Battling Reductive Stress: Pyruvate and L-Carnitine

At the end of my series on how seed oils cause reductive stress, I said I would be back soon with ideas for what to do about it. This is the first article and I’m going to look at two cheap supplements that have been around a long time and look at how they work together.

You can save 12% if you buy these supplements at bulksupplements.com and use the promo code “FIRE”. The funds of these sales help me to run the blog. Thank you!

Watch the video version of this post!

If you’d like to catch up on how seed oils cause reductive stress, here’s the index:

If that’s too much reading, I’ll summarize. Vegetable oils don’t burn cleanly and end in a state of mitochondrial energy overload. This overload is defined by having too much acetyl-CoA – the fuel that carbohydrates and fat are both converted to before entering the Krebs cycle – and too much NADH – the electron carrier that allows us to burn acetyl-CoA. The buildup of acetyl-CoA and NADH blocks key mitochondrial enzymes. Pyruvate Dehydrogenase (PDH) is the key enzyme that allows glucose to enter the krebs cycle. It is directly inhibited by acetyl-CoA and NADH. Obese humans have high acetyl-CoA, high NADH and low PDH activity.

Other mitochondrial enzymes become deactivated by acetylation when NADH and acetyl-CoA are high. These include mitochondrial complexes I and IV, which are naturally acetylated when acetyl-CoA builds up. If complex I is acetylated, NADH cannot be oxidized, adding to the NADH buildup. When NADH and acetyl-CoA are both high, metabolism slows down and calories are shunted into De Novo Lipogenesis (making fat) rather than being burned.

Conversely, when NADH is low, sirtuin enzymes are activated, which deacetylate the mitochondrial enzymes.

Obese and diabetics humans have several characteristics that distinguish them from lean humans: low PDH activity, low activities of mitcohondrial enzymes (especially Complex II, succinate dehydrogenase), high levels of circulating acylcarnitines – unburnt fats – and high levels of circulating lactate​1​.

L-Carnitine gets rid of acetyl-CoA

This figure from my favorite paper grabbed my attention.​2​ This shows the metabolic rate of isolated mouse muscle mitochondria given palmitate (saturated fat) with increasing amounts of l-carnitine.

JO2 is the rate of oxygen consumption of mitochondria when incubated with increasing quantities of l-carnitine

When mitochondria are incubated with increasing amounts of l-carnitine, their metabolic rate increases 8-fold. This is due to an enzyme called Carnitine O-acetyltransferase (CrAT). CrAT actually takes the acetyl groups from acetyl-CoA and transfers them to l-carnitine, which escorts them out of the mitochondria.

Mitochondrial acetyl-CoA directly inhibits metabolic rate and l-carnitine lowers mitochondrial acetyl-CoA.

Fat metabolism is inhibited by acetyl-CoA due to inhibition of beta-oxidation (the process that breaks fat into acetyl-CoA) by the enzyme b-ketoacyl-CoA thiolase.​2​ This is classic end-product enzyme inhibition. The enzyme produces acetyl-CoA until there is enough acetyl-CoA. When acetyl-CoA levels get high, the enzyme stops making more. If fat metabolism stalls out long enough, some of the unburned fats will wind up back in the bloodstream as acylcarnitines.

As I mentioned, pyruvate dehydrogenase is a key mediator of glucose metabolism and it is ALSO inhibited by acetyl-CoA.​3​ In how seed oils cause reductive stress part V I used an example that young men who pre-loaded before exercise with sunflower oil had inhibited pyruvate dehydrogenase activity compared to those who pre-loaded with cream.​4​ Sunflower oil led to decreased metabolic flexibilty. You see this same metabolic trait in obesity: the inability to switch back and forth between glucose and fat burning.

Remember that pyruvate dehydrogenase is a thermogenic enzyme, cranking out ROS as it does its job​5​.

When l-carnitine was used by a group of athletes, pyruvate dehydrogenase activity INCREASED by 80%.​6​ L-carnitine has precisely the opposite effect of sunflower oil. L-carnitine decreases mitochondrial acetyl-CoA, unleashing pyruvate dehydrogenase, allowing people to burn glucose when it is available.

Furthermore, a 2019 paper looked at metabolic flexibilty in overweight adults with normal glucose tolerance and impaired glucose tolerance. The authors conclude that “metabolic flexibility in response to a high-energy meal was decreased in impaired glucose tolerance and could be completely restored with carnitine supplementation.”​7​ 2000mg per day of l-carnitine was enough to restore metabolic flexibilty.

