Dr. Peter Attia, Journal Club

Sponsors: Helix Sleep & Levels

Dreams

Article #1, Metformin, Mitochondria, Blood Glucose

Type 2 Diabetes & Causes, Insulin Resistance

Type 2 Diabetes Medications, Metformin, Geroprotection, Bannister Study

Sponsor: AG1

TAME Trial; Demographics, Twin Cohort

Metformin & Mortality Rate

Kaplan-Meier Mortality Curve, Error Bars & Significance, Statistical Power

Sponsor: InsideTracker

Hazard Ratios, Censoring

Metformin Advantage?, Variables, Interventions Testing Program

Berberine, Acarbose, SGLT2 Inhibitors

Blood Glucose & Energy Balance; Caloric Restriction, Aging Biomarkers

Tool: Reading Journal Articles, 4 Questions, Supplemental Information

Article #2, Belief Effects vs. Placebo Effect

Nicotine Effects

Nicotine Doses & Belief Effects, fMRI Scan

Biological Effects, Dose-Dependent Response & Belief Effects

Biology & Beliefs, Significance, Dopamine Response, Non-Smokers

Dose-Dependence & Beliefs, Side Effects, Nocebo Effect

Zero-Cost Support, YouTube Feedback, Spotify & Apple Reviews, Sponsors, Momentous, Neural Network Newsletter, Social Media

- The Huberman Lab Podcast is hosting its first Journal Club episode with Dr. Peter Atiyah.
- Dr. Atiyah will discuss a paper on metformin and its potential role in longevity.
- Andrew Huberman will present a paper on the placebo effect, specifically related to nicotine.
- The episode aims to educate listeners on the discussed research findings and the process of scientific analysis.
- The podcast is separate from the speaker's teaching and research roles at Stanford.
- The podcast aims to provide free information about science and science-related tools to the general public.
- The first sponsor is Helix Sleep, which offers customized mattresses based on a two-minute quiz.
- The second sponsor is Levels, a program that uses a continuous glucose monitor to provide real-time feedback on how different foods and behaviors affect health.

- The Huberman Lab Podcast is hosting its first Journal Club episode with Dr. Peter Atiyah.
- A Journal Club is a practice where students critique and discuss research papers.
- Dr. Atiyah will discuss a paper on metformin and its potential role in longevity.
- Andrew Huberman will present a paper on the placebo effect, specifically related to nicotine.
- The episode aims to educate listeners on the discussed research findings and the process of scientific analysis.

- The podcast is separate from the speaker's teaching and research roles at Stanford.
- The podcast aims to provide free information about science and science-related tools to the general public.
- The first sponsor is Helix Sleep, which offers customized mattresses based on a two-minute quiz.
- The second sponsor is Levels, a program that uses a continuous glucose monitor to provide real-time feedback on how different foods and behaviors affect health.
- Levels is currently offering two free months of membership.

- InsideTracker is a personalized nutrition platform that analyzes data from blood and DNA to help understand the body and meet health goals.
- Regular blood work is important for understanding immediate and long-term health.
- InsideTracker provides a personalized platform to easily understand blood test results and offers protocols to adjust numbers for optimal health.
- InsideTracker's ultimate plan includes measures of ApoB and insulin, which are indicators of cardiovascular health and energy regulation.
- Visit insidetracker.com/Huberman for a 20% discount on any InsideTracker plan.

- The transcript discusses hazard ratios and their interpretation in relation to the use of metformin in diabetes patients.
- The study shows that individuals on metformin have a higher risk of death compared to their non-diabetic counterparts.
- Adjustments for medications, marital status, and education do not significantly change the hazard ratios.
- The study also examines twins and finds that the risk of death is still higher for the twin with diabetes, even after adjustments.
- Censoring, which stops counting deaths in the metformin group, slightly reduces the hazard ratios but does not negate the benefits observed in a previous study.

