Ketosis Benefits and Cautions--Metabolic Flexibility, Neuroprotection, and Supplement Risks

The Blog of Author Tim Ferriss · January 07, 2026 · Listen to Original Episode →

Original Title:

TL;DR

Ketosis enhances metabolic flexibility by upregulating fatty acid oxidation enzymes, creating a "metabolic memory" that allows the body to more readily access and utilize fat stores even after periods off the diet.
Ketogenic diets can stabilize mood and cognitive function by altering brain neurochemistry, specifically by lowering glutamate and elevating GABA, which has implications for treating psychiatric disorders.
The ketogenic diet targets the glycolytic energy systems of microbes like Borrelia (Lyme disease spirochete) and augments the adaptive immune response, potentially aiding in managing inflammatory and infectious conditions.
Exogenous ketone supplements containing 1,3-butanediol may pose toxicity risks, including liver strain and dependency, necessitating caution and a preference for non-1,3-butanediol based formulations or salts.
Maintaining a Glucose Ketone Index (GKI) between 1 and 4, rather than solely relying on absolute ketone levels, provides a more accurate measure of therapeutic ketosis and metabolic health benefits.
Regular, periodic ketogenic interventions, even as short as one week per month, can confer sustained metabolic and neuroprotective benefits for up to three weeks afterward, supporting long-term health.
High ketone utilization, driven by improved insulin sensitivity and metabolic fitness, can lead to lower blood ketone readings, creating a "false negative" impression of not being in ketosis despite significant metabolic benefits.

Deep Dive

Ketosis offers significant benefits for cognitive function, mood stabilization, and metabolic health, primarily by providing an alternative fuel source for the brain and body and reducing inflammation. While its therapeutic applications are expanding, particularly in metabolic psychiatry and as an adjunct to cancer treatment, the practical implementation and optimal duration of ketogenic diets require careful consideration to maximize benefits and minimize potential drawbacks.

The primary advantages of ketosis, as discussed, stem from its impact on brain function and metabolic regulation. Individuals often report increased mental clarity, reduced need for sleep, and elimination of the afternoon energy dip associated with carbohydrate consumption. More profoundly, ketosis appears to stabilize and enhance mood, minimizing depressive swings without muting positive emotions, which has significant implications for managing conditions like depression and bipolar disorder. Beyond cognitive and mood benefits, ketosis is an effective strategy for weight loss, primarily through reduced insulin levels and increased fat burning. It also offers potential long-term benefits such as neuroprotection and anti-inflammatory effects, with ongoing research exploring its role in conditions like Alzheimer's and Parkinson's disease. For individuals with specific conditions like tick-borne diseases, ketosis may target the energy systems of microbes that rely on glucose and augment the immune response, potentially aiding in managing symptoms.

The practical application of ketosis, however, involves nuances. While extended fasting can yield similar benefits, it carries the risk of muscle loss and fatigue, which ketogenic diets aim to mitigate. The transition into ketosis can be challenging, often referred to as "keto flu," though this can be managed with electrolytes. A critical aspect is understanding metabolic flexibility and "metabolic memory," where consistent adherence to a ketogenic diet or fasting regimen can train the body to efficiently utilize fat, making subsequent transitions easier and potentially conferring lasting benefits even after periods of less strict adherence. This metabolic adaptation is likened to muscle memory, where training and detraining cycles allow for faster reacquisition of fitness.

A significant point of discussion revolves around the measurement of ketosis and interpreting results, particularly for individuals with high metabolic fitness. Low ketone readings (e.g., 0.1-0.4 mmol/L) might not indicate a lack of ketosis but rather high ketone utilization by the body, especially when combined with intermittent fasting or a caloric deficit. This phenomenon, where ketone production equals ketone utilization, can lead to a "false negative" if relying solely on blood ketone levels without considering subjective feelings of well-being and cognitive performance. Breath ketone meters have been suggested as a potentially more accurate indicator during caloric deficits, though further research is needed.