The authors also add “Furthermore, carnitine supplementation reduced long-chain acylcarnitine species in impaired glucose tolerant-subjects, suggesting the stimulation of a more complete fat oxidation in muscle.” The carnitine helped to burn fat completely.

Carnitine is available in the diet. The best sources are lean meats. Beef has 81mg/3Oz, pork has 24 and chicken has 3.

Pyruvate, Lactate and NADH

L-carnitine is very popular in fat burning supplemental mixtures. It can help deal with the acetyl-CoA buildup, but by itself it hasn’t caused huge weight loss in most studies. If we want weight loss, we also have to deal with excess NADH. Enter pyruvate.

When glucose is consumed in glycolysis, it makes two molecules of pyruvate. The pyruvate can then be burned in the Krebs cycle if pyruvate dehydrogenase is active, exported from the cell if not or converted to lactate by lactate dehydrogenase. Cells can use pyruvate to rid themselves of extra electrons held by NADH. They take in circulating pyruvate, convert it to lactate with the enzyme lactate dehydrogenase, and then export the lactate. Converting pyruvate to lactate converts an NADH to NAD+. Cells that need energy can take in lactate, send the electrons into the electron transport chain and export pyruvate. In this way, the tissues of the body can equilabrate the NADH/NAD+ ratio across tissues.​8​

This is a reversible reaction. Cells can convert pyruvate to lactate if they need to get rid of NADH.

By the activity of lactate dehydrogenase, external lactate and pyruvate can drive the NADH/NAD+ ratio of cells. Consider this table​9​:

Healthy cells have around 400 times as much NAD+ as NADH (highly oxidized NAD pool). Cancer cells tend to have less than 300 times as much NAD+. This is reductive stress. The part that I’ve circled in red: this is the same cell line cultured with either pyruvate or lactate. The action of lactate pushes cells into DEEP reductive stress (33:1). Conversely, pyruvate pushes the cells to a much more oxidized state (1300:1)

When you eat pyruvate, it is rapidly absorbed and cells use it to convert NADH to NAD+. Obese and diabetic humans have higher levels of lactate in their bloodstream and higher ratios of lactate/pyruvate​1​.

Dietary pyruvate is a huge buffer, allowing cells to offload surplus NADH. This allows them to activate sirt1, leading to activated AMPK, PGC-1a, upregulated mitochondrial biogensis and increased metabolic rate. It also leads to activated sirt3, allowing your cells to activate their mitochondrial enzymes.

A Fascinating Study

L-carnitine and pyruvate both have long histories of being used for weight loss. Pyruvate was heavily pushed as weight loss aid in the late 1990s. Interestingly research on pyruvate suddenly stopped around the year 2000. This may have been due to it’s patenting as a weight loss supplement.

Logically, l-carnitine and pyruvate should act synergistically, so I wondered if anyone had combined them. I found this:

As the authors point out, this is too small of a trial and too short of a duration to draw any long term conclusions. But it’s enticing and the anecdote at the end perhaps gives a clue as to why pyruvate research stopped in 2000.

HCA is a compound from a tropical fruit that blocks an enzyme that allows formation of acetyl-CoA in the cytoplasm. It should uninhibit the enzyme CPT1, which will increase fat flow to the mitochondria. It should also block De Novo Lipogenesis. I haven’t tried it. Chromium is another fat burning aid. I haven’t tried it.

I HAVE tried l-carnitine and pyruvate together. The thermogenesis from pyruvate is real. Within minutes after drinking 10-15 grams of pyruvate I can feel my body temperature rise. If I’m fasted, my body temperature usually stays in the 98.6-99.0 range. If I then eat a bowl of white rice, my body temp will often shoot to over 100. It’s been a week. My weight this morning dropped below a plateau I’ve been stuck on for a few weeks, so I’m feeling very optimistic about this.

How To Try This

bulksupplements.com is easily the best place to get calcium pyruvate in the quantity you’ll want. If you use the discount code FIRE you’ll save 12% off of your entire order. This helps me run the blog. You can also get calcium pyruvate in capsules, but the study I quoted used a dosage of 12g of pyruvate per day. That would be 20 600mg capsules.

