June 12, 2018

Ketosis

My experience with exogenous ketones

Theory to anecdote: I decided to find out for myself if ketones could, indeed, offer up the same amount of usable energy with less oxygen consumption.

Read Time 10 minutes

I wrote this post at about the same time Germany won the World Cup in Rio de Janeiro in 2014. There’s been a lot of moving and shaking in the world of exogenous ketones since then, not to mention soccer. Looking back on my post, I still consider it relevant in terms of what exogenous ketones possibly can (and cannot) do for performance. In this case, to see if exogenous ketone esters provide me a “boost” by allowing me to do the same amount of work while expending less energy (and work at a relatively lower VO2) compared to no supplementation.

I’m getting an increasing number of questions about exogenous ketones. Are they good? Do they work for performance? Is there a dose-response curve? If I’m fasting, can I consume them without “breaking” the fast? Am I in ketosis if my liver isn’t producing ketones, but my BOHB is 1.5 mmol/L after ingesting ketones? Can they “ramp-up” ketogenesis? Are they a “smart drug?” What happens if someone has high levels of both glucose and ketones? Are some products better than others? Salts vs esters? BHB vs AcAc? Can taking exogenous ketones reduce endogenous production on a ketogenic diet? What’s the difference between racemic mixtures, D-form, and L-form? What’s your experience with MCTs and C8?

Caveat emptor: the following post doesn’t come close to answering most of these questions. I only document my experience with BHB salts (and a non-commercial version at that), but say little to nothing about my experience with BHB esters or AcAc esters. But it will provide you will some context and understanding about what exogenous ketones are, and what they might do for athletic performance. We’ll likely podcast about the questions and topics above and cover other aspects of exogenous ketones in more detail.

—P.A., June 2018

§

Original publication date: August 14, 2014

Last year I wrote a couple of posts on the nuances and complexities of ketosis, with an emphasis on nutritional ketosis (but some discussion of other states of ketosis—starvation ketosis and diabetic ketoacidosis, or DKA). To understand this post, you’ll want to at least be familiar with the ideas in those posts, which can be found here and here.

In the second of these posts I discuss the Delta G implications of the body using ketones (specifically, beta-hydroxybutyrate, or BHB, and acetoacetate, or AcAc) for ATP generation, instead of glucose and free fatty acid (FFA). At the time I wrote that post I was particularly (read: personally) interested in the Delta G arbitrage. Stated simply, per unit of carbon, utilization of BHB offers more ATP for the same amount of oxygen consumption (as corollary, generation of the same amount of ATP requires less oxygen consumption, when compared to glucose or FFA).

I also concluded that post by discussing the possibility of testing this (theoretical) idea in a real person, with the help of exogenous (i.e., synthetic) ketones. I have seen this effect in (unpublished) data in world class athletes not on a ketogenic diet who have supplemented with exogenous ketones (more on that, below). Case after case showed a small, but significant increase in sub-threshold performance (as an example, efforts longer than about 4 minutes all-out).

So I decided to find out for myself if ketones could, indeed, offer up the same amount of usable energy with less oxygen consumption. Some housekeeping issues before getting into it.