The role of protein intake and gluconeogenesis also emerged as a key consideration. While excessive protein can theoretically be converted to glucose, slowing the digestion of protein through meals rich in fat, fiber, and salt, or by using MCT oil, can buffer this effect and delay amino acid absorption. This strategy helps maintain ketosis and mitigate the gluconeogenic response. For individuals with a family history of neurodegenerative or cardiovascular diseases, a strategic approach to ketosis is recommended. This involves periodic ketogenic interventions, such as one week per month or three contiguous weeks per quarter, to leverage "metabolic memory" and protective signaling effects, rather than year-round strict adherence, which may not be necessary and could potentially lead to issues like energy toxicity or reductive stress if ketone levels become excessively high. The sweet spot for therapeutic ketosis is often cited as 1-2 mmol/L, although higher levels might be required for specific medical conditions.

Finally, the discussion on exogenous ketones highlighted potential benefits but also significant risks, particularly with 1,3-butanediol-based products. These can lead to toxicity, liver strain, and even dependency and withdrawal symptoms, mirroring some effects of alcohol. The field is moving towards safer formulations like ketone salts, free acids, and tri-esters with glycerol. MCT oil, while beneficial for stimulating endogenous ketone production, can also cause gastrointestinal distress and potential liver strain at high doses, with recommendations to cap intake and consume it with meals. The key takeaway is that while ketosis offers substantial health advantages, its implementation should be informed, personalized, and mindful of potential pitfalls, emphasizing metabolic health biomarkers, regular exercise, and appropriate use of supplements.

Action Items

Audit exogenous ketone supplements: Identify 1-3 butanediol content and assess toxicity risks based on formulation and dosage.
Implement a weekly ketogenic intervention: Maintain a glucose ketone index (GKI) of 1-4 for 3-7 days to promote metabolic flexibility and neuroprotection.
Track key biomarkers monthly: Monitor hs-CRP, insulin, omega-3 to 6 ratio, and B12 levels to assess cardiometabolic and brain health.
Establish cognitive baselines quarterly: Utilize brain training apps or tests to objectively measure reaction time and cognitive function for long-term tracking.
Optimize dietary fiber intake: Consume 60-70 grams of daily carbohydrates, with at least one-third from fiber-rich sources like broccoli and wild blueberries.

Key Quotes

"well there are a few things immediately i will notice once i get to a certain concentration in my blood and that's generally around let's just call it 0 7 millimolars measured with a finger prick and then more as you get going i need less sleep so instead of 8 to 9 hours 6 hours 6 and a half hours i wake up and i am wide awake so that's another difference i wake up and i am wide awake alert ready to go i don't need an hour of booting up and tons of caffeine to get online i am mentally sharper my verbal acuity my ability to think just has a faster turnover and in the afternoons i do not have what you would typically associate with say a normal diet involving lots of carbohydrates the afternoon dip i don't need a nap i don't need a huge extra cup of coffee around two or three in the afternoon to keep me going that is just unnecessary altogether but those all pale in comparison to the mood stabilizing and enhancing effects it just takes the ups and downs and maybe this is peculiar to me but it preserves the ups right i'm not going through crazy manic swings but it doesn't mute your upside in terms of mood but it really stabilizes and minimizes the downswings and that in and of itself makes it worth it to me"

Tim Ferriss describes several immediate benefits he experiences when reaching a certain concentration of ketones in his blood, around 0.7 millimolars. These include needing less sleep, waking up more alert, experiencing enhanced mental sharpness and verbal acuity, and avoiding the typical afternoon energy dip associated with carbohydrate-heavy diets. Ferriss highlights that these physical benefits are surpassed by the mood-stabilizing and enhancing effects, which he finds particularly valuable.

"there are many benefits to being in ketosis and a ketogenic diet if we're going to go there kind of has the benefits of fasting and there are for millennia we know the benefits of fasting without the baggage without the metabolic baggage you know the muscle loss the fatigue obviously you can't live in a you know that level of caloric deficit but in regards to you know the practical applications of it we know that being in a state of ketosis really quiets the mind and i think that has major implications and this was you know from centuries we knew this and now you know over the past decades this has been like a term kind of used and it's backed up by experimental data to show that there's an elevation of gaba obviously it's silencing a broad array of seizures independent of the ideology temporal lobe seizures you know lennox gastaut syndrome dravet syndrome rare forms of epilepsy the ketogenic diet just quiets the brain lowers glutamate and elevates gaba a brain stabilizing calming neurotransmitter and you know that's why people gravitate towards alcohol right the gaba ergic effects of alcohol and benzodiazepines so you can sort of in a very gentle way transition your physiology to a state of ketosis which changes the neuropharmacology of your brain to sort of quiet it down and that i think really echoes its broad application for metabolic psychiatry which is everything from major depression to bipolar to schizophrenia to anxiety disorders to anorexia nervosa"

Dr. Dominic D'Agostino explains that ketosis offers benefits similar to fasting but without the metabolic drawbacks like muscle loss and fatigue. He emphasizes that ketosis "quiets the mind," which has significant implications, supported by experimental data showing elevated GABA, a calming neurotransmitter. D'Agostino connects this to its effectiveness in managing various neurological and psychiatric conditions, including epilepsy, depression, bipolar disorder, schizophrenia, and anxiety disorders, by altering brain neuropharmacology.