The pyruvate tastes a bit like bitter caramel and is not very soluble in cold water. One level tablespoon is about 17g of calcium pyruvate. I’ve been adding three level tbsp of sugar and one level tbsp of calcium pyruvate into a glass mug and pouring just enough hot water to dissolve the pyruvate from the tea kettle over it. I stir it well, then add enough ice until it’s cold. Then I add as much plain seltzer as will fit. Tastes a bit like cream soda.

Of course, you can add the l-carnitine right to this along with the pyruvate and sweetener. You can also add HCA if you want! If you don’t want to use sugar, they have a whole bunch of sugar free sweeteners. l-carnitine benefit seems to max out at 2g per day and HCA should be kept at 1.5g.

Or you could just add it all to yogurt or a smoothie.

I’ve also noticed very real appetite suppression from l-carnitine and pyruvate. Leptin signals satiety through an NAD+ dependent pathway, after all​10​. Yesterday I did an umplanned semi-fasting day just because I wasn’t hungry.

IMPORTANT UPDATE: As pointed out in the comments by Natalie, if you take 12g of calcium pyruvate, this is a lot of calcium (3g). This is probably a reasonable maximum for the day. You might want to split the 12g into two-three servings. A level measuring teaspoon is 5g of calcium pyruvate. Pyruvate on its own is unstable, the calcium is there to stabilize it. You should also make sure you’re getting adequate vitamin K2 (this doubles as a teaser for my next post) and D3 to make sure the calcium goes where it’s supposed to and discontinue any other calcium supplements.

Since pyruvate and l-carnitine are both natural substances that our body deals with all of the time, there shouldn’t be a lot of safety concerns. I have noticed two side effects with pyruvate. The first is that it can cause digestive upset. The second is that if you overdo it, you can get a kind of spaced out feeling. Almost a headachy kind of feeling. People have reported a similar reaction to alpha lipoic acid, which also reduces lactate levels. Sometimes I get this after my SECOND 15-20g serving of pyruvate, never after the first. This is far more pyruvate than what was used in the study.

Other Supplements?

Can pyruvate and l-carnitine be combined with other supplements that have been discussed here? Certainly!

A difference between pyruvate and alpha lipoic acid (ALA) is that pyruvate doesn’t actually eliminate the extra electrons from the NADH. Any pyruvate that is reduced to lactate winds up circling to be used later. ALA gets rid of the electrons for good. The difference is that pyruvate can be safely used in much larger quantities. Personally I haven’t experienced the same thermogenic aspect with ALA. Perhaps there is a benefit to combining them. Additionally, half of the ALA is r-ALA, which targets mitochondrial NADH directly. Pyruvate reduces cytoplasmic NADH, which I believe helps to bring down mitochondrial NADH via mitochondrial shuttles, but perhaps there is additional benefit to r-ALA.

As I discussed in the last post, NADH drives forward the SCD1 reaction, converting saturated fat into MUFA, which keeps you in reductive stress. Lowering NADH should slow down SCD1, but if you’re struggling with weight loss it still might help to take a little sterculia oil t keep that enzyme at bay.

Lastly, pyruvate and l-carnitine should help activate metabolic enzymes, including Complex II, which is particularly inhibited in obesity. Opening up complex II should increase the effectiveness of supplemental succinate. At the moment my succinade product is sold out but it should be back in stock by months end.