  1. This is a self-experiment, not real “data”—“N of 1” stuff is suggestive, but it prevents the use of nifty little things likes error bars and p-values. Please don’t over interpret these results. My reason for sharing this is to spark a discussion and hope that a more systematic and rigorous approach can be undertaken.
  2. All of the data I’ll present below were from an experiment I did with the help of Dominic D’Agostino and Pat Jak (who did the indirect calorimetry) in the summer of 2013. (I wrote this up immediately, but I’ve only got around to blogging about it now.) Dom is, far and away, the most knowledgeable person on the topic of exogenous ketones. Others have been at it longer, but none have the vast experiences with all possible modalities (i.e., esters versus salts, BHB versus AcAc) and the concurrent understanding of how nutritional ketosis works. If people call me keto-man (some do, as silly as it sounds), they should call Dom keto-king.
  3. I have tried the following preparations of exogenous ketones: BHB monoester, AcAc di-ester, BHB mineral salt (BHB combined with Na+, K+, and Ca2+). I have consumed these at different concentrations and in combination with different mixing agents, including MCT oil, pure caprylic acid (C8), branch-chained amino acids, and lemon juice (to lower the pH). I won’t go into the details of each, though, for the sake of time.
  4. The ketone esters are, hands-down, the worst tasting compounds I have ever put in my body. The world’s worst scotch tastes like spring water compared to these things. The first time I tried 50 mL of BHB monoester, I failed to mix it with anything (Dom warned me, but I was too eager to try them to actually read his instructions). Strategic error. It tasted as I imagine jet fuel would taste. I thought I was going to go blind. I didn’t stop gagging for 10 minutes. (I did this before an early morning bike ride, and I was gagging so loudly in the kitchen that I woke up my wife, who was still sleeping in our bedroom.) The taste of the AcAc di-ester is at least masked by the fact that Dom was able to put it into capsules. But they are still categorically horrible. The salts are definitely better, but despite experimenting with them for months, I was unable to consistently ingest them without experiencing GI side-effects; often I was fine, but enough times I was not, which left me concluding that I still needed to work out the kinks. From my discussions with others using the BHB salts, it seems I have a particularly sensitive GI system.

The hypothesis we sought out to test

A keto-adapted subject (who may already benefit from some Delta G arbitrage) will, under fixed work load, require less oxygen when ingesting exogenous ketones than when not.

Posed as a question: At a given rate of mechanical work, would the addition of exogenous ketones reduce a subject’s oxygen consumption?

The “experiment”

  • A keto-adapted subject (me) completed two 20-minute test rides at approximately 60% of VO2 max on a load generator (CompuTrainer); such a device allows one to “fix” the work requirement by fixing the power demand to pedal the bike
  • This fixed load was chosen to be 180 watts which resulted in approximately 3 L/min of VO2—minute ventilation of oxygen (this was an aerobic effort at a power output of approximately 60% of functional threshold power, FTP, which also corresponded to a minute ventilation of approximately 60% of VO2 max)
  • Test set #1—done under conditions of mild nutritional ketosis, while still fasted
  • Test set #2—60 minutes following ingestion of 15.6 g BHB mineral salt to produce instant “artificial ketosis,” which took place immediately following Test set #1
  • Measurements taken included whole blood glucose and BHB (every 5 minutes); VO2 and VCO2 (every 15 seconds); HR (continuous); RQ is calculated as the ratio of VO2 and VCO2. In the video of this post I explain what VO2, VCO2, and RQ tell us about energy expenditure and substrate use—very quickly, RQ typically varies between about 0.7 and 1.0—the closer RQ is to 0.7, the more fat is being oxidized; the reverse is true as RQ approaches 1.0

Results

Test set #1 (control—mild nutritional ketosis)

The table below shows the data collected over the first 20 minute effort. The 20 minute effort was continuous, but for the purpose of presenting the data, I’ve shown the segmental values—end of segment for glucose and BHB; segment average for HR, minute ventilation (in mL per min), and RQ; and segment total for minute ventilation (in liters).

Glucose and BHB went down slightly throughout the effort and RQ fell, implying a high rate of fat oxidation. We can calculate fat oxidation from these data. Energy expenditure (EE), in kcal/min, can be derived from the VO2 and VCO2 data and the Weir equation. For this effort, EE was 14.66 kcal/min; RQ gives us a good representation of how much of the energy used during the exercise bout was derived from FFA vs. glucose—in this case about 87% FFA and 13% glucose. So fat oxidation was approximately 12.7 kcal/min or 1.41 g/min. It’s worth pointing out that “traditional” sports physiology preaches that fat oxidation peaks in a well-trained athlete at about 1 g/min. Clearly this is context limited (i.e., only true, if true at all, in athletes on high carb diets with high RQ). I’ve done several tests on myself to see how high I could push fat oxidation rate. So far my max is about 1.6 g/min. This suggests to me that very elite athletes (which I am not) who are highly fat adapted could approach 2 g/min of fat oxidation. Jeff Volek has done testing on elites and by personal communication he has recorded levels at 1.81 g/min. A very close friend of mine is contemplating a run at the 24 hour world record (cycling). I think it’s likely we’ll be able to get him to 2 g/min of fat oxidation on the correct diet.