"the spirochete borrelia that spirochete is essentially 100 glycolytic and when you limit glucose availability and glycolysis you are targeting the energy systems of that microbe so that's one thing to think about and it's well established now it wasn't three years ago but a ketogenic diet in particular beta hydroxybutyrate elevated in the blood stimulates the adaptive immune response and that's essentially your body's ability to target foreign invaders and neutralize them and that has become a rapidly growing area of interest university of pennsylvania they're doing car t therapy and checkpoint inhibitors because of the ketogenic enhancement of the adaptive immune response so and i think that plays a role and situationally i have observed that you go into ketosis if you have an inflammatory process and lyme disease is inflammatory but people who have shingles and herpes simplex things like that i had an inbox full of people that do that and i would like to do experimentally go down that direction to understand why but i think there's two reasons you're targeting the energy systems and you're augmenting the immune response to keep the spirochete in a dormant stage or maybe eradicating it in some context"

Dr. Dominic D'Agostino proposes two primary mechanisms by which a ketogenic diet may help combat tick-borne diseases like Lyme disease. First, he explains that the Borrelia spirochete is "100% glycolytic," meaning it relies heavily on glucose for energy. By limiting glucose availability through ketosis, the diet targets the microbe's energy source. Second, D'Agostino highlights that elevated beta-hydroxybutyrate (BHB) from ketosis stimulates the adaptive immune response, enhancing the body's ability to neutralize foreign invaders.

"i would say absolutely i think the science is still working to clarify that and make it less ambiguous the benefits that we are deriving from that but that is kind of like you know one of the pitches for the fasting mimicking diet by dr valter longo who was one of our keynote speakers at metabolic health summit and he's presented some really compelling research on that that opened my eyes to that five days of fasting can have i think he presented the time even three months of effects on sort of cardiometabolic biomarkers in his case this would be the fast mimicking diet so a few hundred calories a day yeah like 600 you know using his protocol of various foods kind of gravitating towards more of a plant based lower protein you know strategy and i think that it's promoting metabolic flexibility and ramping up fatty acid oxidation enzymes and much like muscle memory i think there's a metabolic memory so the more you stay in ketosis the easier it gets and the more benefits you derive from it and the more that you shift your body to being more fat adapted just like you can build your vo2 when you build your vo2 max or you build up to like you know a 400 pound bench press and you take like months off and you go back and you can only do like 225 for a couple of reps it only takes like two or three months to get back but it took you 10 years to get there you know that muscle memory snaps back quick and everybody agrees that there's this metabolic memory and i think there's a lot of things that play including you know gene programs epigenetic regulation that comes into play so first and foremost is changing our mitochondrial function and mitochondrial capacity so the number of mitochondria increase and then when you take a break and then get that stimulation again that mitochondria is kind of there and it responds very rapidly"

Dr. Dominic D'Agostino affirms the idea of "met

Resources

External Resources

Books

"The Four Hour Body" by Tim Ferriss - Mentioned as a reference for past dietary experiments and advice.

Articles & Papers

"Spark" - Mentioned as an outdated book covering exercise and brain health.

People

Dr. Dominic D’Agostino - Guest on the podcast, associate professor at the University of South Florida Morsani College of Medicine, visiting senior research scientist at the Institute for Human and Machine Cognition, researcher on nutritional strategies and metabolic therapies.
Dr. Walter Longo - Mentioned for his work on fasting mimicking diets.
Dr. Rhonda Patrick - Mentioned for her research and conversations on intermittent fasting.
Mark Mattson - Mentioned for his research related to intermittent fasting.
Chris Palmer - Mentioned for his work on ketogenic diets and metabolic psychiatry.
Diana Tedone - Mentioned as a patient stabilized by ketogenic diet after ALS diagnosis.
Dr. Ben Bikman - Mentioned for his work on insulin resistance and ketogenic diets.
Dr. Patrick Arnold - Mentioned for his work on ketone esters.
Dr. Richard Veech - Mentioned as a co-inventor of bonded monoester ketone, student of Hans Krebs, and mentor.
Dr. Henri Bruningrabber - Mentioned as a developer of triester ketone.
Dr. Sammy Hashem - Mentioned as a developer of triester ketone.
Dr. Annette Bosworth (Dr. Boz) - Mentioned for popularizing the concept of "sardine fasting."

