [1:50:30]; Potential applications of MVX for predicting treatment response, surgical resilience, and clinical trial outcomes, and the barriers to broader use [2:00:00]; ApoB versus LDL-P: their clinical similarities, the additional information provided by NMR, and barriers to broader adoption [2:07:30]; Interpreting the effects of the CETP inhibitor, obicetrapib, on LDL-P, apoB, and small HDL particles [2:13:00]; The future of NMR diagnostics and MVX: translating scientific potential into broader clinical use [2:20:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter In this episode, Peter takes a deep dive into colorectal cancer (CRC) screening, explaining why it is one of the most preventable cancers and why getting screening right can have life-saving implications. He walks through how colorectal cancer develops and why it is uniquely well-suited to early detection and prevention, with a particular emphasis on the dual role of colonoscopy as both a diagnostic and therapeutic tool. Peter also examines the concerning rise in early-onset CRC among younger adults, highlighting why awareness and timely screening matter more than ever. The episode provides a practical guide to preparing for and evaluating the quality of a colonoscopy, including how to think about appropriate screening intervals and the real risks and tradeoffs involved. Finally, Peter explores the expanding landscape of non-invasive screening options, offering clear insight into what these alternatives can and cannot do so listeners can make informed decisions about their care at any age. We discuss: CRC statistics and goals for this episode [1:00]; Colorectal cancer development: polyp progression, risk types, and the window for prevention [4:00]; Why colorectal cancer is uniquely screenable: direct visualization and the dual role of colonoscopy [6:30]; Colonoscopy effectiveness: prevention through polyp removal and interpreting the NordICC trial data [8:15]; Rising colorectal cancer in younger adults: trends, possible causes, and the case for earlier screening [12:15]; Colonoscopy preparation: why bowel prep matters and how newer options improve the experience [16:45]; Colonoscopy quality, polyp miss rates, and personalized screening intervals [20:00]; Colonoscopy risks versus colorectal cancer risk: understanding the true risk-benefit tradeoff [29:30]; Non-invasive screening options for CRC: benefits, limitations, and their role alongside colonoscopy [37:00]; Colorectal cancer prevention principles: why screening matters and the role of colonoscopy [39:30]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube