Tim Ferriss hosts Dr. Dominic D'Agostino, tenured associate professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida, Morsani College of Medicine. Dom is also a research investigator and crew member on NASA's Extreme Environment Mission Operations, focusing on nutritional strategies and metabolic-based therapies for neurological disorders, psychiatric conditions, cancer, and human performance optimization.

This conversation takes place midway through Tim's month-long ketosis experiment using both continuous glucose and ketone monitors. They discuss practical implementation of ketogenic diets, troubleshooting low ketone readings despite subjective benefits, and the science behind ketosis for mood stabilization, cognitive enhancement, and potential neuroprotection.

The discussion covers Tim's successful use of ketosis to treat Lyme disease cognitive symptoms, explores the benefits and risks of exogenous ketones, and examines how intermittent fasting may enhance ketone utilization. They also address safety concerns with certain ketone supplements and optimal dosing strategies for therapeutic ketosis.

Ketosis Benefits: From Seizures to Metabolic Psychiatry

Ketosis 'quiets the mind' by lowering glutamate and elevating GABA, the brain-stabilizing neurotransmitter, which explains its effectiveness against seizures and psychiatric disorders

The ketogenic diet provides 'the benefits of fasting without the metabolic baggage' and has applications for major depression, bipolar disorder, schizophrenia, anxiety, and anorexia nervosa

Primary physical benefits include rapid weight loss (partly fluid), blood pressure reduction, and improved insulin sensitivity for those with insulin resistance

Tim experiences enhanced verbal acuity, elimination of afternoon energy dips, reduced sleep needs (6-6.5 hours vs 8-9), and mood stabilization without muting positive emotions

Lyme Disease Recovery Through Ketosis Mechanisms

Tim achieved complete remission of Lyme-induced cognitive symptoms and joint pain within 3-4 days of strict ketosis, with no recurrence

The Borrelia spirochete is '100% glycolytic' - limiting glucose availability through ketosis targets the pathogen's energy systems directly

Beta-hydroxybutyrate 'stimulates the adaptive immune response,' enhancing the body's ability to target and neutralize foreign invaders like tick-borne pathogens

Dom receives 'dozens, if not hundreds' of communications from people with tick-borne diseases reporting similar benefits from ketosis

Troubleshooting Low Ketone Readings Despite Benefits

Tim's ketone levels consistently read 0.1-0.4 millimolar despite feeling sharp and energetic, creating apparent 'failure' at ketosis

High insulin sensitivity from intermittent fasting can increase ketone utilization 2-5 times, meaning 'you could have two to five times higher ketone utilization with high metabolic fitness' - Dom

Blood ketone measurements reflect both production and utilization - elite athletes and metabolically fit individuals may show lower readings due to rapid ketone uptake

Breath ketones (acetone) may be a 'better indicator of ketosis' than blood measurements, especially during caloric deficits or high activity levels

Protein Intake and Gluconeogenesis Management

Rapid amino acid entry from liquid protein can 'shut off ketosis' by triggering insulin and gluconeogenesis, but this can be buffered with fat, fiber, and salt

The pyloric sphincter remains closed with fatty, salty, high-fiber meals until stomach contents become isotonic, delaying amino acid absorption

Dom consumes 200-240 grams of protein daily while maintaining ketosis by using MCT oil, long-chain fats, and fiber to slow gastric emptying

Large meals can activate the sympathetic nervous system through stretch receptors, potentially enhancing gluconeogenesis via catecholamine release

Exogenous Ketones: Benefits and Serious Safety Warnings

Dom warns that 1,3-butanediol-based ketone supplements cause liver toxicity with chronic use, showing 'inflammation in the liver, TNF-alpha, sinusoidal dilation' in animal studies

1,3-butanediol creates dependency and withdrawal symptoms similar to alcohol, with 'narcotic-like properties' that can cause severe intoxication

Ketone esters with rapid pharmacokinetics can spike insulin, shut off endogenous ketone production, and create 'hypoketotic and hypoglycemic' states

Safer alternatives include ketone salts, free acids, and triester formulations with glycerol that avoid 1,3-butanediol toxicity concerns

MCT Oil Dosing and Liver Safety Concerns

MCT oil should be capped at 40ml daily (20ml twice per day) based on studies showing benefits, with higher doses causing liver fat accumulation

Animal studies at human-equivalent doses of 80-100ml daily showed 'globules of fat all in the liver' and elevated inflammatory markers

MCT oil delays gastric absorption and stimulates endogenous ketone production, making it useful for buffering rapid ketone ester effects

MCT is 'much more tolerable when you take it with a meal' versus on an empty stomach, which can cause gastrointestinal distress

Optimal Ketosis Protocols and Metabolic Memory

Target glucose ketone index (GKI) of 1-4 for therapeutic benefits, calculated by dividing glucose (in mmol/L) by ketone levels

Dom recommends one week per month of aggressive ketosis, achieving GKI of 1-2 for at least three days to stimulate autophagy and signaling benefits

Metabolic memory effects mean 'the more you stay in ketosis, the easier it gets and the more benefits you derive from it' - similar to muscle memory

Periodic ketosis increases mitochondrial number and enhances metabolic flexibility, with benefits potentially lasting months between interventions

Alzheimer's Prevention and Metabolic Health Biomarkers

Key biomarkers for brain health include insulin below 12, high-sensitivity C-reactive protein below 0.6, optimized hemoglobin A1C, and omega-3 to omega-6 ratios

Continuous glucose monitors could help delay Alzheimer's onset by providing awareness of food responses, especially for at-risk family members

Exercise produces muscle-derived hormones that are neuroprotective, with muscle size being 'tightly linked to brain size' - making resistance training crucial

Spark covers exercise benefits like BDNF but is 'very outdated' according to Tim, though the core principles of exercise for brain health remain valid