- The Keys paper suggests that metformin does not offer an advantage to individuals with type two diabetes.
- It is difficult to isolate the specific contribution of metformin in studies due to the use of other medications.
- The study highlights the challenge of controlling for all variables in research.
- The speaker questions the validity of the Bannister paper and stopped taking metformin for a different reason.
- Without a randomized control trial, the true benefits of metformin will remain unknown.

- The speaker used to take metformin to buffer blood glucose levels.
- They stopped taking metformin due to nausea and high lactate levels at rest.
- The speaker used berberine to buffer blood glucose during cheat days on a specific diet.
- They experienced headaches when taking berberine without consuming enough carbohydrates.
- The speaker currently takes an SGLT2 inhibitor due to its potential benefits for non-diabetics.

- Caloric restriction may not offer a survival advantage to humans and is not practical for most people.
- Energy balance plays a greater role in glucose homeostasis than the specific constituents of a meal.
- Metformin may have geroprotective benefits, but more research is needed.
- Short periods of caloric restriction may not have a significant impact on cellular health or longevity.
- Biomarkers for aging are lacking, making it difficult to determine the effectiveness of interventions.

- When reading papers, it is important to spend time with them and read them multiple times.
- It can be helpful to start by identifying the general and specific questions being asked in the paper.
- Understanding the methods used in the study is important, even if you don't need to know every detail.
- The figures in the paper can provide information about what the authors believe they found.
- It is crucial to critically evaluate whether the conclusions drawn in the paper are supported by the findings and methods.

- The transcript discusses a paper that is not yet published but is available on bioRxiv.
- The paper explores how our beliefs about drugs impact their effects on us at a biological level.
- Belief effects are different from placebo effects and can shift psychology and physiology.
- Examples of belief effects include how stress affects performance and how information about a milkshake affects hunger levels.
- Informed hotel workers who were told about the health benefits of exercise lost 12% more weight compared to the control group, despite no difference in actual movement.

- Nicotine improves cognitive performance and enhances focus by increasing the signal-to-noise ratio of sensory information in the brain.
- Nicotine affects various sites in the brain, including the basal forebrain, nucleus basalis, and pedunculopontine nucleus.
- Nicotine increases dopamine release in the mesolimbic reward pathway, which contributes to its reinforcing properties.
- The thalamus sends information to the ventromedial prefrontal cortex, which is involved in attention and focus.
- Nicotine can have a calming effect in the periphery, providing muscle relaxation.

- The study involved smokers who were given a vape pen with different doses of nicotine.
- The participants were then put into a functional magnetic resonance imaging (fMRI) machine to measure brain activity.
- The fMRI machine detects changes in blood flow, indicating brain activation.
- The researchers found that participants' subjective experience of nicotine matched what they were told about the dose.
- The activation of specific brain areas related to attention also correlated with the participants' beliefs about the nicotine dose, even though all participants received the same amount of nicotine.

- The study examined the effects of belief about nicotine strength on brain activation.
- Activation of the thalamus to the ventromedial prefrontal cortex pathway increased with the belief of higher nicotine strength.
- The study did not include a control group with zero nicotine.
- The findings suggest that what we are told about the dose of a drug can influence our physiological response to it.
- The dose-dependent response to belief effects is a novel finding in drug studies.

- The speakers are excited to discuss papers they find interesting in real time on a podcast.
- They want to share their excitement about these findings and help people learn how to analyze scientific papers.
- They used to run a journal club where they would analyze papers in a formal presentation.
- They chose two papers that illustrate opposite ends of the spectrum in terms of technicality.
- They briefly discuss a dream one of them had about a special drink and collecting dew.

- The transcript discusses the activation between the thalamus and the ventromedial prefrontal cortex in relation to nicotine.
- The researchers were surprised that there was no raw difference in thalamus activation, but a difference showed up in the output to the prefrontal cortex.
- The study had a small sample size, which limited the statistical significance of the findings.
- The researchers found that belief about nicotine strength did not modulate the reward response in the brain.
- The discussion raises the question of how nonsmokers would respond to the same experiment.