  1. 1.
    Konrad T, Vicini P, Kusterer K, et al. alpha-Lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diabetes Care. Published online February 1, 1999:280-287. doi:10.2337/diacare.22.2.280
  2. 2.
    Smith CD, Schmidt CA, Lin CT, Fisher-Wellman KH, Neufer PD. Flux through mitochondrial redox circuits linked to nicotinamide nucleotide transhydrogenase generates counterbalance changes in energy expenditure. Journal of Biological Chemistry. Published online November 2020:16207-16216. doi:10.1074/jbc.ra120.013899
  3. 3.
    Pettit FH, Pelley JW, Reed LJ. Regulation of pyruvate dehydrogenase kinase and phosphatase by acetyl-CoA/CoA and NADH/NAD ratios. Biochemical and Biophysical Research Communications. Published online July 1975:575-582. doi:10.1016/s0006-291x(75)80185-9
  4. 4.
    Bradley NS, Heigenhauser GJF, Roy BD, et al. The acute effects of differential dietary fatty acids on human skeletal muscle pyruvate dehydrogenase activity. Journal of Applied Physiology. Published online January 2008:1-9. doi:10.1152/japplphysiol.00636.2007
  5. 5.
    Fisher-Wellman KH, Lin CT, Ryan TE, et al. Pyruvate dehydrogenase complex and nicotinamide nucleotide transhydrogenase constitute an energy-consuming redox circuit. Biochemical Journal. Published online April 2, 2015:271-280. doi:10.1042/bj20141447
  6. 6.
    Arenas J, Huertas R, Campos Y, Díaz AE, Villalón JM, Vilas E. Effects of<scp>l</scp>-carnitine on the pyruvate dehydrogenase complex and carnitine palmitoyl transferase activities in muscle of endurance athletes. FEBS Letters. Published online March 14, 1994:91-93. doi:10.1016/0014-5793(94)80246-7
  7. 7.
    Bruls YM, de Ligt M, Lindeboom L, et al. Carnitine supplementation improves metabolic flexibility and skeletal muscle acetylcarnitine formation in volunteers with impaired glucose tolerance: A randomised controlled trial. EBioMedicine. Published online November 2019:318-330. doi:10.1016/j.ebiom.2019.10.017
  8. 8.
    Rabinowitz JD, Enerbäck S. Lactate: the ugly duckling of energy metabolism. Nat Metab. Published online July 2020:566-571. doi:10.1038/s42255-020-0243-4
  9. 9.
    Zhao Y, Wang A, Zou Y, Su N, Loscalzo J, Yang Y. In vivo monitoring of cellular energy metabolism using SoNar, a highly responsive sensor for NAD+/NADH redox state. Nat Protoc. Published online June 30, 2016:1345-1359. doi:10.1038/nprot.2016.074
  10. 10.
    Sasaki T. Age-Associated Weight Gain, Leptin, and SIRT1: A Possible Role for Hypothalamic SIRT1 in the Prevention of Weight Gain and Aging through Modulation of Leptin Sensitivity. Front Endocrinol. Published online July 16, 2015. doi:10.3389/fendo.2015.00109
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89 thoughts on “Battling Reductive Stress: Pyruvate and L-Carnitine”

      1. If you driving pyruvate towards lactare instead of acetyl Co A, the lactate build, what happens to all that lactate?
        Wouldn’t supplemental niacinamide help convert NADH to NAD+?
        will taking lots of thiamin result in excess NADH (generating pyruvate from lactate)?

        1. Remember that it’s the ratio of NADH/NAD+ that controls the enzymes. It only takes a tiny amount of NADH to gum things up because healthy cells have a ratio of 400:1 NAD+/NADH in the cytoplasm. A ratio of 200:1 is severe reductive stress! This tiny ratio is opposite in lactate/pyruvate ratio. There is already 20-30 times as much lactate as pyruvate. So a few grams of pyruvate won’t push up lactate levels as much as you think since there is already far more lacate. What it will do is take away some of the NADH and add a little pyruvate. Think of it as increasing the buffer to offload electrons onto to get things moving.

          Also, from a redox persepctive, lactate is pretty similar to glucose, so lactate isn’t really BAD per se.

          Niacinimide will add to the NAD+ total. So yes, that’s another way to increase the ratio and I recommend it. Given the option, I’d prefer to subtract a little NADH than try to add a lot of NAD+ but it can’t hurt to do both.

          Thiamine is necessary for several enzymes that produce NADH. BUT!! All of those enzymes also produce ROS (ie pyruvate dehydrogenase, a-ketoglutarate dehydrogenase), which will help take care of extra NADH. We shouldn’t be afraid to burn the bodies natural fuels since evolution already thought about this and compensated for it.

          Brad

          https://www.sciencedirect.com/science/article/abs/pii/S0891584916303021

  1. Awesome post, Brad. I’m so hyped to have a few more tools in the appetite suppression and fat loss toolbox, with some mechanistic evidence to back it up to too. Keep up the great work, man!

  2. A quick search has shown me there are numerous forms of l-carnitine, some of which I know to be touted for different biological action, like acetyl l-carnitine’s use in pre-workouts or nootropic formulas. For the effects discussed in this article, are we interested in anything sold as l-carnitine fumarate?

    1. I would just use regular “l-carnitine”. The others have specific uses (acetyl-l-carnitine, for instance, crosses the blood barrier I believe, but you don’t really want the extra acetyl groups)

      1. It seems L-carnitine tartrate is almost used as a synonym for L-carnitine in many products. Is this form also different? Any drawbacks with this form? For example the product Carnipure that’s easy to get in Europe seems to be this form.

