The Tim Ferriss Show - Ep. #845:

How to Use Ketosis for Enhanced Mood, Cognition, and Long-Term Brain Protection — A Practical and Tactical Guide with Dr. Dominic D'Agostino

Date: January 7, 2026
Host: Tim Ferriss
Guest: Dr. Dominic D’Agostino, PhD (Professor and Researcher in Metabolic Therapies)

Episode Overview

This episode offers an in-depth, practical guide to ketosis: what it is, why it matters, and how to optimize it for mood, cognitive clarity, physical performance, and long-term brain health. Tim shares wild results from his latest month-long ketogenic experiment, and Dr. Dom D’Agostino unpacks the science, strategies, and potential pitfalls of ketogenic diets, fasting, exogenous ketones, metabolic flexibility, and more. Throughout, pragmatic tips, troubleshooting, and poignant cautionary tales make it actionable for both beginners and experienced self-experimenters.

Key Topics & Discussion Highlights

1. Personal Motivations and Real-Life Results

• Why Tim uses ketosis: For enhanced mood, sharper cognition, stable energy, and potentially long-term neuroprotection.
• Symptoms Tim notices in ketosis:
  • Needs 1.5–2 hours less sleep
  • Sharper, more agile thinking
  • No afternoon energy crashes
  • Dramatic mood stabilization:
    “...it preserves the ups...[but] stabilizes and minimizes the downswings. That in and of itself makes it worth it to me.” (A, 01:49)
• Notable experiment: Tim tracked both glucose (Dexcom G7) and ketones (continuous ketone monitor) throughout a strict month-long cycle.

2. Physiology and Benefits of Ketosis

• Dr. D’Agostino on why ketosis matters:
  • Neurocalming effects: “Being in a state of ketosis really quiets the mind... backed up by experimental data to show an elevation of GABA...” (B, 06:20)
  • Proven applications: Epilepsy (various forms), metabolic psychiatry (depression, bipolar, schizophrenia), stubborn weight loss, insulin resistance.
  • Reduces inflammation, may support anti-cancer therapies, and enhances fat-burning and metabolic flexibility.
• Expanded benefits:
  “Ketones have a broad array of applications, metabolic signaling, epigenetic, that have real world applications.” (B, 08:17)

3. Practical Experimentation: Tim’s Keto Journey

• Tim’s strict protocol:
  • Moderate protein, 50%+ calories from fat, <20g carbs/day
  • Two meals/day, often canned mackerel + MCT oil + vinegar
  • Intermittent fasting: “I’ve been intermittent fasting pretty much every day for the last six months... 2pm-8pm window.” (A, 21:55)
• Effects on cognition & Lyme disease:
  “Within three or four days, effectively all of my cognitive symptoms disappeared... had complete remission of any of the cognitive symptoms plus the joint pain symptoms and those never came back.” (A, 13:09)

4. Metabolic Memory & Frequency of Ketosis

• Lasting impacts:
  • Repeated ketosis “trains” metabolic flexibility; effect persists between cycles.
  • “Much like muscle memory, I think there’s a metabolic memory.” (B, 24:40)
• Dr. Dom’s recommendation:
  • 1 week/month of strict ketosis or several weeks per year, even for those who don’t wish to stay keto long-term (B, 74:22).

5. Troubleshooting Ketosis: False Negatives, Monitoring, and "Failing" at Keto

• Tim’s issue: Low blood ketone readings despite clear cognitive and energy benefits.
• Dom’s explanation:
  • Enhanced fat and ketone utilization in people with high insulin sensitivity = lower measured circulating ketones.
  • “When you measure ketones in the blood, that’s a function of both production and utilization.” (B, 35:31)
  • Breath acetone may better reflect deep ketosis during caloric deficit or high fitness (B, 38:35).
• Continuous monitoring caveats: Devices may drift over time and require recalibration.

6. Diet Composition, Protein Intake & Gluconeogenesis

• Possible impact of protein: Protein load can reduce ketosis, especially if rapidly absorbed; fat, fiber, and salt can slow absorption and sustain ketosis even with higher protein. (B, 41:17)
• Practical tip:
  • Mix proteins with MCT, fat, and fiber to “buffer” gluconeogenic effect.
• Walking after meals:
  • 10–20 min walk post-meal dampens glucose spike and sustains ketosis (B, 49:07).
• “Rabbit starvation” & lean protein:
  • Very high protein with low fat is not sustainable and leads to problems (loss of energy, fat, or health); dietary fat remains important even if you have significant body fat (B, 59:57).

7. Ketosis, Neurodegenerative Diseases, and Long-Term Brain Health

• Current evidence:
  • “Your metabolic health is tightly linked to your brain health and can dramatically delay the onset of Alzheimer’s disease.” (B, 68:03)
  • Key markers: Lower insulin, lower inflammation (hsCRP), optimize omega-3s, B12, exercise, and lean body composition.
  • Exogenous ketones may offer acute benefit but are not a substitute for overall metabolic health.

