Mind & Matter

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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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AquaTru: Water filtration devices that remove microplastics, metals, bacteria, and more from your drinking water. Through link, $100 off AquaTru Carafe, Classic & Under Sink Units; $300 off Freestanding models.
Seed Oil Scout: Find restaurants with seed oil-free options, scan food products to see what they’re hiding, with this easy-to-use mobile app.
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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.
Support the show
Health Products by M&M Partners:
SporesMD: Premium mushrooms products (gourmet mushrooms, nootropics, research). Use code 'nickjikomes' for 20% off.
Lumen device: Optimize your metabolism for weight loss or athletic performance. MINDMATTER gets you 15% off.
AquaTru: Water filtration devices that remove microplastics, metals, bacteria, and more from your drinking water. Through link, $100 off AquaTru Carafe, Classic & Under Sink Units; $300 off Freestanding models.
Seed Oil Scout: Find restaurants with seed oil-free options, scan food products to see what they’re hiding, with this easy-to-use mobile app.
KetoCitra—Ketone body BHB + electrolytes formulated for kidney health. Use code MIND20 for 20% off any subscription (cancel anytime)
For all the ways you can support my efforts