- The speaker finds it interesting that the dose dependence of belief is being explored in various contexts, such as drugs and vaccines.
- They discuss the impact of beliefs on the brain's reaction to drugs and how it relates to appetite reduction.
- The speaker suggests that belief can affect the effectiveness of lower doses of medication, using the example of ADHD medication.
- They discuss the importance of beliefs in the interpretation of drug side effects and how it can impact the perception of a drug's effectiveness.
- The speaker mentions the nocebo effect and how some individuals are highly impacted by it, making it difficult for them to take medication.

- The speaker asks listeners to support the podcast by subscribing to their YouTube channel, Spotify, and Apple Podcasts, and leaving a five-star review.
- They encourage viewers to leave questions and comments in the YouTube comment section.
- The podcast has partnered with Momentus Supplements, offering a 20% discount on their products.
- They promote their Neural Network newsletter, which provides summaries of podcast episodes and protocols for improving various aspects of health.
- The speaker invites listeners to follow them on social media platforms, where they discuss science-related topics.

- The paper being discussed is titled "Reassessing the Evidence of a Survival Advantage in Type 2 Diabetics Treated with Metformin Compared with Controls Without Diabetes, a Retrospective Cohort Study" by Matthew Thomas Keyes and colleagues.
- The paper is important because it sparked excitement about the potential for geroprotection with metformin.
- Metformin is a drug used for over 50 years as a first-line treatment for type 2 diabetes.
- Metformin inhibits complex one of the mitochondria, which affects the production of ATP.
- Metformin reduces hepatic glucose output and helps control high glucose levels in type 2 diabetes.

- Metformin is a recommended first-line drug for type 2 diabetes.
- Insulin resistance occurs in the muscles, leading to the need for more insulin to transport glucose into cells.
- Insulin resistance is marked by increased insulin levels, not increased glucose levels.
- Inactivity and sleep deprivation can contribute to insulin resistance.
- Insulin resistance can lead to fat accumulation in the muscles, liver, and pancreas, worsening the condition.

- Metformin is a first-line drug for type 2 diabetes and works by addressing hepatic glucose output.
- Other drugs for type 2 diabetes either increase insulin production or provide more insulin.
- GLP-1 agonists increase insulin sensitivity and also stimulate insulin production.
- Berberine is a natural substance with similar properties to metformin and does not require a prescription.
- A study found that patients with type 2 diabetes on metformin had a 15% relative reduction in all-cause death over 2.8 years.

- The speaker has been taking AG1 daily since 2012 and is happy that they are sponsoring the podcast.
- AG1 is a vitamin mineral probiotic drink that provides foundational nutrition.
- The speaker tries to get enough vitamins and minerals from whole food sources but often can't, so AG1 helps fill that gap.
- AG1 also contains adaptogens to help with stress and improves focus, energy, and sleep.
- The speaker recommends AG1 as the one supplement to take and offers a special offer for trying it.

- The Bannister study was previously considered the best evidence for the benefits of metformin.
- The TAME trial is a clinical trial that aims to investigate the effects of metformin on aging.
- The Keys study used a larger sample size and included discordant twins to compare the effects of metformin.
- The study found differences in medication usage between individuals with and without diabetes, which is a limitation.
- Epidemiology studies cannot control for all variables, unlike experimental studies.

- The experiment included a twin trick and a sensitivity analysis with and without informative censoring.
- The crude mortality rate per 1,000 person years was compared between different groups.
- The mortality rate is a way of normalizing and comparing the number of deaths in a specific time period.
- Adjusting for age revealed similar crude death rates between the metformin group and the twin group.
- The study showed a difference in mortality rates between people with diabetes and those without, but it is important to consider the underlying health issues.

- The transcript discusses the use of Kaplan-Meier curves in studies on mortality.
- The curves show cumulative survival over time, with the Y-axis representing cumulative survival and the X-axis representing time.
- The curves in the study show that individuals with type 2 diabetes taking metformin have a higher mortality rate compared to matched controls.
- The shading around the curves represents a 95% confidence interval.
- The transcript also mentions the importance of statistical power and sample size in determining significance in experiments.

Journal Club with Dr. Peter Attia | Metformin for Longevity & The Power of Belief Effects