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Pregnenolone, a neurosteroid derived from cholesterol, affects brain activity and shows promise for treating mood and substance abuse disorders.
TOPICS DISCUSSED:
Steroid Biosynthesis: Cholesterol converted to pregnenolone, the precursor for all steroid hormones including cortisol, aldosterone, and sex hormones.
Corticosteroids: Synthetic versions like prednisone primarily target glucocorticoid receptors for anti-inflammatory uses but can impact mood and cognition.
Pregnenolone Mechanisms: Positive allosteric modulator of NMDA receptors for cognition and negative allosteric modulator of CB1 cannabinoid receptors.
Allopregnanolone: GABAergic derivative of pregnenolone; its IV form Brexanolone is FDA-approved for postpartum depression.
Clinical Trials: Pregnenolone at 100-500 mg improved depressive symptoms in placebo-controlled studies of bipolar disorder patients.
Cannabis Interaction: THC robustly induces brain pregnenolone production; supplementation may reduce cannabis and alcohol use.
Corticosteroid Brain Impact: Prednisone use associated with smaller hippocampal volumes and memory deficits.
ABOUT THE GUEST: Sherwood Brown, MD, PhD is Vice Chair for Clinical Research in the Department of Psychiatry at the University of Texas Southwestern Medical Center in Dallas. With a background in chemistry, his research focuses on steroids and comorbidities in people with mood disorders.
RELATED EPISODE:
M&M 124: Hormonal Contraception, Sex Hormones, Menstruation, Pregnancy, Puberty, Estrogens, Androgens, Effects of Birth Control on Cognition | Adriene Beltz
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How omega-3 fats in human health, including dietary intake needs, supplements, & omega fat testing.
TOPICS DISCUSSED:
ω-3 chemistry: EPA and DHA differ from plant ALA in chain length and double-bond count, making them structurally and biologically distinct — and largely irreplaceable by ALA conversion.
ALA-to-EPA/DHA conversion: A small percentage of dietary ALA converts to EPA, and conversion to DHA is even lower; vegans rely on this inefficient pathway for all long-chain omega-3s.
Cardiovascular mechanisms: ω-3s lower triglycerides, reduce platelet stickiness, improve endothelial function, and slow resting heart rate, reducing cardiovascular risk.
ω-3 Index: Defined as red blood cell EPA+DHA as a percent of total fatty acids; 8–12% is the target range, while most Americans sit around 4–5%.
Brain & dementia risk: Higher DHA blood levels are associated with significantly lower risk of dementia and Alzheimer’s in large cohorts including the UK Biobank and Framingham.
Linoleic acid nuance: Higher blood levels of dietary linoleic acid (omega-6) associate with lower dementia and cardiovascular risk; downstream omega-6 metabolites — not linoleic acid itself — associate with adverse outcomes.
Supplementation practicalities: Most people need 1–2 g/day of EPA+DHA to reach an ω-3 Index >8%; oxidation concerns with fish oil supplements may be overstated.
ABOUT THE GUEST: Bill Harris, PhD is founder of both OmegaQuant Laboratory and the Fatty Acid Research Institute (Sioux Falls, SD), where his work centers on blood fatty acid biomarkers as predictors of disease risk in large population cohort studies.
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OmegaQuant: At-home blood testing to see fatty acid profiles, including omega-3 fatty acids. Use link to see options and support M&M.
RELATED EPISODE:
M&M 134: Omega Fats, Vegetable & Seed Oils, Sugar, Processed Food, Metabolic Health & Dietary Origins of Chronic Inflammatory Di
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OmegaQuant: At-home blood testing to see fatty acid profiles, including omega-3 fatty acids. Use link to see options and support M&M.
SiPhox Health: Comprehensive, cost-effective bloodwork from the comfort of home. Use code TRIKOMES for 20% off.
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How dietary fatty acids regulate the initiation, propagation, and resolution of inflammation.
TOPICS DISCUSSED:
Parenteral nutrition history: IV nutrition evolved from soybean oil alone in the 1960s to complex blends including fish oil as the biology of ω-3s became understood.
Three phases of inflammation: Initiation, propagation (driven by ω-6–derived prostaglandins and leukotrienes), and active resolution (driven by ω-3-derived resolvins and protectins).
Pro-resolving mediators: Resolution is an active biological process, not passive; EPA and DHA generate resolvins and protectins that actively terminate inflammation.
Aspirin’s ω-3 mechanism: Aspirin inhibits arachidonic acid metabolism but allows EPA/DHA to access COX-2, upregulating pro-resolution mediators — a likely underappreciated mechanism of action.
Cell membrane competition: EPA and DHA physically displace arachidonic acid in membranes, shifting the balance of mediators produced and improving resolution capacity.
Linoleic acid & EPA synthesis: High linoleic acid intake saturates shared desaturase enzymes, inhibiting the body’s conversion of ALA to EPA — meaning reducing ω-6 can raise ω-3 levels without supplementation.
Dose & timing of ω-3 incorporation: ~2g/day of EPA+DHA shifts the arachidonic acid-to-EPA ratio enough to measurably reduce prostaglandin E2 production; white blood cells reflect changes within a month.