Organizations & Institutions

University of South Florida Morsani College of Medicine - Affiliation of Dr. Dominic D’Agostino.
Institute for Human and Machine Cognition - Affiliation of Dr. Dominic D’Agostino.
NASA - Mentioned in relation to Dr. D’Agostino's research.
Office of Naval Research - Mentioned as a supporter of Dr. D’Agostino's research.
Department of Defense - Mentioned as a supporter of Dr. D’Agostino's research.
NIH (National Institutes of Health) - Mentioned as a supporter of Dr. D’Agostino's research.
Bazuki Group - Mentioned as a funder of research in metabolic psychiatry.
University of Pennsylvania - Mentioned for their work on CAR T therapy and checkpoint inhibitors in relation to ketogenic diets.
Harvard - Affiliation of Dr. Chris Palmer.
Exploding Kittens - Company associated with the card game "Coyote."
National Football League (NFL) - Mentioned in relation to sports analytics.
Pro Football Focus (PFF) - Mentioned as a data source for player grading.
New England Patriots - Mentioned as an example team for performance analysis.
CDC (Centers for Disease Control and Prevention) - Mentioned in relation to Lyme disease testing.
Hygienics - Mentioned in relation to Lyme disease testing.
Society for Integrative Metabolic Oncology - Group discussing Glucose Ketone Index (GKI).
National Institute of Health (NIH) - Mentioned for a grant on brain training games.
Exploding Kittens - Company associated with the card game "Coyote."
DARPA - Mentioned in relation to funding for ketone ester research.
Oxford - Mentioned for acquiring intellectual property related to ketone esters.
NIH (National Institutes of Health) - Mentioned in relation to Dr. Richard Veech's lab.
Meta Foods - Company mentioned for whole-food based ketogenic diet prescription foods.
Quest Nutrition - Mentioned as a company that previously offered ketogenic diet foods.

Tools & Software

Continuous Glucose Monitor (CGM) - Used to track glucose levels.
Continuous Ketone Monitor (CKM) - Used to track ketone levels.
Aura Ring - Used to track sleep architecture.
Keto Mojo - Device used for measuring blood glucose and ketones.
Precision Extra (Abbott) - Device for measuring blood glucose.
Dexcom G7 - Continuous glucose monitor.
Cybio - Continuous ketone monitor.
Joggle - NIH toolbox for cognitive function tests.
Brain Training Apps - Used for assessing cognitive function.

Websites & Online Resources

Seed.com - Website for Seed's DSO1 Daily Symbiotic.
Keto nutrition.org - Information website.
The Metabolic Link Podcast - Podcast hosted by Dr. D'Agostino.
Metabolic Health Initiative - Education platform.

