Mind & Matter

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Gene regulation through RNAs, the neurobiology of opioid addiction, and how psychedelics affect drug-seeking by modulating inflammation and plasticity. Not medical advice.

TOPICS DISCUSSED:

• Gene regulation basics: DNA transcribes to RNAs, including non-coding types like microRNAs that inhibit mRNA translation into proteins, influencing up to 60% of the proteome.
• Non-coding RNAs in neuroplasticity: MicroRNAs and circular RNAs regulate synaptic changes, with activity-induced ones like miR-485-5p linked to rapid responses in drug cue memory and addiction reinforcement.
• Opioid addiction models: Rats self-administer heroin or fentanyl via levers, showing compulsive seeking; fentanyl’s higher potency drives faster learning but similar long-term effects to heroin when doses are equated.
• Differences between opioids: Heroin and fentanyl both activate mu-opioid receptors for euphoria and dopamine release, but fentanyl lingers longer; no major behavioral differences in seeking once potency is matched.
• Psilocybin’s effects on addiction: A single psilocybin dose post-abstinence reduces heroin-seeking in rats by dampening neuroinflammation in brain regions like the nucleus accumbens and prefrontal cortex.
• Brain Inflammation: Opioids induce pro-inflammatory changes via cytokines like IL-17A and pathways like TNF-alpha, leading to glial activation and blood-brain barrier leaks; psilocybin counters this.
• MicroRNA biomarkers: Blood microRNAs reflect gene expression patterns tied to disease states, with potential to predict opioid relapse risk, treatment response, or neonatal withdrawal severity non-invasively.
• Future research: Ongoing work links psilocybin’s serotonin 2A activation to anti-inflammatory gene changes, plus human studies on microRNAs for personalized addiction treatments.

ABOUT THE GUEST: Stephanie Daws, PhD is an associate professor at Temple University in the Center for Substance Abuse Research and Department of Neurosciences, where she researches mechanisms of drug-seeking behavior with a focus on opioids and psychedelics.

RELATED EPISODE:

• M&M 2 | Psilocybin, LSD, Ketamine, Inflammation & Novel Psychedelic Medicines | Charles Nichols

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The biology of fat tissue, estrogen's role in metabolism and health, and how exercise interacts with these processes, especially during menopause.

TOPICS DISCUSSED:

• Adipose tissue basics: White fat primarily stores energy in large lipid droplets, while brown fat burns fatty acids for heat via high mitochondrial density; white fat can “brown” with exercise or certain foods like capsaicin.
• Fat distribution & health: Subcutaneous fat (under skin) is more insulin-sensitive and less problematic than visceral fat (around organs), which links to metabolic issues; females store more subcutaneously pre-menopause, shifting to visceral post-menopause.
• Estrogen signaling: Estradiol binds nuclear and membrane receptors to regulate gene expression and mitochondrial function; it enhances insulin sensitivity and browning in fat cells, with receptors like ER-alpha feminizing fat distribution.
• Fat storage: Fat cells enlarge (hypertrophy) more than multiply in obesity, leading to hypoxia, inflammation, and insulin resistance; excess fatty acids spill to liver and muscle, worsening metabolic dysfunction.
• Menopause effects: Estrogen drop causes visceral fat gain, reduced energy expenditure, insulin resistance, and higher metabolic disease risk; symptoms include hot flashes and reduced exercise motivation, modeled in rodents via ovary removal.
• Exercise & estrogen links: Exercise boosts estrogen receptor expression and mitochondrial density in fat, mimicking estrogen’s browning effects; synergism may explain reduced exercise responsiveness post-menopause.
• Brain-fat connections: Estrogen in the nucleus accumbens influences exercise motivation and fat browning; manipulations there alter running behavior and adipose metabolism in rodents.

ABOUT THE GUEST: Victoria Vieira-Potter, PhD leads a lab at the University of Missouri, studying how estrogen and exercise influence adipose cells.

RELATED EPISODE:

• M&M 174 | Adipose Tissue & Body Fat: Obesity, Insulin, Leptin, Fertility, Weight Loss & GLP-1 Drugs | Sean Hartig

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The brain's mysterious claustrum region, its role in cognitive flexibility, and how substances like alcohol and psychedelics affect neural circuits and behavior. Not medical advice.