The graph, below, shows the continuous data for VO2, VCO2 (measured), and RQ (calculated).

Test set #2 (ingestion of 15.6 g BHB salt 60 minutes prior)

The table below shows the same measurements and calculations as the above table, but under the test conditions. You’ll note that BHB is higher at the start and falls more rapidly, as does glucose (for reasons I’ll explain below). HR data are almost identical to the control test, but VO2 and VCO2 are both lower. RQ, however, is slightly higher, implying that the reduction in oxygen consumption was greater than the reduction in carbon dioxide production.

If you do the same calculations as I did above for estimating fat oxidation, you’ll see that EE in this case was approximately 13.92 kcal/min, while fat oxidation was only 67% of this, or 9.28 kcal/min, or 1.03 g/min. So, for this second effort (the test set) my body did about 5% less mechanical work, while oxidizing about 25% less of my own fat. The majority of this difference, I assume, is from the utilization of the exogenous BHB, and not glucose (again, I will address below what I think is happening with glucose levels).

The graph once again shows the continuous data for VO2, VCO2 (measured), and RQ (calculated).

Side-by-side difference

The final graph, below, shows the continuous data for only VO2 side-by-side for the 20 minute period. The upper (blue) line represents oxygen consumption under control conditions, while the lower line (red) represents oxygen consumption following the BHB ingestion. In theory, given that the same load was being overcome, and the same amount of mechanical work was being done, these lines should be identical.

The hypothesis being tested in this “experiment” is that they would not be the same. Beyond visual inspection, the difference between the lines appears to grow as the test goes on, which is captured in the tabular data showing 5 minute segmental data.

Limitations

The most obvious limitation of this endeavor is the fact that it’s not an appropriately controlled experiment. Putting that aside, I want to focus on the nuanced limitations—which don’t impact the primary outcome of oxygen consumption—even if one were appropriately doing a real experiment.

  1. It’s not clear that the Weir coefficients used to estimate EE are relevant for someone in ketosis, let alone someone ingesting exogenous BHB. (The Weir formula states that EE is approximated by 3.94 * VO2 + 1.11 * VCO2, where VO2 and VCO2 are measured in L/min; 3.94 and 1.11 are the Weir coefficients, and they are derived by tabulating the stoichiometry of lipid synthesis and oxidation of fat and glucose and calculating the amount of oxygen consumed and carbon dioxide generated.) While this doesn’t impact the main observation—less oxygen was consumed with higher ketones—it does impact the estimation of EE and substrate use.
  2. In addition to the Weir coefficients being potentially off (which impacts EE), the RQ interpretation may be incorrect in the presence of endogenous or exogenous ketones. As a result, the estimation of fat and glucose oxidation may be off (though it’s directionally correct). That said, the current interpretation seems quite plausible—greater fat oxidation when I had to make my ketones; less when I got my ketones for “free.”

Observations from this “experiment” (and my experience, in general)

Animal models (e.g., using rat hearts) and unpublished case reports in elite athletes suggest supplemented BHB produces more ATP per unit carbon and per unit oxygen consumed than glycogen and FFA. This appears to have been the case in my anecdotal exercise.

The energy necessary to perform the mechanical work did not appear to change much between tests, though the amount of oxygen utilization and fat oxidation did go down measurably. The latter finding is not surprising since the body was not sitting on an abundant and available source of BHB—there was less need to make BHB “the old fashioned way.”

