00:00 Dr. Peter Atia and Andrew Huberman discuss two papers in their first online collaborative Journal Club, one on metformin for longevity and another on the dose response of the placebo effect using nicotine.

07:02 The paper discussed in this section is titled "Reassessing the Evidence of a Survival Advantage in Type 2 Diabetics Treated with Metformin, Paired with Controls Without Diabetes, A Retrospective Cohort Study" and it is important because it challenges the previous findings that suggested a survival advantage with metformin treatment for type 2 diabetes.

15:01 Metformin works by changing the way the body partitions fuel, reducing the amount of glucose the liver puts out, and improving insulin resistance in muscles, making it a first-line agent for type 2 diabetes.

22:44 Type 2 diabetes is characterized by insulin resistance, which leads to elevated glucose levels and a vicious cycle of glucose accumulation in the liver and inability of muscles to dispose of it, ultimately requiring exogenous insulin; causes of insulin resistance include energy imbalance, inactivity, sleep deprivation, and hypercortisolemia, among others; metformin is a first-line drug for type 2 diabetes and addresses the problem of glucose output by the liver.

29:59 A study found that patients with type 2 diabetes who took metformin had a 15% reduction in all-cause mortality over 2.8 years, suggesting that metformin may have benefits beyond lowering blood glucose levels.

38:02 A study used a larger sample size and a twin analysis to investigate the effects of metformin on mortality rates, but the study had limitations due to unmatched medication use among participants.

45:55 The study analyzed mortality rates per 1,000 person years and found a difference between individuals with diabetes who took metformin and those who did not, indicating that metformin may be associated with a higher mortality rate in individuals with diabetes.

54:08 The study used a mathematical model called a Cox proportional hazard to predict mortality rates over time and the shaded areas on the graph represent the 95% confidence intervals.

01:01:48 The study found that individuals taking metformin had a 48% greater chance of dying in any given year than their non-diabetic counterparts, and even after adjusting for various factors, the hazard ratio remained at 1.32, indicating a 32% increased risk of death.

01:09:42 The speaker stopped taking metformin for geroprotection after noticing high lactate levels at rest.

01:17:14 The speaker used berberine as a glucose disposal agent to buffer blood glucose levels and prevent spikes in blood sugar after cheat days on a slow carb diet.

01:24:43 The speaker discusses the potential benefits and drawbacks of caloric restriction and fasting for longevity, but concludes that there is currently no evidence to suggest that short periods of caloric restriction or intermittent fasting can help us live longer.

01:32:46 The speaker discusses their process for reading scientific papers, which involves asking four key questions: the general and specific questions being asked, the approach used to test the question, what was found, and whether the conclusions are supported by the findings; they also mention the importance of looking up unfamiliar methods and the abundance of supplemental information in papers.

01:40:01 Belief effects, which are different from placebo effects, can significantly impact performance and physiology, such as stress decreasing performance and belief in stress enhancing performance, and belief in the health benefits of exercise leading to greater weight loss, suggesting that the brain can activate physiological mechanisms based on one's beliefs.

01:47:02 Nicotine can enhance focus in the brain while providing muscle relaxation in the periphery, making it a potentially ideal drug, as shown in a study where experienced smokers were given different doses of nicotine and then underwent functional magnetic resonance imaging to measure brain activity.

01:53:52 Functional magnetic resonance imaging (fMRI) has limitations in terms of resolution, but it can be used to measure brain activity during resting state and activation state, and a study using fMRI showed that belief effects can actually change the way the brain responds to nicotine.

02:00:57 The study found that the belief about the dose of nicotine induced a dose-dependent response in the thalamus, and the activation of the thalamus was amplified as it made its way forward in the brain.

02:08:38 Belief about the dose of a drug can impact the activation of reward pathways in the brain, suggesting that the power of belief plays a role in how our brain reacts to drugs and interventions.

02:16:19 The power of belief can lead to the nocebo effect, making it difficult for some individuals to take medication due to the anticipation of side effects, and medical students often develop a warped sense of the prevalence of certain conditions.