The Peter Attia Drive

Patrick Radden Keefe is an award-winning staff writer at The New Yorker and the bestselling author of Empire of Pain: The Secret History of the Sackler Dynasty. In this episode, Patrick tells the story of the Sackler family and Purdue Pharma - makers of the pain management drug OxyContin, providing the backdrop for the ensuing opioid epidemic and public health crisis. He reveals the implicit and sometimes explicit corruption of all parties involved in the development, approval, and marketing of OxyContin, leading to a cascade of unintended consequences including addiction and death. He explains the unfortunate lack of accountability for the current crisis, as well as what it all means for those with legitimate pain management needs. Finally, he examines the difficult path ahead towards finding a solution. We discuss:

• Patrick's investigation into distribution and use of drugs in our society [3:55];
• The scale of the opioid crisis [9:15];
• The Sackler brothers: family life, career in the pharmaceutical industry, and role in the current crisis [11:45];
• Purdue Pharma: origins, early years, and move towards pain management drugs [17:30];
• The development of OxyContin: its conception, marketing, and the controversy around the FDA approval process [25:30];
• Early reports of OxyContin addiction and unintended consequences and how Purdue Pharma sidestepped responsibility [40:45];
• The many paths to addiction and abuse of OxyContin and the ensuing downfall of Purdue Pharma [47:15];
• Peter's personal experience with OxyContin [57:00];
• Pain—the "fifth vital sign," how doctors are trained in pain management, and the influence of money [1:08:00];
• Other players that helped facilitate the eventual opioid crisis [1:16:15];
• Lack of accountability following the investigation and prosecution of Purdue and the Sackler family [1:23:30];
• Legacy of the Sackler family and their disconnect from reality [1:34:45];
• Patrick's views on the regulation and use of pain management drugs [1:42:15];
• The difficult path forward [1:44:45]; and
• More.

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Allan Sniderman is a highly acclaimed Professor of Cardiology and Medicine at McGill University and a foremost expert in cardiovascular disease (CVD). In this episode, Allan explains the many risk factors used to predict atherosclerosis, including triglycerides, cholesterol, and lipoproteins, and he makes the case for apoB as a superior metric that is currently being underutilized. Allan expresses his frustration with the current scientific climate and its emphasis on consensus and unanimity over encouraging multiple viewpoints, thus holding back the advancement of metrics like apoB for assessing CVD risk, treatment, and prevention strategies. Finally, Allan illuminates his research that led to his 30-year causal model of risk and explains the potentially life-saving advantages of early intervention for the prevention of future disease. We discuss:

• Problems with the current 10-year risk assessment of cardiovascular disease (CVD) and the implications for prevention [4:30];
• A primer on cholesterol, apoB, and plasma lipoproteins [16:30];
• Pathophysiology of CVD and the impact of particle cholesterol concentration vs. number of particles [23:45];
• Limitations of standard blood panels [29:00];
• Remnant type III hyperlipoproteinemia—high cholesterol, low Apo B, high triglyceride [32:15];
• Using apoB to estimate risk of CVD [37:30];
• How Mendelian randomization is bolstering the case for ApoB as the superior metric for risk prediction [40:45];
• Hypertension and CVD risk [49:15];
• Factors influencing the decision to begin preventative intervention for CVD [58:30];
• Using the coronary artery calcium (CAC) score as a predictive tool [1:03:15];
• The challenge of motivating individuals to take early interventions [1:12:30];
• How medical advancement is hindered by the lack of critical thinking once a "consensus" is reached [1:15:15];
• PSK9 inhibitors and familial hypercholesterolemia: two examples of complex topics with differing interpretations of the science [1:20:45];
• Defining risk and uncertainty in the guidelines [1:26:00];
• Making clinical decisions in the face of uncertainty [1:31:00];
• How the emphasis on consensus and unanimity has become a crucial weakness for science and medicine [1:35:45];
• Factors holding back the advancement of apoB for assessing CVD risk, treatment, and prevention strategies [1:41:45];
• Advantages of a 30-year risk assessment and early intervention [1:50:30];
• More.