As seen in this exercise, glucose tends to fall quite precipitously following exogenous ketone ingestions. Without exception, every time I ingested these compounds (which I’ve probably done a total of 25 to 30 times), my glucose would fall, sometimes as low as 3 mM (just below 60 mg/dL). Despite this, I never felt symptomatic from hypoglycemia. Richard Veech (NIH) one of the pioneers of exogenous ketones, has suggested this phenomenon is the result of the ketones activating pyruvate dehydogenase (PDH), which enhances insulin-mediated glucose uptake. (At some point I will also write a post on Alzheimer’s disease, which almost always involves sluggish PDH activity —in animal models acute bolus of insulin transiently improves symptoms and administration of exogenous ketones does the same, even without glucose.)

In addition, the body regulates ketone production via ketonuria (peeing out excess ketones) and ketone-induced insulin release, which shuts off hepatic ketogenesis (the liver making more ketones when you have enough).   The insulin from this process could be increasing glucose disposal which, when coupled with PDH activation, could drive glucose levels quite low.

If that explains the hypoglycemia, it would seem the absence of symptoms can be explained by the work of George Cahill (back in the day; see bottom figure in this post)—when ketone levels are high enough they can dominate brain fuel, even ahead of glucose.

Finally, these compounds seemed to have a profound impact on my appetite (they produced a strong tendency towards appetite suppression). I think there are at least two good explanations for this, which I plan to write about in a dedicated post. This particular topic—appetite regulation—is too interesting to warrant anything less.

Open questions to be tested in real experiments

  1. Are these results reproducible? If so, how variable are the results across individuals (by baseline metabolic state, diet, fitness)?
  2. Would the difference in oxygen consumption be larger (or smaller) in an athlete not already keto-adapted (i.e., not producing endogenous ketones)?
  3. Would the observed effect be greater at higher plasma levels of BHB (e.g., 5 to 7 mM), which is “easily” achievable with exogenous ketones?
  4. Would the observed effect be the same or different at higher levels of ATP demand (e.g., at FTP or at 85-95% of VO2 max)?
  5. Would the trend towards improved energy efficiency continue if the exercise bout was longer in duration (say, greater than 2 hours)?
  6. How will exogenous ketones impact exercise duration and lactate buffering?
  7. Why do exogenous ketones (both BHB and AcAc it seems) reduce blood glucose levels so much, and can this feature be exploited to treat type 2 diabetes?
  8. Are there deleterious effects from using exogenous ketones, besides GI side-effects?
  9. What are the differences between exogenous BHB and AcAc (which in vivo exist in a reversible equilibrium) on this particular phenomenon? (Work by Dom D’Agostino’s group and others have shown other differences in metabolic response and clinical application, including their relative impact on neurons.)

Photo by Alexey Lin on Unsplash

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376 Comments

  1. Looking at your AT pre vs during ketosis, you used more O2 in ketosis, but how much more work were you actually doing? Same question at VO2max. After all it is how fast you are going, not how much O2 you are using, that wins prizes. Thanks.

  2. Peter,

    I would love to send you some samples of an exogenous ketone product I came across. Several years ago, I put myself into ketosis through diet and felt great! This product makes me feel the same way. I would love to get your opinion of this product.

    Thanks,
    Tim

  3. Hi Peter, huge fan of your work, your podcast with Tim and your blog… I started Ketogenic diet after listening to your podcast and Dr. D’Agastino with Tim Ferris… I did 90% fat and less than 20g of carbs and 30-50g of protein for 3 weeks to get keto adapted… I was using a blood ketone tester to keep track of my ketosis… I was in ketosis after the 2nd day of starting my diet and in 3 weeks, the highest I tracked was 4.5 mmol/L of ketones… All good there…

    I then did a cheat day last week, on Sunday, and after that day, I have been on the same diet I followed previously, but my ketone levels have not gone above 0.7 mmol/L and most times it is below 0.5 mmol/L… I am not eating too much carbs or protein… I have stopped taking protein supplements… I drink 3-4 Bulletproof Coffee a day with a extra-large serving of butter and MCT oils and lunch is half a roast chicken with lot of MCT oil and at night usually 6 eggs or 500g of steak with a lot of butter…

    I also workout 3-4 days, heavy weight training and some HIIT on a treadmill.