Other Resources

Ketosis - Metabolic state discussed for various benefits.
Exogenous Ketones - Supplemental ketones.
Endogenous Ketones - Ketones produced by the body.
Ketogenic Diet - Dietary approach focused on ketosis.
Intermittent Fasting - Eating pattern involving periods of fasting.
Time Restricted Feeding - A form of intermittent fasting.
Glycogen Depletion - Process of reducing glycogen stores.
Glycogen Loading - Process of replenishing glycogen stores.
Lyme Disease - Tick-borne illness discussed in relation to ketosis.
Babesiosis - Coinfection associated with Lyme disease.
Pseudo Dementia - Cognitive impairment discussed in relation to Lyme disease.
Borrelia - Spirochete responsible for Lyme disease.
Glycolysis - Metabolic process of breaking down glucose.
GABA (Gamma-Aminobutyric Acid) - Neurotransmitter.
Glutamate - Neurotransmitter.
Metabolic Psychiatry - Field of study concerning mental health and metabolism.
Atkins Diet - Mentioned as a past diet trend.
Insulin Resistance - Condition where cells do not respond well to insulin.
Ketogenesis - Process of producing ketones.
Metabolic Signaling - Communication pathways within cells.
Epigenetics - Study of heritable changes in gene expression.
Chemo Brain - Cognitive impairment following chemotherapy.
Cyclical Ketogenic Diet - A ketogenic diet with carb refeeds.
Fasting Mimicking Diet - Diet designed to mimic fasting.
Metabolic Flexibility - Body's ability to switch between fuel sources.
Fatty Acid Oxidation - Process of breaking down fatty acids for energy.
Muscle Memory - Body's ability to recall learned physical movements.
Metabolic Memory - Body's ability to retain adaptations from past metabolic states.
Mitochondrial Function - The efficiency of mitochondria in producing energy.
Mitochondrial Capacity - The potential of mitochondria to produce energy.
Gene Programs - Sets of genes activated for specific functions.
Autophagy - Cellular process of self-cleaning.
P62 - Biomarker related to autophagy.
Glucose Ketone Index (GKI) - Ratio of glucose to ketones.
Beta Hydroxybutyrate (BHB) - A type of ketone.
Acetoacetate - A precursor to ketones.
Acetone - A ketone byproduct.
Gluconeogenesis - Process of producing glucose from non-carbohydrate sources.
Pyloric Sphincter - Muscle controlling the passage of stomach contents to the small intestine.
Isotonic - Having the same osmotic pressure.
Catecholamines - Hormones like adrenaline and noradrenaline.
Sympathetic Nervous System - Part of the autonomic nervous system.
Parasympathetic Nervous System - Part of the autonomic nervous system.
Cholecystokinin (CCK) - Gut hormone.
Glut4 (Glucose Transporter Type 4) - Protein that transports glucose.
Rabbit Starvation - Condition caused by excessive lean protein intake.
Lean Body Mass - Total body weight minus fat mass.
MCT Oil (Medium-Chain Triglyceride Oil) - A type of fat.
Omega-3 to Omega-6 Ratio - Ratio of essential fatty acids.
High-Sensitivity C-Reactive Protein (hs-CRP) - Marker of inflammation.
LDL (Low-Density Lipoprotein) - Type of cholesterol.
Statins - Medications to lower cholesterol.
Aromatase Inhibitors - Medications used in cancer treatment and hormone therapy.
Letrozole - Aromatase inhibitor.
Estrogen Blocker - Medication that blocks estrogen.
Repatha - Medication for cholesterol management.
Zempic - Medication for diabetes and weight management.
Nexlizet - Medication for cholesterol management.
Nicotinic Acid - A form of niacin used for cholesterol management.
APOE33/APOE34 - Genetic variants related to Alzheimer's risk.
Cardiometabolic Biomarkers - Indicators of cardiovascular and metabolic health.
Cardio-Immuno-Metabolic Biomarkers - Indicators of cardiovascular, immune, and metabolic health.
Fasting - Abstaining from food.
Broccoli - Vegetable mentioned as a fiber source.
Wild Blueberries - Berries mentioned as a fiber source.
Apples - Fruit mentioned as a fiber source.
Pectin - Type of fiber found in apples.
FODMAP - Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols.
Macadamia Nuts - Nuts mentioned as a snack.
Walnuts - Nuts mentioned as a snack.
Oxtail Soup - Food item mentioned.
Lamb Chops - Food item mentioned.
Ribeye - Cut of beef.
Chicken of the Sea - Brand of canned fish.
King Oscar - Brand of canned fish.
Season's Brand - Brand of canned fish.
Mackerel - Type of fish.
Sardines - Type of fish.
Oysters - Shellfish.
Canned Fish - General category of food.
Eggs - Food item.
Beef - Food item.
Turkey - Food item.
Whey Protein Isolate - Protein supplement.
Weight Gainers - Nutritional supplements.
Ketone Salts - Supplemental ketones.
Ketone Monoester - A type of exogenous ketone.
Ketone Diester - A type of exogenous ketone.
1,3 Butanediol - A ketogenic agent.
Racemic D,L-Beta Hydroxybutyrate - A mixture of D and L forms of beta hydroxybutyrate.
L-Beta Hydroxybutyrate - The L enantiomer of beta hydroxybutyrate.
D-Beta Hydroxybutyrate - The D enantiomer of beta hydroxybutyrate.
Ketone Ester - A type of exogenous ketone.