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Today's episode of The Drive is a rebroadcast of the conversation with Rick Johnson (originally released January 6th, 2020). This episode was one of the most popular discussions to-date and is a prelude to an upcoming follow-up discussion which will be coming out in February 2022 along with the release of Rick's new book. In this episode, Rick Johnson, professor of nephrology at the University of Colorado, explains how his research into the causes of blood pressure resulted in a change of research direction to focus more on how fructose has such profound metabolic effects. Rick begins by talking about the relationship between salt and high blood pressure, then provides a masterclass into uric acid, and then expertly reveals the mechanisms and pathways by which sugar (specifically fructose) can profoundly impact metabolic health. From there, he explains how he applies this information to real life patients as well as touches on some of the most promising ideas around pharmacotherapy that are being developed in response to the epidemics of fatty liver, insulin resistance, diabetes, and obesity. Furthermore, Rick gives his take on artificial sweeteners compared to real sugar, discusses cancer's affinity for fructose, and much more. We discuss:

• The connection between blood pressure and fructose that shifted Rick's professional focus [3:00];
• The relationship between salt and blood pressure (and the role of sugar) [4:45];
• Defining fructose, glucose, and sugar [18:30];
• An ancient mutation in apes that explains why humans turn fructose into fat so easily [22:00];
• The problems with elevated uric acid levels, and what it tells us about how sugar causes disease [30:30];
• How sugar causes obesity—explaining the difference in glucose vs. fructose metabolism and the critical pathway induced by fructose [39:00];
• Why drinking sugar is worse than eating it [49:00];
• Unique ability of sugar to drive oxidative stress to the mitochondria, insulin resistance, and diabetes [53:00];
• Why cancer loves fructose [59:20];
• The many areas of the body that can use fructose [1:04:00];
• Fructokinase inhibitors—a potential blockbuster? [1:06:15];
• Treating high uric acid levels—Rick's approach with patients [1:09:00];
• Salt intake—what advice does Rick give his patients? [1:15:30];
• How excess glucose (i.e., high carb diets) can cause problems even in the absence of fructose [1:20:00];
• Artificial sweeteners vs. real sugar—which is better? [1:28:15];
• Umami, MSG, alcohol, beer—do these have a role in metabolic illness? [1:32:45];
• Fructose consumption—Is any amount acceptable? Is fruit okay? Where does Rick draw a hard line? [1:37:45]
• How does Rick manage the sugar intake of his young kids? [1:42:00]; and
• More.

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In this "Ask Me Anything" (AMA) episode, Peter and Bob discuss all things related to GLP-1 agonists—a class of drugs that are gaining popularity for the treatment of obesity. They cover the discovery of these peptides, their physiology, and what it is they do in their natural state. Next, Peter and Bob break down a recently published study which showed remarkable results for weight loss and other metabolic parameters using a once-weekly injection of the GLP-1 agonist drug semaglutide, also known as Ozempic, in overweight and obese patients. Finally, they compare results from the semaglutide study to results from various lifestyle interventions and give their take on the potential future of GLP-1 agonists. If you're not a subscriber and 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 on our website at the AMA #29 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here. We discuss:

• Remarkable results of a recent study in overweight adults [2:15];
• Key background on insulin, glucagon and the incretin effect [4:00];
• What is GLP-1 and how does it work? [16:30];
• 2021 semaglutide study: remarkable results, side effects, and open questions [30:00];
• Semaglutide vs. lifestyle interventions: comparing results with semaglutide vs. lifestyle interventions alone [44:00];
• Closing thoughts and open questions on the therapeutic potential of semaglutide [47:30]; and
• More

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James Clear is the author of the New York Times bestseller Atomic Habits. His extensive research into human behavior has helped him identify key components of habit formation and develop the "Four Laws of Behavioral Change." In this episode, James provides insights into how both good and bad habits are formed, including the influence of genetics, environment, social circles, and more. He points to changes one can make to cultivate more perseverance and discipline and describes the profound impact habits can have when tying them into one's self-identity. Finally, James breaks down his "Four Laws of Behavioral Change" and how to use them to create new habits, undo bad habits, and make meaningful changes in one's life. We discuss:

• Why James became deeply interested in habits [1:45];
• Viewing habits through an evolutionary lens [6:00];
• The power of immediate feedback for behavior change, and why we tend to repeat bad habits [9:15];
• The role of genetics and innate predispositions in determining one's work ethic and success in a given discipline [14:30];
• How finding one's passion can cultivate perseverance and discipline [23:15];
• Advantages of creating systems and not just setting goals [29:15];
• The power of habits combined with self-identity to induce change [36:30];
• How a big environmental change or life event can bring on radical behavioral change [50:30];
• The influence of one's social environment on their habits [54:15];
• How and why habits are formed [1:00:30];
• How to make or break a habit with the "Four Laws of Behavior Change" [1:09:30];
• Practical tips for successful behavioral change—the best strategies when starting out [1:16:15];
• Self-forgiveness and getting back on track immediately after slipping up [1:30:30];
• Law #1: Make it obvious—strategies for identifying and creating cues to make and break habits [1:39:45];
• Law #2: Make it attractive—ways to make a new behavior more attractive [1:47:45];
• Law #3: Make it easy—the 2-minute rule [1:58:45];
• Law #4: Make it satisfying—rewards and reinforcement [2:03:30];
• Advice for helping others to make behavioral changes [2:06:00];
• More.