    Do you see any mistakes in the diet or anything else I could do to get past the block? It has been 5 days since I am back on the diet after the cheat day… Appreciate you reading this and your help… Thanks.

    • First of all, great stuff here!

      I am no expert but I went through the FASTER study done by Jeff Volek and the blood ketone levels from the graphs there are a lot lower then I suspected.
      My own levels rarely are above 0.5mmol/l in the morning and I am on a low carb diet for years after being on a paleo diet for 5 years before.
      Keto-adaptation is not the same as in ketosis. Being keto-adapted means you can burn fat like a boss while not strictly in nutritional ketosis.

    • HI Peter:

      According to your artical ,you took some preparations of exogenous ketones, like BHB monoester, AcAc di-ester , BHB mineral salt
      1. May I ask where can I buy those exogenous ketones?
      2. Which brand can produce higher ketone level?
      Since I adopt keto diet three months ago; however, plenty social parties let me out ketogenesis all the time
      Recently, I discover that ketone esters can increase brown fat, beginning searching relative information.

      truly hoping you can tell me where to buy those ketone esters

      I have tried the following preparations of exogenous ketones: BHB monoester, AcAc di-ester, BHB mineral salt (BHB combined with Na+, K+, and Ca2+). I have consumed these at different concentrations and in combination with different mixing agents, including MCT oil, pure caprylic acid (C8), branch-chained amino acids, and lemon juice (to lower the pH). I won’t go into the details of each, though, for the sake of time.

      • At the time I did this they were not for sale ad I was using specific formulations prepared for research use. Today, one can easily obtain BHB salts (Ca, Na, Mg), but not sure if the ester or AcAc diester are commercially available. I think the salts are plenty good. Prototype Nutrition sells them.

  4. Hello Peter,

    I must admit; this has been a remarkable journey for me and my wife. We started with Nutritional Ketosis July 2015, lost weight AND gained muscle (we train compound and weight training 2-3 times a week (2hrs) starting with 20 min of HIT).

    We have grown and our body has completely changed where we can see muscle definitions like never before and we have been training since 2003 (with some intervals 🙂 ). These past 6 months have been really a game changer.

    Overtime we tried everything from: Body for Life, reducing refined sugar intake, substituting to complex, non-refined and low glycemic carbohydrates, increasing protein intake, calorie reduction and always reducing the fat content in our food intake.

    With this new lifestyle we are able to control weight, reduce appetite and cravings (esp. during our business travel), enhance our performance in the gym and increase muscle while reducing our subcutaneous fat.
    Thank you for your material and thorough investigations. It helped us a lot in our quest to a healthier body and lifestyle and we are still looking to increase performance and optimize our physique, ready to take the next step to exogenous ketones.

  5. Hi Dr. Attia,

    Will water fasting for 3-10 days speed up the process of the body becoming fat-adapted? (Have you read the study that water fasting for 2-5 days causes autophagy, and refeeding after that period triggers stem cell regeneration? So water fasting should kill the cells with carb-reliant mitochondria, and the stem cell regeneration when refeeding while doing keto should cause birth of cells that are fat-adapted?)

    Thanks,
    Rawnaq

  6. Peter, I am confused by the NuSI website, where you are no longer listed as President of NuSI – it lists Chris Ochner as President. And there is no mention of you from the Leadership link at the top. Is it possible you have left NuSI? If so what are you up to these days? Or if not – you should let them know they need to fix their pages. Thanks!

    • “Body weight is determined by calories in, calories out; how much you eat and drink versus the calories that we expend.”

      Chris Ochner, CBS This Morning, 1/23/14

      DEAR GOD NO!!!!!!!!!!!!!!!!!!!!!

  7. Peter – fasting is not starvation. One is voluntary the other is not. Like saying bulimia is the same as projectile vomiting

  8. Dr. Attia,

    Do you intend to share the details of your departure from NuSI at any point? I understand, if you’d rather not.