ABOUT THE GUEST: Philip Calder, PhD is Professor of Nutritional Immunology in the Faculty of Medicine at the University of Southampton. His research focuses on how dietary fatty acids — particularly omega-3s — modulate immune responses and inflammatory processes across clinical and healthy populations.
RELATED EPISODE:
M&M 200: Dietary Fats & Seed Oils in Inflammation, Colon Cancer & Chronic Disease | Tim Yeatman & Ganesh Halade
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OmegaQuant: At-home blood testing to see fatty acid profiles, including omega-3 fatty acids. Use link to see options and support M&M.
SiPhox Health: Comprehensive, cost-effective bloodwork from the comfort of home. Use code TRIKOMES for 20% off.
KetoCitra—Ketone body BHB + electrolytes formulated for kidney health. Use code MIND20 for 20% off any subscription (cancel anytime)
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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A metabolic view of Alzheimer's disease & the recent discovery of compounds that reverse advanced disease symptoms in mouse models by restoring mitochondrial health.
TOPICS DISCUSSED:
Classic Alzheimer’s pathology: amyloid plaques and tau tangles identified over 120 years ago, long assumed to drive irreversible neuron loss.
Limitations of amyloid focus: plaques appear in some cognitively normal brains; antibody therapies have shown limited clinical benefit.
Metabolic perspective: brain energy failure as a tipping point where repair mechanisms are overwhelmed, linking genetics, injury, and aging.
Neuroprotection via P7C3 compounds: discovered through hippocampal neurogenesis screen; preserves mitochondrial function and normalizes NAD/NADH ratio without elevating NAD excessively.
Recovery in models: treatment after symptom onset reversed cognitive deficits, blood-brain barrier damage, oxidative stress, and axon issues in amyloid and tau mouse models, despite persistent plaques.
Broader implications: energy restoration enables surviving neurons to function; similar protective effects seen in TBI and other organs under stress.
ABOUT THE GUEST: Andrew Pieper, MD, PhD, is a board-certified psychiatrist and neuroscientist, professor at Case Western Reserve University, and director of the Brain Health Medicines Center at the Harrington Discovery Institute. He directs a research group focused on neuroprotection after brain injury and neurodegenerative disease.
RELATED EPISODE:
M&M 208: Glyphosate, Choline & Alzheimer’s: Toxins & Nutrition to Prevent Neurodegeneration | Ramon Velazquez
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Health Products by M&M Partners:
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.
OmegaQuant: At-home blood testing to see fatty acid profiles, including omega-3 fatty acids. Use link to see options and support M&M.
SiPhox Health: Comprehensive, cost-effective bloodwork from the comfort of home. Use code TRIKOMES for 20% off.
KetoCitra—Ketone body BHB + electrolytes formulated for kidney health. Use code MIND20 for 20% off any subscription (cancel anytime)
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.
SporesMD: Premium mushrooms products (gourmet mushrooms, nootropics, research). Use code 'nickjikomes' for 20% off.
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How exercise in parents can improve the metabolic and cardiovascular health of their offspring through epigenetic mechanisms.
TOPICS DISCUSSED:
Parental exercise & offspring metabolic health: exercise before and during pregnancy improves glucose tolerance and reduces fat gain in offspring.
Paternal effects via sperm: moderate voluntary wheel running alters small non-coding RNAs, especially tRNA fragments, in sperm and enhances glucose clearance, with stronger benefits in female offspring.
Maternal exercise mechanisms: benefits arise from in utero environment, placental changes, and breast milk composition rather than major oocyte alterations.
Human milk oligosaccharides: exercise increases 3’-sialyllactose in milk, linked to better offspring microbiome and metabolic outcomes.
Sex-biased & intergenerational effects: maternal exercise impacts male offspring metabolism more; effects can transmit to F2 generation depending on the transmitting parent’s sex.
ABOUT THE GUEST: Kristin Stanford, PhD is an associate professor in the Department of Physiology and Cell Biology at The Ohio State University Wexner Medical Center, where she serves as associate director of the Diabetes and Metabolism Research Center. Her lab investigates molecular mechanisms by which exercise enhances metabolic and cardiovascular health, with a focus on intergenerational effects.
RELATED EPISODE:
M&M 145: Epigenetics, Endocrine Disruptors, Obesogens & Obesity, Inheritance of Acquired Characteristics | Bruce Blumberg
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Health Products by M&M Partners:
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.
OmegaQuant: At-home blood testing to see fatty acid profiles, including omega-3 fatty acids. Use link to see options and support M&M.
SiPhox Health: Comprehensive, cost-effective bloodwork from the comfort of home. Use code TRIKOMES for 20% off.
KetoCitra—Ketone body BHB + electrolytes formulated for kidney health. Use code MIND20 for 20% off any subscription (cancel anytime)
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.
SporesMD: Premium mushrooms products (gourmet mushrooms, nootropics, research). Use code 'nickjikomes' for 20% off.
For all the ways you can support my efforts