          1. The tartrate gives it a specific PK profile. That form is usually used in exercise studies due to this profile.

  3. wrt the strange feelings and headaches using calcium pyruvate, I would guess it’s because taking 20g of calcium pyruvate means ingesting 3g of calcium, which is a bonkers amount from a single thing. Too much calcium can cause heart attacks and put people in comas, and 3g is amongst the upper limits suggested for an entire day. So even if you got zero calcium from diet it’s pushing it, and doing it twice just seems like a bad idea.

    1. Good points. The second serving is not necessary, to be clear, even 10g of calcium pyruvate sends my body temp up for hours/most of the day. I was just curious what would happen.

      Brad

      1. Could you take the pyruvate in a different form than with calcium? Is it mainly because that’s the easiest version to find?

        1. It’s pretty unstable in the pure form, calcium pyruvate is stable. Methyl-pyruvate is interesting but very expensive.

    2. If you get more familiar with Ray Peat’s work, he talks about the “Calcium Paradox.” Basically, Calcification of soft tissues usually starts to happen when dietary calcium is too low…. because we all have a skeleton, and low dietary intake causes PTH and Prolactin to rise, mobilizing calcium from bones, and this is what leads to higher serum calcium, and eventually, calcium deposits in veins and arteries and heart issues. People who have done heavy or all milk diets are often get more calcium than this (5 grams or more a day), and some people use a lot of calcium carbonate as phosphate binders, and can be ingesting 6 grams of calcium a day, or more.

      Having said all that, I do think it’s wise to increase calcium intake slowly, (and hence, Calcium Pyruvate too). Too much calcium too soon can cause constipation

  4. Some comments:

    – When I see mention of increased temperature I wonder if if ETC uncoupling is involved.

    – Since glucose is converted to pyruvate, can you just increase foods like white potatoes, sweet potatoes, rice etc?

    – Seems like the old meat and potatoes of the 1950s was not so bad after all.

    1. As to glucose… I started this section in the post but it kind of convoluted. Glycolysis breaks glucose into two pyruvate and creates two NADH to do so. If you then reduce the pyruvate to lactate it uses the two NADH made in glycolysis, but there is no NET reduction in cytosolic NADH from glucose. Pyruvate, of course, skips glycolysis and therefore can act to offload electrons from NADH.

      Brad

    2. As to uncoupled, I doubt that uncoupling proteins are involved. The thermogenesis is likely due to ROS generation because pyruvate dehydrogenase and beta-oxidation are sped up, both of which produce ROS. ROS production and regeneration via glutathione/glutathione reductase/NNT is a type of uncoupling: using electrons from food without generating ATP.

      Brad

  5. Pyruvate

    • Anionic form of the three-carbon organic acid, organic acid, pyruvic acid
    • Present in red apples (∼450 mg), red wine and dark beer (∼75 mg), and cheeses.
    • Serves as a biological fuel, converted to acetyl-coenzyme A, which enters the Krebs cycle and is metabolized to produce ATP aerobically
    • Anaerobically energy is obtained when pyruvate is formed as an end-product of glycolysis and then reduced to lactate
    • Known for infomercial with Steve Garvey where drug effects were misrepresented and resulted in $10 million settlement against the company

  6. Would love to try this but unfortunately after doing a quick search It seems the pyruvate would be to expensive to ship to England where I live, and can’t find it cheaply where I am. Oh well

  7. In Ch 9 of ‘Oxygen’, Nick Lane suggests that Vitamin C is essential for carnitine to function – should you up the OJ as well?

  8. Do you have any suggestions as to timing of the pyruvate and l-carnitine and whether to split the dosing? The study combined empty stomach dosing and one with lunch, at three times from sunrise to sunset. I also wonder how to determine the best dosing (number of mg, rather than number of doses daily) on an individual basis as this obviously will need a bit of trial and error given the limited data. How did you determine your personal dosing, as it differs from the study? Do you see timing with or away from meals as any possible advantage?

    This is all fascinating to try to comprehend and I hope people will check in with updates on their experiences! Thank you!

    1. I’ve been drinking the pyruvate on an empty stomach and it definitely gets my body temp up to 98.6 within an hour. If I then eat a bowl of rice, my BT will shoot to over 100. I assume this is due to insulin and blood glucose driving pyruvate dehydrogenase activity.