    Ali

  9. Hmmm, well if we aren’t going to be privy to what went down hopefully we can at least benefit from more frequent blog posts 🙂

  10. Peter,

    I am a motivational speaker and part time athlete. I am all about finding ways to increase my energy and focus. I have recently tried a product, Keto OS exogenous ketones and it has been helpful. I would be interested in how you feel I should ingest ketones and what possible side effects there might be in the future. So far, so good for me, but I want to make sure I am doing the right thing. Is there anything you would suggest doing along side BHB salts for enhanced energy and focus?

    Scott Goyette

    • Dom knows Patrick Arnold. Listen to the Tim Ferriss Patrick Arnold podcast at about 105 minutes in for an answer to your question.

  11. My 3/2/2016 PET bone scan shows a recurrent prostate cancer tumor and 3 bone metastases sites of my aggressive prostate cancer (T3N1 Gleason 10).

    Despite having had external radiation (and hormone) therapy 4 years ago, my radiation oncologist says I did not experience radionecrosis (delayed radiation injury) so I’m not approved for Hyperbaric Oxygen Therapy by US Food and Drug Administration (FDA),
    http://www.hyperbariclink.com/diseases-and-conditions/radiation-injury.aspx#.VshSm5MrKRs/.

    In https://youtu.be/yWRnma8Tet0?t=38m38s Dom showed that ketones, even in presence of glucose, increases cancer cell death and decreases cancer cell proliferation.

    I’ve proved to myself that I am following a ketogenic diet by putting my diabetes in remission (A1C 6.9 to 5.5) and losing 30 lbs and 6 inches on belt (BMI 31.4 to 27). I try to do no carbs, but do have a salad and a serving of very low glycemic vegetables (<20g / day).

    So I'd like to boost the ketones from my diet by adding exogenous ketones like in this post; hoping to slow my cancer's progression.

    What should I add and how much? Where do I get them? Are they affordable?

    Thanks,
    -Steve

  12. i have a lot to add to this, my child has a fatty oxidation disease, in essence he cant eat fat or protein as his body cannot break them down. He has been on artificial ketones since 6 months of age which saved his life as he was dying. The ketones provide the energy for his brain and other vital body organs – he doesn’t produce any ketones at all so supplementation is essential. I also was an endurance athlete and right from the start I decided to go into fat adaptation as my training tool (not carb loading), being in ketosis for my long distance tri training was amazing, I felt fabulous and was able to train daily. The fat adaptation method is still very new for athletes, but for me made a lot of sense, and i had a very good grasp on ketones and ketosis. I do have a medical supply of DL Hydroxybutyric Acid that is for my child, I have sometimes thought i should be taking it too, but the supply I have is heavily monitored. I know it would give me huge advantages in energy, as this is what is keeping my child alive.

  13. Peter, We started on the Keto eating this week and all going well. I got some KetoSport Ketoforce which is an exogenous ketone salt. What would be good times to take this?
    I am thinking that this was suggested to me since we are just starting out to help us over the rough spots. But we have not had any yet.

  14. Dr. Peter,

    I am a student at university, and am currently in the process of writing a proposal for an independent study on exogenous ketone supplementation and the effect it has on oxygen consumption. I would value your feedback and take into great consideration any suggestions you may have as to how to conduct this research.

    Thank you for your consideration,
    Jack

  15. Peter- thanks for all your efforts here. You spoke of ketonuria above. How can I measure the efficiency of my ketone utilization. For example: if I test using urine samples and I am getting a higher reading of ketones in the urine, does that indicate I am in Ketosis, or, I am just flushing the ketones out and not using them for fat oxidation? I find I am in the darker pink range until I take MCTs. Then, the reading goes to purple. Any info is appreciated.

  16. Hey Peter- You wrote in this post that “A very close friend of mine is contemplating a run at the 24 hour world record (cycling). I think it’s likely we’ll be able to get him to 2 g/min of fat oxidation on the correct diet.” … so 1) Did your friend set the record? and 2) Were you able to get him to 2 g/min?

  17. Hi Peter

    Thank you for all your effort and all the great information. I was researching for a paper I am currently working on and cound’t find a definite answer to the question – how much ATP per mol BHB is actually produced?

    Cheers Jula

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