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

Huberman Lab

Sun Sep 10 2023



Kaplan-Meier Curves:

  • The Kaplan-Meier curves in Figure 1 show the cumulative survival over time for the matched singletons and discordant twins.
  • In both sets of curves, the line representing people with type 2 diabetes on metformin is consistently below the line representing their matched controls, indicating a higher mortality rate for those taking metformin.

Crude Mortality Rate:

  • Table 2 presents the crude mortality rate per thousand person years.
  • For the singletons, the rate is 16.86 deaths per thousand person years for those without diabetes and 24.93 deaths per thousand person years for those with diabetes on metformin.
  • When comparing twins, there is a similar pattern with a higher crude mortality rate among individuals with type 2 diabetes who take metformin compared to their non-diabetic counterparts.

Informative Censoring:

  • The study also conducted a sensitivity analysis that included or excluded informative censoring, which means they considered whether or not to count patients who deviated from inclusion criteria due to various factors such as being lost to follow up or progressing to needing more significant medication.
  • This analysis was done because excluding patients who progressed may have biased the results by only including a specific subset of patients.

Medication Differences:

  • One limitation of this study is that medication usage varied significantly between groups, particularly when comparing those with diabetes taking metformin versus those without diabetes.
  • These differences make it difficult to isolate the effects of metformin alone since other medications could contribute to outcomes.

Confidence Intervals:

  • In parentheses after each value presented in the table, there are confidence intervals indicating the range within which the true value likely falls with 95% confidence.
  • If a confidence interval does not include zero (for relative values) or does not overlap between groups (for absolute values), it suggests statistical significance.

Study Design:

  • This study used a larger sample size than previous studies, including both singletons and discordant twins to allow for further comparison.
  • The inclusion of twin pairs with one having diabetes and the other not provides a unique opportunity to investigate potential genetic or environmental factors influencing outcomes.

Age Adjustment:

  • Age adjustment was also conducted to account for any differences in mortality rates based on age among the groups.
  • After adjusting for age, the crude mortality rate among individuals with type 2 diabetes taking metformin remained significantly higher compared to those without diabetes.

Belief Effects:

  • Belief effects are different from placebo effects as they involve the impact of our beliefs on the actual biological response to a drug or intervention.
  • This paper explores how beliefs about drugs can influence their effectiveness and shows that our perceptions and expectations play a significant role in shaping the physiological response.

Examples of Belief Effects:

  • Studies have shown that people who believe stress impairs performance often perform worse under stressful conditions, while those who believe stress enhances performance tend to perform better.
  • The way we perceive medication can also have an impact. For example, participants who believed they were taking a high-calorie shake experienced more suppression of ghrelin (hunger hormone) than those who believed they were having a low-calorie shake when both groups consumed identical shakes.

Study on Nicotine and Belief Effects:

  • In this study, researchers investigated the cognitive-enhancing effects of nicotine and examined whether these effects could be influenced by individuals' beliefs about nicotine's cognitive benefits.
  • Participants were randomly assigned to either the "Nicotine" group or the "No Nicotine" group. However, all participants received identical 3 mg nicotine lozenges. The only difference was in the instructions given to each group. Result: - Results showed that participants in the "Nicotine" group performed significantly better on cognitive tasks compared to those in the "No Nicotine" group, even though both groups received identical treatments.:

Limitations and Future Directions:

  • While this study provides compelling evidence for belief effects on nicotine's cognitive benefits, further research is needed to validate and explore these findings.
  • It is essential to examine other factors that may modulate belief effects, such as individual differences in susceptibility to placebo effects, prior experience, and the role of expectations.
  • Future studies should also explore the underlying mechanisms behind belief effects and how they can be harnessed in clinical settings for improved treatment outcomes.

Thalamus and Nicotine:

  • Thalamus serves as a gateway for sensory information, including visual and auditory information.
  • The thalamus contains nicotinic receptors that are activated by nicotine or the release of nicotine by the pedunculopontine nucleus.
  • Nicotine increases the signal-to-noise ratio of sensory information coming into the cortex, enhancing conscious perception of senses.

Brain Activation and Belief Effects:

  • Our beliefs about drugs can impact how our brain responds to them.
  • In a study on nicotine dosage belief effects, people's subjective feeling of being on the drug matched what they were told about the dose.
  • Brain activation in areas such as the thalamus scaled with perceived nicotine dosage, even when all participants received the same low amount of nicotine.

Reward Pathways and Ventromedial Prefrontal Cortex:

  • The thalamus sends information to reward centers in the brain and to the ventromedial prefrontal cortex (VMPFC), which regulates focus and attention.
  • ADHD medications like Adderall can enhance VMPFC function, allowing better engagement and focus. This circuitry plays a role in attention disorders. Consideration Note: People with ADHD have difficulty engaging their minds in certain tasks but can be more focused when interested or engaged.:

Placebo Effects:

  • Beliefs about drugs can affect placebo responses and even influence response patterns in specific brain areas.
  • Experimentation has shown that side effects reported during drug trials can be interpreted differently depending on beliefs about those side effects.

Implications for Medicine:

  • Understanding belief effects is important for drug development and dosing strategies.
  • By harnessing belief effects, it may be possible to optimize medication efficacy while minimizing side effects.
  • Other factors like nutrition and lifestyle changes may also impact health outcomes through belief-mediated mechanisms.