TOPICS DISCUSSED:

• Cerebral cortex structure: Described as a six-layered structure with pyramidal neurons and inhibitory interneurons; information flows between layers and regions to process sensory input and enable complex behaviors.
• Claustrum anatomy & connectivity: A sheet-like subcortical structure embedded in white matter, bidirectionally connected to cortical areas, especially prefrontal regions in rodents, with broader connections in primates and humans suggesting an integrative role.
• Claustrum function in cognition: Experiments show claustrum activation during task switches from easy to demanding modes, synchronizing cortical networks via inhibition and rebound excitation, potentially enabling flexible behavior.
• Mouse models in neuroscience: Mice are used for genetic tractability to manipulate and monitor specific circuits, revealing claustrum’s role in vigilance tasks but not simple ones.
• Alcohol’s effects on brain circuits: Chronic alcohol promotes inflexible behaviors by altering striatal interneurons and inhibitory inputs, leading to compulsive drinking despite aversive consequences.
• Psychedelics & brain networks: Psilocybin disrupts default mode and other networks, inhibits claustrum via serotonin 1B receptors, with effects persisting 24 hours, possibly contributing to therapeutic benefits.
• Evolution of claustrum: Connectivity expands from rodents to humans, shifting from cognitive-specific to broader network control, including anti-correlated states like default mode versus task-engaged.
• Integration of claustrum & basal ganglia: Claustrum funnels prefrontal signals to basal ganglia for action selection; alcohol may impair this, exacerbating inflexibility in addiction.

ABOUT THE GUEST: Brian, PhD is a professor in the Department of Pharmacology and Physiology at the University of Maryland School of Medicine, where he leads a neuroscience lab studying brain circuits underlying flexible and inflexible behaviors using mouse models, with a focus on alcohol use disorder.

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Pharmacology & neurobiology of psychedelics & MDMA, focusing on isomers, sex-specific effects, and mechanisms in animal models. Not medical advice.

TOPICS DISCUSSED:

• Biased agonism: Different drugs activate the same receptor (e.g., 5-HT2A) but trigger varied intracellular pathways, explaining why LSD is psychedelic while similar lisuride is not.
• Enantiomers & isomers: Mirror-image versions of drugs like MDMA (S and R forms) and LSD (four isomers) often produce distinct effects; only one LSD isomer is psychedelic, for example.
• MDMA isomer effects: S-MDMA induces stronger head twitches (psychedelic proxy) via serotonin release, and increases dendritic spines in male mice but not females; R-MDMA has somewhat different effects.
• Sex-specific drug responses: In mice, females show stronger psychedelic effects (head twitches) from psilocybin and DOI at the same dose, but males exhibit greater post-acute benefits like reduced opioid withdrawal.
• Psilocybin in opioid addiction models: A single dose reduces place preference for oxycodone and withdrawal symptoms in male mice more than females, with opposite spine density effects in reward-related brain areas.
• Mechanisms beyond 5-HT2A: Psychedelics involve other receptors like metabotropic glutamate receptors, forming dimers with 5-HT2A to enable dual signaling pathways; effects in subcortical regions like nucleus accumbens are 5-HT2A-independent.
• Clinical implications: Street MDMA may vary in S/R ratios, affecting experiences; clinical trials often use racemic mixtures without weight-adjusted dosing, potentially missing sex differences.

ABOUT THE GUEST: Javier Gonzalez-Maeso, PhD is a professor of pharmacology and toxicology at Virginia Commonwealth University, with a PhD in medicine from Spain focused on G-protein coupled receptors and human brain studies in depression and addiction.

RELATED EPISODE:

• M&M 230 | Psilocybin & MDMA: Inflammation, Stress & Brain-Body Communication | Michael Wheeler

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The AMP kinase pathway's role in cellular energy sensing, nutrient allocation, and its connections to health practices like fasting, exercise, and diet.

TOPICS DISCUSSED:

• Cellular energy basics: ATP/ADP/AMP as energy currencies; AMP kinase activates on low ATP to conserve and redirect resources, like a budget manager.
• AMP kinase mechanics: Heterotrimeric enzyme phosphorylating 100+ substrates; localizes dynamically in cytosol, mitochondria, nucleus to integrate signals.
• Nutrient detection: Senses fatty acids in fasting/ketogenic states, boosting fat oxidation and mitochondria independent of energy drops.
• Fasting/exercise impacts: Elevate AMP kinase for mitophagy, better fuel switching; mimic historical scarcity absent under modern constant feeding.
• mTOR relationship: AMP kinase inhibits mTOR to stop growth in low energy states; feedback loop disrupted by abundance, promoting tissue buildup.
• Disease links: Low AMP kinase in obesity/diabetes reduces flexibility; activation prevents cancer but may aid tumor survival in therapy.
• Drugs/diets: Metformin and GLP-1s like Ozempic activate AMP kinase for glucose control/weight loss; ketogenic diets activate at intermediate levels for fat efficiency.

ABOUT THE GUEST: Gregory Steinberg, PhD is a Professor of Medicine at McMaster University and co-directs the Centre for Metabolism, Obesity, and Diabetes Research, focusing on cellular energy sensors like AMP kinase.