      Brad

  9. How important do you think keeping the low fat portion of the trial is? At my TDEE recommendations, 10% fat would be roughly met by the stearic acid banana milkshake. Not complaining, just curious.

    1. I don’t know that it’s important. I expect this would in combination with high fat keto as long as the fat is relatively saturated. I am personally doing mixed fat and carbs. The supplements blunt my appetite, though, so I’m not eating that much ATM.

      Brad

  10. Any idea if “creatine pyruvate” would have the same effects as “calcium pyruvate”? The former is more easily available in powdered form over here.

  11. Brad –
    Before I saw your video above, I expected you to be slim.
    You have access to all these supplements.
    But you are obese — face, shoulders, chest loaded with fat.
    In your next email or blog post, I hope you will explain why, exactly.
    Thank you.

    1. I’m stubborn. I could do keto or intermittent fasting to lose the weight, but I don’t think that fixes the problem. I insist on eating a mixed diet with fat and carbs. I want to show that I can get down to my ideal weight without resorting to keto by fixing my metabolism. This is the hard road, the road less travelled and I expect setbacks. And I’ve had plenty of them! I’m in this journey with everyone else. I’m a fat guy on the spectrum with a taste for alcohol.

      Having said that, I am maintaining a weight that is 30 lbs less than I used to weigh, which is a lot of progress for many!! With understanding of the problem comes better approaches. I think this is the clearest/best idea to date. I am having the same kind of success I had when I did the original croissant diet. I’m hoping to ride this wave all of the way down. We’ll see!

      Brad

      1. Brad, have you toyed around any with a very low fat, high starch diet yet? Jw. Not as appealing as buttery croissants, surely, so that’s a strike against!

        1. Actually, I’m giving that a shot for the nest couple weeks. I’ve tried it (briefly) in the past, without the pyruvate and l-carnitine. I just made a big pot of potatoes and a salad dressing something like:
          1 cup water
          1 cup apple cider vinegar
          1/2 cup sugar
          1/4 cup mustard
          3 tbsp beef gelatin
          salt to taste

          Add some liquid to the gelatin to temper it, boil the vinehar, water, gelatin, salt and sugar to dissolve everything, whisk in mustard as it cools. Toss boiled potatoes, chopped onion, parsley and cracked pepper in the sauce. Serve warm or cold.

          Pretty tasty!
          Brad

      2. I’ve been eating a mixed diet for the last year, and I’ve lost about 60 pounds of weight spread out continuously over that period. I’ve also gone from being ravenously hungry throughout the day, to easy satiation and sometimes skipping meals due to lack of hunger. This occurs even, or especially, when I’m eating well under 2000 calories a day, as a 6’3″ man in his late twenties.

        I’ve implemented several strategies taken from a few sources on the internet, including this blog. On the one hand, it’s worked; on the other hand, I can’t tell what the causative factor or factors are. Below is a rough description of what I’ve done. These aren’t recommendations, just information. Hope you can pull something useful from it:

        Eliminations:
        -No seed oils (thanks, Brad!)
        -No sugar, except from whole fruits or in small amounts used for cooking (e.g. adding a pinch of sugar to a pot of curry, or using teriyaki sauce with fish and rice).
        -No seed foods (grains, legumes) at all except white rice or fermented products; no cow dairy except for butter; no alcohol. These last measures were intended to combat an autoimmune disorder, not necessarily for weight loss, but may have played a role. Recently, I’ve allowed one cheat per category per week, without slowing my progress much.
        -No factory farmed meat. Mostly an ethical concern, but can’t hurt.
        -No calories outside of a 6-8 hour window. I.E. two-meal-a-day intermittent fasting.
        -No more than 20-30% of my daily calories from carbs, often limited to one out of my two meals.

        Positive measures:
        -A lot of fatty fish; it’s my main protein source. This is half preference, half finances (canned salmon and mackerel are pretty affordable compared to pasture-raised meat), but again, can’t hurt.
        -A lot of grass-fed butter and coconut oil, lesser amounts of tallow, palm oil, and olive oil.
        -For the first six months, a regular berberine+cinnamon supplement. Aside from common vitamins and magnesium, that was the only supplement I bothered with.
        -Overlapping with the start of the dietary changes, I did serious weight training three times a week for three months. Stopped after that, but just that short period felt like it kick-started my body out of slug-mode.

