How to Use Ketosis for Enhanced Mood, Cognition, and Long-Term Brain Protection — Dr. Dom D'Agostino

Ketosis is often pigeonholed as a weight-loss strategy, but for those operating at the cutting edge of metabolic health, the conversation has shifted toward the brain. In a dense and technical discussion, Dr. Dom D’Agostino and Tim Ferriss explore the nuanced physiology of the ketogenic diet, intermittent fasting, and exogenous ketones. Their dialogue moves beyond basic macros into the realms of neuropharmacology, immune system modulation, and the specific mechanics of "metabolic memory." Whether you are using ketosis to manage Lyme disease symptoms, stabilize mood disorders, or protect against neurodegeneration, the following insights provide a blueprint for optimizing your metabolic machinery.

Key Takeaways

• Neuroprotective Neuropharmacology: Ketosis elevates GABA and lowers glutamate, stabilizing brain chemistry in ways that mirror anti-seizure medications and mood stabilizers, offering promise for metabolic psychiatry.
• The "False Negative" Phenomenon: Low blood ketone readings in fit individuals often indicate high utilization rather than low production; measuring tissue uptake is distinct from measuring circulating fuel.
• Immune Modulation and Lyme Disease: Ketosis may suppress glycolytic bacteria (like the Lyme spirochete) while simultaneously boosting the adaptive immune response.
• Metabolic Memory: Similar to muscle memory, cycling in and out of ketosis builds mitochondrial density and enzymatic machinery, making it easier to adapt to fat burning over time.
• Exogenous Ketone Safety: Caution is advised regarding ketone esters containing 1,3-butanediol due to potential liver stress and alcohol-like intoxication effects, particularly in older adults.

The Neuropharmacology of Ketosis and Mental Health

While weight loss is the most visible effect of a ketogenic diet, the profound impact on brain chemistry is arguably its most valuable application. By shifting the brain's fuel source, we alter the ratio of neurotransmitters that govern mood and excitability.

"The ketogenic diet just quiets the brain, lowers glutamate and elevates GABA, a brain stabilizing, calming neurotransmitter."

• GABA vs. Glutamate Balance: The metabolic shift facilitates the conversion of glutamate (an excitatory neurotransmitter) into GABA (an inhibitory, calming neurotransmitter), which explains the "quieting of the mind" reported by practitioners.
• Seizure Control Mechanisms: This neurochemical stabilization is the primary mechanism behind the diet's century-long success in treating drug-resistant epilepsy, specifically by silencing temporal lobe seizures and rare syndromes like Lennox-Gastaut.
• Metabolic Psychiatry: Emerging research suggests these stabilizing effects extend to psychiatric conditions, including bipolar disorder, major depression, schizophrenia, and anorexia nervosa, effectively treating them as metabolic disorders of the brain.
• Alcohol and Benzodiazepine Parallels: The anxiolytic (anxiety-reducing) effects of ketosis mimic the GABAergic pathways targeted by alcohol and benzodiazepines, but without the toxicity or dependency issues.
• Fluid Volume Reduction: The initial weight loss in ketosis is largely diuretic; as insulin drops, the kidneys excrete sodium and water, which decreases blood volume and can naturally lower high blood pressure.
• Insulin Suppression: The primary metabolic lever of the diet is the suppression of insulin, which unlocks stored body fat for oxidation and triggers the liver to produce ketone bodies (acetoacetate and beta-hydroxybutyrate).

Immune Function, Lyme Disease, and Cancer Defense

Beyond the brain, the restriction of glucose creates a hostile environment for glucose-dependent pathogens and cells. This "metabolic starvation" strategy offers a compelling adjuvant therapy for infectious diseases and oncological care.