RELATED EPISODE:

• M&M 260 | Energy Resistance Principle in Life, Healing & Disease | Martin Picard & Nirosha Murugan

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How industrial farming, seed oils, soy, and pesticides impact food nutrition and health. Not medical advice.

TOPICS DISCUSSED:

• Soy’s rise in farming: Originating from paint uses and wartime chemicals, soy became dominant due to subsidies and large-scale farming practices, but introduces high PUFAs, phytoestrogens, and pesticides into animal feeds.
• Feed’s impact on eggs: Chicken feeds high in soy and corn raise linoleic acid levels in eggs compared to low-soy alternatives; low-PUFA eggs improve digestibility for many.
• PUFAs & health effects: Feeding PUFAs fattens animals faster and disrupts human gut lining and metabolism; body fat composition changes take time, linking to chronic issues like low energy.
• Phytoestrogens in soy: These compounds pass into animal products, affecting estrogen signaling and gut health; mainstream nutrition often overlooks their risks despite historical low exposure.
• Dairy variations: Raw milk retains lactoferrin for iron regulation and gut support, plus enzymes and probiotics destroyed in pasteurization; it may resolve dairy intolerances for some.
• Regenerative farming model: Armstrong’s cooperative emphasizes traditional feeds to “resaturate” foods, reducing PUFAs; supports small farms amid declining farm numbers.
• Ancestral diets insight: Traditional diets vary but share low PUFA levels, avoiding modern chronic illnesses tied to industrial fats.

ABOUT THE GUEST: Ashley Armstrong, PhD co-founded Angel Acres Farm in Michigan and now runs Nourish Food Club, a cooperative of small farms producing low-PUFA, soy-free animal foods.

RELATED EPISODE:

• M&M 273: Nutrition Content of Animal & Plant Foods: Beef, Plant-Based Meat, Raw vs. Processed Milk

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How individuals vary in responses to carbs, fibers, and fats.

TOPICS DISCUSSED:

• Personalized health profiling: Snyder’s lab sequences genomes and measures molecules from blood, urine, and microbiomes to detect diseases early, emphasizing data-driven discovery over assumptions.
• Fiber variations and effects: Responses to dietary fibers vary individually, with microbiome playing a key role.
• Glycemic responses to carbs: People spike differently to foods like rice, potatoes, or bread; tied to insulin resistance subtypes in muscles, liver, or pancreas.
• Type 2 diabetes heterogeneity: 90% of diabetes cases are type 2 with subtypes like muscle or hepatic resistance; triggers include genetics and infections, with prediabetes often undetected.
• Continuous glucose monitors (CGMs): Affordable tools measure glucose every five minutes, revealing personal food triggers; spikes link to risks like cardiovascular disease and cancer.
• Lipidomics: Lipids are diverse, serving as energy sources, structural components, and signaling molecules; understudied but key in metabolism and gene expression.
• Maternal health & pregnancy: Metabolomics shows thousands of changes, including hormone shifts; cord blood analysis reveals fetal nutrient use and drug transfers, with markers for preterm birth or healthy outcomes.
• Future research: Exploring epigenetic changes in diabetes, personalized nutrition mitigation, and digital markers from wearables for mental health tied to diet and gut-brain axis.

ABOUT THE GUEST: Michael Snyder, PhD is the Stanford W. Ascherman Professor of Genetics and former chair of the Department of Genetics at Stanford University School of Medicine, where he directs the Center for Genomics and Personalized Medicine.

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How agricultural practices influence the nutrient density of foods, particularly meat, and the importance of hidden compounds beyond standard nutrition labels.

TOPICS DISCUSSED:

• Nutrient density profiling: Labs analyze thousands of compounds beyond macros and vitamins; this “dark matter” includes phytonutrients that may support health despite not being essential.
• Phytonutrients in foods: Plant secondary metabolites like polyphenols act as antioxidants and influence pathways like mTOR; animals convert plant compounds into bioactives humans access via meat.
• Red meat definition: Refers to meats high in myoglobin, including beef and lamb; most meats are red in wild forms, but human intervention affects color and classification.
• Ruminant animals: Animals like cows that have multi-chambered stomachs to digest plants; this metabolism differs from non-ruminants (e.g. chickens), affecting nutrient profiles in their meat.
• Grass-fed vs. grain-fed beef: Grass-fed has higher omega-3 fats and phytonutrients from diverse plants; studies show it improves human omega-6:3 ratios and biomarkers from grass-fed, pastured-raised animals.
• Farming practices & variations: Plant diversity boosts beef nutrients.
• Upcoming research: Long-term trials on effects of pasture-raised foods on human health; interactive dashboards for farmers to profile nutrients and inform policy.