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David Nutt is a psychiatrist and a neuroscientist at Downing College, Cambridge. His research focuses on illicit drugs—their harm, classification, and potential for therapeutic use in psychiatry. In this episode, David discusses his framework for assessing the potential harm caused by common recreational drugs and explains how they are regulated, which is oftentimes misaligned with actual risk. He describes in detail the neurobiology, mechanisms of action, and addiction potential of alcohol, opiates, cocaine, and methamphetamine and contrasts those with psychedelics, which have been given a similar regulatory classification despite their relatively low risk of harm and their numerous potential therapeutic uses. Additionally, David explains the promise of psychedelics like ketamine, MDMA, and psilocybin for treating drug addiction and depression and discusses how political pressures have created roadblocks to future necessary research. We discuss:

• David's early interest in the brain and experience in psychiatry [2:45];
• David's brief work on government drug policy in the UK [10:15];
• A scale for rating the relative harm of certain drugs [13:45];
• The contrast in regulation between cannabis vs. alcohol and why research on potential benefits of cannabis is lacking [19:15];
• The opiate crisis and rise of fentanyl: the cause and potential solution [25:00];
• The science of addiction and the potential use of psychedelics for treating drug addiction [35:00];
• Cocaine: mechanisms of action and risks [41:45];
• Methamphetamine and crystal meth: mechanisms of action and neurotoxicity [48:15];
• How psychedelics came to be classified as schedule I drugs despite their numerous therapeutic uses [52:45];
• The history of MDMA and the bad science and political forces leading to its demonization [1:08:45];
• History of ketamine, medical use of esketamine, and the waning effects of psychedelics with increasing usage [1:13:30];
• Psilocybin for depression: David's promising research and the roadblocks to more robust experiments [1:20:15];More.

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Robert (Bob) Gatenby is a radiologist who specializes in exploring theoretical and experimental models of evolutionary dynamics in cancer and cancer drug resistance. He has developed an adaptive therapy approach for treating cancer which has shown promise in improving survival times with less cumulative drug use. In this episode, Bob explains what brought him into medicine, his search for organizing principles from which to understand cancer, and the mathematical modeling of other complex systems that led him to model the dynamics of tumor cell changes in cancer. He discusses his pilot clinical trial treating metastatic prostate cancer, in which he used an evolutionary game theory model to analyze patient-specific tumor dynamics and determine the on/off cycling of treatment. He describes how altering chemotherapy to maximize the fitness ratio between drug-sensitive and drug-resistant cancer cells can increase patient survival and explains how treatment of metastatic cancer may be improved using adaptive therapy and strategic sequencing of different chemotherapy drugs. We discuss:

• Bob's unlikely path to medicine and disappointment with his medical school experience [1:45];
• Rethinking the approach to cancer: using first principles and applying mathematical models [12:15];
• Relating predator-prey models to cancer [26:30];
• Insights into cancer gathered from ecological models of pests and pesticides [32:15];
• Bob's pilot clinical trial: the advantages of adaptive therapy compared to standard prostate cancer treatment [41:45];
• New avenues of cancer therapy: utilizing drug-sensitive cancer cells to control drug-resistant cancer cells [48:15];
• The vulnerability of small populations of cancer cells and the problem with a "single strike" treatment approach [56:00];
• Using a sequence of therapies to make cancer cells more susceptible to targeted treatment [1:05:00];
• How immunotherapy fits into the cancer treatment toolkit [1:15:30];
• Why cancer spreads, where it metastasizes, and the source-sync trade off [1:20:15];
• Defining Eco- and Evo-indices and how they can be used to make better clinical decisions [1:29:45];
• Advantages of early screening for cancer [1:40:15];
• Bob's goals for follow-ups after the success of his prostate cancer trial [1:42:15];
• Treatment options for cancer patients who have "failed therapy" [1:51:15];
• More.

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In this "Ask Me Anything" (AMA) episode, Peter and Bob discuss all things related to testosterone: what happens when testosterone levels are low, and the potential benefits and risks of testosterone replacement therapy (TRT). They explain the physiology of testosterone, how it works, and how its level changes over the course of a person's life. They have a detailed discussion about existing literature, which reveals vast potential structural, functional, and metabolic benefits of testosterone replacement therapy. They also take a very close look at potential risks of this therapy, with a focus on the controversial effects on cardiovascular disease and prostate cancer. If you're not a subscriber and 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 on our website at the AMA #28 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here. We discuss:

