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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 ped

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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:

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Neurobiology of maternal care in mammals: hormonal influences, stress effects & a study on psilocybin's unexpected effects during the postpartum period.

Sponsor: SporesMD. Use code TRIKOMES for 20% off pharmaceutical-grade mushroom liquid cultures & mycology products.

Topics Discussed:

• Maternal care behavior in rodents: Nursing, pup retrieval, grooming, and nest-building, essential for altricial pups’ survival; conserved across mammals but varies by species.
• Hormonal changes in pregnancy: Estradiol and progesterone surge then drop at birth, crossing the blood-brain barrier to enable infant attraction and care via gene expression and neuroplasticity.
• Brain circuitry for parenting: Medial preoptic area acts as a central hub, coordinating motivation and sensory inputs; present in both sexes but activated differently by hormones and experience.
• Stress impacts on mothers: Social stressors like male intruders dysregulate care, leading to frantic behaviors and avoidance; models human psychosocial stress linked to postpartum mood disorders.
• Sex differences in pup care: Mothers groom male pups more, influencing sexual behaviors, which effects future behavior.
• Psilocybin in postpartum mice: Single dose increased anxiety in mothers, showed no antidepressant effects, and transferred via milk, causing long-term anhedonia and impairments in offspring as adults.
• Serotonin system development: Early exposure to serotonergic drugs like psilocybin or SSRIs alters lifelong behavior, highlighting sensitive periods in brain reorganization.

Practical Takeaways:

• Reduce postpartum stress through social support to enhance maternal bonding and minimize mood disorder risks.
• Approach psychedelics cautiously during postpartum due to potential anxiety increases and offspring effects via milk.
• Recognize hormonal shifts heighten sensitivity to infant cues, aiding natural caregiving instincts.
• Monitor environmental factors like food availability or threats that could disrupt parental behaviors in high-stress scenarios.

About the guest: Danielle Stolzenberg, PhD is an associate professor of psychology at the University of California, Davis, where her lab studies the neurobiology of maternal care.

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Metabolic effects of soybean oil and linoleic acid on obesity, fatty liver, and liver function.

Topics Discussed:

• Historical trends in soybean oil use: Consumption increased dramatically since the 1960s due to farming subsidies, now providing over 10% of calories for many Americans, far exceeding the 1-2% required biologically.
• Soybean oil’s effects in mice: Diets with 8-10% linoleic acid cause obesity, fatty liver, and diabetes over weeks, unlike coconut oil diets; effects persist even after diet switch unless combined with fasting.
• Role of HNF4 protein: This conserved liver transcription factor binds linoleic acid, regulating gene expression for metabolism; variants shift between carbohydrate and fat processing, with imbalances linked to fatty liver and cancer.
• Oxylipins from linoleic acid: Conversion in liver drives obesity; mice unable to produce them resist weight gain on soybean oil, suggesting these metabolites are key culprits.
• Vitamin B1 & soybean oil: Diets deplete B1 in liver and blood, contributing to obesity; supplementation with B1 analogs prevents weight gain, unlike beef tallow diets which preserve B1 levels.
• Gut & microbiome impacts: Soybean oil alters gut bacteria, potentially reducing B1 production and increasing permeability, leading to inflammation; farm animals fed soybean meal pass effects to consumers.
• Broader health implications: Reanalysis of old human studies questions linoleic acid’s heart benefits; focus on reducing processed foods and seed oils, while noting olive oil’s advantages from historical contexts.

Practical Takeaways:

• Limit processed foods and seed oils like soybean to reduce linoleic acid intake, aiming for 1-2% of calories; read labels and opt for olive oil or home-cooked meals.
• Incorporate intermittent fasting, such as 12-16 hours without eating daily, to help reverse obesity effects from high-linoleic diets, based on mouse reversibility studies.
• Choose grass-fed or naturally fed animal products to avoid indirect soybean oil exposure from feed, potentially preserving nutrient levels like vitamin B1.
• Monitor diet when traveling or changing habits, as shifts in oil types can affect medication metabolism via liver enzymes.

About the guest: Frances Sladek, PhD is a professor

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How seasonal changes in light and dietary unsaturated fats affect circadian rhythms in mammals.

Topics Discussed:

• Evolutionary context of circadian rhythms: All organisms have adapted to Earth’s 24-hour day for survival, with internal clocks slightly offset and adjusted by environmental cues.
• Molecular clock mechanism: Involves a feedback loop where proteins turn on/off genes, lasting ~24 hours, regulated by phosphorylation and degradation for timing precision.
• Genetic variations in sleep: Families with mutations in clock genes like PER2 cause extreme morning lark behavior, altering protein stability and period length by hours.
• Light entrainment: Morning light shortens human clocks (average 24.2 hours) to match 24-hour days; seasonal day length changes require gradual adjustments.
• Food & metabolic links: Seasonal food scarcity/abundance affects clock via glucose and fatty acids competing for protein modifications, as shown in diabetic mouse models.
• Role of unsaturated fats: Paper finds MUFA/PUFA ratios in diet alter phosphorylation of clock proteins, speeding or slowing adaptation to winter/summer light cycles in mice.
• Modern environmental impacts: Artificial light extends “daytime” signals, while constant food access erases seasonal patterns, contributing to obesity and diabetes risks.
• Jet lag & adaptations: Sudden time shifts mimic seasonal experiments; high-sugar/fat intake may phenocopy genetic effects to aid adjustment, though not recommended for health.

Practical Takeaways:

• Expose yourself to morning natural light to help synchronize your internal clock and improve daily energy.
• Consume main meals during daylight hours and avoid late-night eating to align with natural metabolic rhythms.
• Limit evening screen time to reduce artificial blue light disrupting sleep onset.
• Consider varying diet seasonally, favoring diverse, whole foods to mimic natural availability patterns for better health.

About the guest: Louis Ptacek, MD is a neurologist and professor at the University of California, San Francisco. He researches inherited neurological diseases and sleep traits, including genetic variations causing extreme early rising.

Related Episode:

• M&M 237:

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