• Starving Glycolytic Pathogens: The Lyme disease spirochete (Borrelia) is essentially 100% glycolytic, meaning it relies entirely on sugar for survival; strict ketosis targets the energy systems of the microbe directly.
• Boosting Adaptive Immunity: Elevated beta-hydroxybutyrate (BHB) does more than provide fuel; it acts as a signaling molecule that stimulates the adaptive immune response, helping the body identify and neutralize foreign invaders.
• Symptom Remission: Anecdotal evidence, including Tim Ferriss’s personal experience, suggests that nutritional ketosis can lead to the remission of cognitive "pseudo-dementia" and joint pain associated with post-treatment Lyme syndromes.
• Targeting Cancer Metabolism: Approximately 80% of cancers are highly glycolytic (the Warburg Effect); restricting glucose slows tumor growth, though it should be viewed as a "brake" rather than a standalone cure.
• Chemo-Sensitization: Ketosis enhances the efficacy of standard-of-care treatments like radiation, chemotherapy, and immune-based therapies, potentially protecting healthy cells while sensitizing tumor cells to treatment.
• Neuroprotection During Treatment: There is growing interest in using ketosis to mitigate "chemo brain," leveraging the neuroprotective properties of ketones to preserve cognitive function during aggressive cancer therapies.

Metabolic Memory and Long-Term Adaptation

Just as a weightlifter regains strength quickly after a hiatus due to muscle memory, the metabolism possesses a "memory" for fat adaptation. This concept suggests that long-term adherence isn't required to reap long-term benefits if the metabolic machinery has been previously built.

"Muscle memory is metabolic memory... The more you stay in ketosis, the easier it gets and the more benefits you derive."

• Mitochondrial Biogenesis: Periodic ketosis stimulates the creation of new mitochondria, increasing the cellular engine's capacity to process fat for fuel.
• Enzymatic Upregulation: The body increases the production of fatty acid oxidation enzymes; these physiological changes persist even during periods of carbohydrate consumption, allowing for a faster return to ketosis.
• The "Rust" Concept: If you step away from ketosis for months, you may lose some efficiency (like a drop in max bench press), but the pathway to regain that efficiency is significantly shorter than the initial adaptation period.
• Cycling Protocols: A "one week per month" or "three weeks per quarter" approach can be sufficient to maintain metabolic flexibility and capture 80% of the benefits without the social rigidity of a permanent ketogenic lifestyle.
• Preventing "Rabbit Starvation": While protein is essential, reliance on lean protein without adequate fat can lead to "rabbit starvation"; cycling high-protein/low-fat days (Protein Sparing Modified Fast) works best intermittently rather than chronically.
• Preserving Muscle Mass: Contrary to fears of muscle loss during fasting or keto, high protein intake combined with resistance training and ketone signaling (which is anti-catabolic) effectively preserves lean tissue even in a caloric deficit.
• Carryover Effects: There appears to be a protective carryover effect where periods of ketosis confer neuroprotective and anti-inflammatory benefits that last beyond the dietary intervention itself.

The Measurement Paradox: Why Low Numbers Can Be Good

A common source of frustration for fit individuals is low ketone readings despite strict adherence to the diet. This "false negative" often indicates a highly efficient metabolism rather than a failure to produce ketones.

• Production vs. Utilization: A blood meter measures the fuel waiting in the tank, not the fuel being burned; high metabolic fitness leads to rapid ketone uptake, resulting in lower circulating levels despite high production.
• Transporter Upregulation: Adapted individuals upregulate Monocarboxylate Transporters (MCTs), which shuttle ketones out of the blood and into tissues (brain and muscle) at a rate 2-3 times faster than unadapted individuals.
• The Lean Engine Analogy: A tuned engine burns fuel cleanly with no spillover; seeing high ketones in the blood or urine can sometimes represent "spillover" fuel that the body hasn't figured out how to use yet.
• Breath vs. Blood: In deep caloric deficits, blood ketones may drop while breath acetone rises, suggesting that breath meters might occasionally offer a more accurate picture of fat oxidation during intense fasting.
• Glucose Ketone Index (GKI): The gold standard for therapeutic ketosis is the GKI (Glucose divided by Ketones); a ratio of 1:1 or 2:1 is the therapeutic "sweet spot," though 1:4 is sufficient for general health.
• The Role of Insulin Sensitivity: High insulin sensitivity drives glucose into cells efficiently; if you have low glucose (e.g., 65-80 mg/dL) and low ketones, you are likely still in a functional state of ketosis, termed "running lean."