ABOUT THE GUEST: Stephan Van Vliet, PhD is an Assistant Professor in the Department of Nutrition, Dietetics, and Food Sciences at Utah State University, where he directs the Center for Human Nutrition Studies, focusing on linking food production systems to nutrient profiles and conducting clinical trials on health impacts.

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Cellular metabolism, mitochondrial health, and the roles of diet and environment in metabolic health, fetal & child development, and Alzheimer's.

TOPICS DISCUSSED:

• Cellular growth vs. burning: Cells alternate between growing (using glucose for building blocks in low-oxygen environments) and burning (generating ATP in mitochondria with oxygen); dysregulation leads to metabolic issues.
• Key regulatory enzymes: PI3 kinase imports glucose, AMP kinase builds mitochondria, and mTOR drives cell division; their synchronization determines healthy modes, while desynchronization causes diseases.
• Fructose as a dose-dependent mitochondrial toxin: High fructose intake inhibits AMP kinase, reducing mitochondrial function and diverting energy to fat storage; it is dose-dependent, like alcohol, and unnecessary in the diet.
• Obesogens & endocrine disruptors: Chemicals like tributyltin (TBT) alter gene expression across generations, promoting obesity unrelated to calories; modern exposures increase reactive oxygen species (ROS), burdening cells.
• Fetal & neonatal development: Maternal diet, especially high sugar or formula feeding, can cause neonatal obesity and fatty liver; breastfeeding supports proper jaw development and oxygen intake.
• Brain metabolism & Alzheimer’s: The brain’s high energy needs make it vulnerable to mitochondrial issues and ROS; energy deficits from diet, stress, and toxins lead to synapse loss and inflammation, treatable via prevention.
• ROS & health: Mitochondria produce ROS as a byproduct of ATP generation; excess from diet or environment causes damage, but antioxidants and lifestyle can mitigate risks.

PRACTICAL TAKEAWAYS:

• Limit added sugars in your diet to reduce mitochondrial stress and ROS, focusing on whole foods over ultra-processed items for better metabolic health.
• Prioritize breastfeeding for infants when possible to support proper physical development and reduce future metabolic risks.
• Incorporate regular exercise and social activities to manage stress and boost brain-protective factors like BDNF, aiding neurodegeneration prevention.
• Get adequate sleep to regulate cortisol and maintain cellular energy balance, helping prevent brain fog and chronic diseases.

ABOUT THE GUEST: Robert Lustig, MD is a pediatric endocrinologist and Professor Emeritus at the University of California, San Francisco, with a background in neuroendocrinology and obesity research.

*Not medical advice.

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Deep dive into how ketogenic diets and carbohydrate intake effect exercise performance, and misconceptions in sports nutrition.

TOPICS DISCUSSED:

• Insulin as a powerful metabolic hormone: regulates nutrient storage across tissues, overriding others like glucagon to promote fat and glucose storage during abundance.
• Glucagon & GLP-1 roles in metabolism: Glucagon mobilizes liver glucose during scarcity; GLP-1, amplified in drugs like Ozempic, suppresses hunger but originated as a diabetes treatment.
• Transition to ketosis in fasting or low-carb diets: Low insulin enables fat breakdown into ketones for brain fuel, allowing survival for weeks without food, with adaptation taking about four weeks.
• Hypoglycemia vs. glycogen depletion: Low blood sugar causes fatigue and irritability due to brain energy deficit, while muscle glycogen levels do not directly limit performance.
• Ketogenic diets & exercise performance: Studies show no difference in endurance after adaptation, with some athletes performing better on low-carb due to enhanced fat oxidation.
• High-carb diets in athletes: In one study, about 30% developed prediabetes-like fasting glucose elevations, linked to total carb intake, despite leanness and fitness.
• Misconceptions in sports nutrition: Guidelines recommend 60-90g carbs/hour, but evidence shows 10g suffices to maintain blood sugar and performance, avoiding insulin spikes that impair fat use.
• Individual variability in diet response: Athletes vary in optimal fuel sources; it’s possible to by athletic and lean but also metabolically unhealthy.

PRACTICAL TAKEAWAYS:

• For workouts over ~60 minutes, consume ~10g carbs per hour (e.g., a third of a banana) to maintain blood sugar and prevent fatigue, regardless of overall diet.
• Allow at least four weeks for adaptation when trying a ketogenic diet, enabling the body to fully transition to the ketogenic state.
• Monitor personal responses to carb intake, as high levels can elevate fasting glucose even in fit individuals; consider lower-carb options if experiencing metabolic issues.
• Prioritize metabolic flexibility through varied diets or fasting periods to improve energy stability, but consult resources for proper formulation to support health.

ABOUT THE GUEST: Andrew Koutnik, PhD earned a PhD in biomedical sciences with a focus on exercise physiology and metabolic health, informed by his personal diagnosis of type 1 diabetes in childhood.

*Not medical advice.

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