8. Exogenous Ketones: Science, Pitfalls, and Practical Warnings

• Types: Monoester, diester, salts, MCT-based.
• Risks of butanediol-based esters:
  • Chronic use can stress/damage liver (animal studies, limited human data); can also cause narcotic effects, dependence, and withdrawal:
    “I made 1,3-butanediol Jello shots... Two or three and just be buzzing. It’s a lesser of two evils when we’re talking about, about ethanol.” (B, 120:35)
• Pragmatic guidance: For daily/long-term use, favor ketone salts, D+L enantiomers, or free acids. Avoid chronic high doses of 1,3-butanediol-based esters, especially in older adults (B, 101:59, 109:41).

Notable Quotes & Memorable Moments

• On cognitive transformation:
  “...within three or four days, effectively all of my cognitive symptoms disappeared. And I stayed in that state through nutritional ketosis for a few weeks... had complete remission…”
  — Tim Ferriss, recounting return from Lyme-related “pseudo-dementia” (A, 13:09)

• On quieting the mind:
  “Being in a state of ketosis really quiets the mind. And I think that has major implications...”
  — Dr. D’Agostino (B, 06:20)

• Pragmatic on affordability:
  “It’s as cheap as dog food... you can get almost a pound of mackerel... the Omega 3s are off the charts, the heavy metals are low... a non-issue for me.”
  — Dr. D’Agostino on budget keto meals (B, 29:49)

• On "failing" at keto with low ketone readings:
  “...that’s a function of both production and utilization... you could have two to five times higher ketone utilization with high metabolic fitness.”
  — Dr. D’Agostino (B, 35:14)

• On exogenous ketones & toxicity:
  “[1,3] butanediol by itself is more toxic than [its] ketone esters...when consumed chronically, when we go beyond our experimental window... we see signs that are kind of scary.”
  — Dr. D’Agostino (B, 101:59)

• On getting buzzed from ketone esters:
  “I chugged a small can... I felt like I could barely walk to the bathroom. I was smashed. It almost knocked the glass off the table.”
  — Tim Ferriss (A, 119:09)

• On brain health and metabolic health:
  “...if you can lower, for example, your insulin and keep that between 2 and 6... and your hemoglobin A1c or glucose...carrying that over can dramatically delay the onset of Alzheimer’s disease.”
  — Dr. D’Agostino (B, 66:20)

Practical Guidance and Key Timestamps

What Are the Tangible Benefits of Ketosis?

• Mental sharpness, stable energy, decreased sleep needs (00:00-02:30)
• Mood stabilization surpasses even cognitive and energy perks (01:49)
• Proven therapy for epilepsy, mood, and psychiatric disorders (06:03)

How to Start and Optimize Ketosis

• Diet composition: moderate protein, high fat, <20g carbs (21:59)
• “Mackerel bowls” and meal templates for affordability and ease (29:41)
• Use intermittent fasting for easier adaptation (26:37)
• Post-meal brisk walking to blunt glucose/insulin spikes (49:09)

Common Pitfalls and Advanced Metrics

• Interpretation of low finger-stick ketones: high utilization, not low production (35:31)
• Cautions about exogenous ketones: avoid chronic butanediol esters, mind pharmacokinetics (98:11, 101:59)
• Understand measurement devices' limitations, calibrate when possible (53:40, 55:48)
• GLucose-Ketone Index (GKI): target 1–2 (therapeutic), but up to 4 can still be beneficial for most (83:12, 88:00)

Brain Health & Long-Term Protection

• Regular short cycles (ex: 1 week per month) better for “resetting” metabolism (74:22)
• Emphasize physical/brain training, fiber, omega-3s, B12 for holistic protection (66:20, 78:28)
• Plant foods (broccoli, berries, apples) can be included for fiber, micronutrients without derailing ketosis (125:38)

Tools, Resources & Further Learning

• Continuous Glucose & Ketone Monitors: Dexcom G7; CyBio
• Meal template: Canned mackerel, MCT oil, vinegar, proteins, fibrous veg
• Brain/computer training: Use apps for baseline and ongoing measures (93:18)
• Further podcasts and platforms:
  • Dr. D’Agostino’s Metabolic Link Podcast
  • Metabolic Health Initiative (CME credit)
  • Reference: ketonutrition.org (information-only)

Closing Thoughts

This episode is a practical, honest look at the science, real-world experience, and subtle art of applying ketosis in life. The conversation threads together powerful benefits for mood, cognition, body composition, and long-term health; actionable troubleshooting tips; and critical safety warnings about “biohacking” shortcuts. The big message: ketosis is potent, cycling matters, measurement is helpful but not always conclusive, and context and self-tuning are everything.

Select Timestamps

• 00:00 – Tim’s intro & main reasons for ketosis
• 06:03 – Established and emerging benefits of ketosis
• 13:09 – Tim on using ketosis for Lyme symptoms
• 23:59 – “Metabolic memory” from cycling ketosis
• 35:14 – Why “low” ketone readings may be misleading
• 41:17 – Protein, gluconeogenesis, slowing absorption
• 59:57 – Why lean-protein/low-fat keto doesn’t work
• 66:20 – Metabolic health and brain health/Alzheimer’s
• 83:12 – Calculating the Glucose Ketone Index (GKI)
• 101:59 – Exogenous ketone types, toxicity warnings
• 119:09 – Tim’s “buzzed” experience with 1,3 butanediol
• 125:38 – Favorite fiber/plant sources on keto
• 133:04 – Final words, Dr. Dom’s links and resources

For more details, referenced studies, and further resources, see the show notes at Tim.blog/podcast.