Practical Nutrition: Foods, Fiber, and Timing

Implementing a ketogenic lifestyle requires navigating the balance between macronutrients and micronutrients. The goal is to suppress insulin without creating nutrient deficiencies or gut dysbiosis.

• The "Dog Food" Protocol: A staple meal for efficacy and cost is canned mackerel (high Omega-3s, low mercury) mixed with MCT oil and apple cider vinegar; it provides essential fats and satiation for under $3.
• Fiber Sources: To maintain gut health without breaking ketosis, prioritize low-glycemic fiber sources like broccoli florets, wild blueberries (smaller and more fibrous than conventional), and asparagus.
• Nutrient Density: Regular consumption of eggs, sardines, and organ meats ensures adequate B12 and mineral intake, preventing the brain atrophy associated with B-vitamin deficiencies.
• Protein Thresholds: Fears of gluconeogenesis (protein turning to sugar) are often overstated; fat, fiber, and salt delay gastric emptying, buffering the insulin response of high-protein meals.
• Carbohydrate Timing: Walking for 20-30 minutes immediately after a meal activates GLUT4 transporters independent of insulin, blunting any potential glucose response from incidental carbohydrates.
• Salt and Hydration: Ketosis is natriuretic (sodium-excreting); liberal use of quality salt is required to maintain blood volume and prevent the "keto flu" symptoms of dizziness and fatigue.

Exogenous Ketones: Safety, Toxicity, and Selection

The market for exogenous ketones ranges from helpful tools to potentially toxic compounds. Understanding the source molecule is critical for safety, particularly regarding products containing 1,3-butanediol.

Risks of 1,3-Butanediol

"1,3-butanediol is an alcohol dimer... it essentially creates alcohol withdrawal... and chronic use shows signs of liver inflammation."

• Toxicity Profile: 1,3-butanediol is metabolized via alcohol dehydrogenase; chronic high-dose use depletes liver NAD+ and ATP, leading to inflammation and potential necrosis even if liver enzymes (ALT/AST) appear normal.
• Intoxication Risks: It has a narcotic effect similar to ethanol; moderate doses can cause severe dizziness, loss of motor control, and "the spins," posing a fall risk for older adults.
• Addiction Potential: Animal studies suggest 1,3-butanediol can create dependency and precipitate withdrawal symptoms upon cessation, mimicking alcohol withdrawal.

Selecting the Right Supplement

• Ketone Salts vs. Esters: Ketone salts (beta-hydroxybutyrate bound to minerals) generally offer a safer profile than di-esters or mono-esters derived heavily from 1,3-butanediol.
• Pharmacokinetics: An ideal supplement raises blood ketones gradually; rapid spikes (characteristic of some esters) can trigger a counter-regulatory insulin surge, shutting down endogenous fat burning.
• L-Enantiomer Benefits: Most supplements are racemic (D and L forms); the L-form (L-BHB) stays in circulation longer and has specific vascular benefits, essentially "un-kinking the hose" of the vascular endothelium to improve blood flow.
• MCT Oil Usage: MCT oil is a potent endogenous ketone booster; taking it with food mitigates gastrointestinal distress. Doses should be capped around 20ml per serving to avoid liver stress.
• Formulation Matters: A combination of ketone salts and MCT oil often provides a more sustained, therapeutic elevation of ketones compared to a mono-therapy of esters.
• Label Reading: Consumers must vigilantly check labels for 1,3-butanediol, which is often used because it is cheaper to manufacture, despite its inferior safety profile compared to free acids or salts.

Conclusion

Ketosis is a metabolic tool that extends far beyond the number on a scale. Whether used therapeutically for Lyme disease, preventatively for Alzheimer's, or tactically for cognitive performance, its power lies in measuring and managing metabolic health biomarkers—specifically insulin, inflammation (hs-CRP), and glucose variability. By combining intermittent fasting with a nutrient-dense ketogenic diet and exercising caution with exogenous supplements, you can leverage "metabolic memory" to protect your brain and optimize your physiology for the long haul. The goal is not just to burn fat, but to build a metabolic engine that is resilient, flexible, and capable of powering high-level cognitive function well into aging.