• A primer on the hormone testosterone and how it influences gene expression [3:30];
• How the body naturally regulates testosterone levels [11:30];
• The defining threshold for "low testosterone," how low T impacts men, and why free testosterone is the most important metric [16:15];
• When it makes sense to treat low testosterone [26:00];
• The structural and metabolic benefits of testosterone replacement therapy [29:15];
• Body composition changes with TRT [45:30];
• Changes in bone mineral density with TRT [48:15];
• The metabolic impact of TRT: glucose, insulin, triglycerides, and more [52:30];
• A study investigating testosterone replacement therapy for prevention or reversal of type 2 diabetes [59:30];
• The impact of TRT on metabolic parameters and body composition—A study comparing results from continuous vs. interrupted treatment [1:07:15]
• The controversy over TRT and cardiovascular disease [1:21:45];
• Two flawed studies that shaped perceptions of risks associated with TRT [1:44:15];
• The controversy over TRT and prostate cancer [1:56:45];
• Other potential risks with testosterone replacement therapy [2:02:15]; and
• More

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Jeremy Loenneke has a Ph.D. in exercise physiology, a Master's in nutrition and exercise, and is currently the director of the Kevser Ermin Applied Physiology Laboratory at the University of Mississippi, where he focuses his research on skeletal muscle adaptations to exercise in combination with blood flow restriction (BFR). In this episode, Jeremy explains the science of BFR and the mechanisms by which BFR training can produce hypertrophy using low loads. Here, he reviews anatomy and terminology of muscle structure and discusses the evidence that increasing muscular strength may not be dependent on increasing muscle size. Additionally, Jeremy goes into depth on how one might take advantage of BFR training, including practical applications for athletes and average people, as well as the situations for which BFR training would be most advantageous. We discuss:

• Jeremy's interest in exercise and weightlifting and his scientific training [3:30];
• The microstructure and physiology of muscle [8:00];
• Definitions of fast-twitch and slow-twitch muscle fibers [12:45];
• Comparison of strength vs. hypertrophy [21:30];
• Blood flow restriction training and the origins of the Kaatsu system [28:30];
• The details and metrics related to exercise under blood flow restriction [44:45];
• Considerations when training with blood flow restriction: loading, pace, rest, and risks [53:00];
• Blood flow restriction studies and the relationship between muscle size and muscle strength [1:04:15];
• Evidence that increasing muscular strength is not dependent on increasing the size of the muscle [1:16:30];
• Practical applications of blood flow restriction training for athletes and average people [1:27:30];
• Situations in which blood flow restriction training is most advantageous [1:35:30];
• The mechanisms by which blood flow restriction training can produce so much hypertrophy at such low loads [1:39:45];
• Applications of "passive" blood flow restriction training [1:47:15];
• What experiments would Jeremy do if he had unlimited resources? [1:51:45];
• More.

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Lance Armstrong is a legendary figure in professional cycling having won seven consecutive Tour de France titles but also a controversial figure facing scrutiny for the use of performance enhancing drugs. In this episode, Lance takes us through his meteoric rise to one of the most famous athletes in the world and his equally accelerated fall from grace. Lance describes how he persevered through his brutal diagnosis of testicular cancer before rattling off a historic run of seven consecutive Tour de France titles all while facing tremendous scrutiny for his alleged use of performance enhancing drugs such as EPO and cortisone. Lance opens up about his decision to come clean about his use of performance enhancing drugs, the remorse for how he treated other people during that time in his life, and the personal growth that's helped him emerge on the other end of that. Finally, Lance recounts some of favorite stories from his cycling career, reflects on his legacy, and explains how he stays fit at age 50. We discuss:

• What everyone wants to know—yes and no questions [2:15];
• Lance's childhood and beginnings of a great athlete [4:15];
• Lance's realization that he had a knack for racing after his first pro race at age 15 [13:00];
• The move to cycling full time and a desire to compete in the Olympics [16:30];
• Metrics tracked early in Lance's career and his time with Motorola team [20:00];
• The grueling nature of the Tour de France and the beginnings of serious drug usage in cycling [27:00];
• The impact of EPO on cycling performance [35:15];
• Testicular cancer diagnosis—denial, torturous symptoms, and treatment [38:15]
• Livestrong is born [50:45];
• Return to cycling post-cancer and a crossroad in Lance's career [53:45]
• Lance's rise to prominence in the late 90s and the growing use of EPO in the sport [1:00:00];
• Racing in the early 2000's, blood transfusions, and rivalry with Jan Ulrich [1:12:00];
• Retirement in 2005 and a comeback in 2009 [1:22:45];
• Lance's decision to come clean and tell the truth [1:27:30];
• Growth through downfall: learning from his mistakes and helping others after their own fall from grace [1:33:00];
• Moving forward: Living his life, reflecting on his legacy, the state of Livestrong [1:42:30];
• Turning back the clock: Advice Lance would give to his 15 year-old self [1:46:45];
• Keeping fit at age 50 [1:51:00];
• More.

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