        Subjectively, there was a clear shift after the weight-training and the diet change from obese-mode to healthy-mode. I’m still 50-60 pounds overweight, but instead of my body demanding more food than a lean person’s would, it understands that it needs less. Why eat more, when we’ve already got so much concentrated energy waiting to be burned? I know you see that effect temporarily, but it’s been more or less permanent for me over an entire year.

        My guess as to the advantage I have over you would be my carb strategy. If there’s a biological purpose to the “eat more!” switch, it has to be to store up food in times of plenty. In our ancestral state, this meant carbohydrates, which could cover a lot of our caloric needs, but could also be highly seasonal – especially sugar-loaded sources like fruit and honey.

        What’s been increasing in consumption over the last 70 years alongside seed oils? Sugar. Either of them on their own is enough to trigger obesity (cf. see the example of ancient nobles, who had no access to refined seed oils, but did have unique access to a lot of honey and sugar). You’ve explained on this blog how seed oils work to keep us fat – but clearly, that can’t be the whole picture. I posit that once the body enters an obesogenic state, it needs a carb shock to truly exit it: Something to tell our body that autumn is over, the fruits are gone, and we’ve gone back to hunting bison over picking apples.

        This would explain why keto works for so many people, and why my own diet has worked for me. All of them force the body into extended periods where carbohydrate metabolism just isn’t an option. By the time lunch rolls around, I’ve had 16-24 hours of metabolism running off of a carbohydrate input of just 4-600 calories. If my body wasn’t efficient at metabolizing fat, I would starve. But once the the switch is flipped, even if I still eat a fair amount of carbs per day (the equivalent of 2-3 cups of steamed rice, a similar amount of cooked pasta, or 5 croissants), my body has no problem making up caloric deficits by accessing stored fat.

        I’m just a layman who’s read some blogs and watched some youtube videos, so take my theorizing with a grain of salt. But for whatever reason, my diet works, at least on the existing sample size of 1. Hope this can be of help to someone.

  12. Brad – this is very interesting. Any thoughts on combining this with Apigenin and Nicotinimide? The forumula Nuchido Time has in place seems to make a lot of sense in terms of inhibiting C-38 and then providing the raw material to increase NAD+.

    1. Apigenin is very interesting, although I have my concerns with flavones and their effect on overall NAD metabolism. Nicatinamide is good. According to Georgi Dinkov, Niacinimide is just as good and a lot cheaper. Neither one of them help the true problem, which is too much NADH. The cytoplasm in a healthy cell has 400 times as much NAD+ as NADH. A cancer cell is 200:1. It’s easier to take away a little NADH than to add a huge amount more NAD+.

  13. Trying to stay on top of recommendations, my literacy in biochem is much lower than I would like, are you still advising Berberine in conjunction with SO? And is there any reason that all the supplements together should be timed in any certain way? The study seemed very specific about timing.

    Thank you!

    1. I’m not recommending berberine anymore. I just took down that old page. Berberine is a hack to stimulate sirt1/AMPK. It’s kind of effective, but I no longer think it’s the right way to do it.

  14. Hey Brad,

    Chiming in from a bodybuilding perspective re fat loss supplementation:

    L-Carnitine gets bashed for poor bioavailability, but this can me mitigated by a 5g dose. Interestingly L-Carnitine serves as an androgen receptor upregulator, with testosterone being important to holding muscle in deficits, having more “bang for your buck” from natural test production can really help while leaning out and keeping muscle.

    You may also be interested in Rawoulscine (alpha-yohimbe) which is an alpha-2 adrenoreceptor agonist, when combined with a beta agonist like any of the common bodybuilder fat loss drugs like clenbuterol/albuterol or ephedrine (these do have negative sides) results in minimal muscle loss while maximizing fat loss.

    I’ll give the pyruvate a try alongside my L-Carnitine. Thanks for all your work!

    1. I wonder if the effect of l-carnitine on androgen receptors is downstream of fixing reductive stress/generating NAD+?

      I think you’ll like the pyruvate. Let me know how it goes!

      1. Just in relation to l-carnitine and testosterone… a significant number of ppl have noticed improvements with acne by combining l-carnitine with B5 (pantethine). Not sure how this figures in biochemically but thought I’d chuck it in the mix.

  15. Hey Brad,
    How do you think increased production and retention of CO2 would affect reductive stress?

    I ask because people who do hypercapnic breathing (elevated CO2) often report supression of appetite.
    I think incorrect breathing patterns (mouth breathing, excessive sighing and coughing, sleep apnea and snoring) can be a potential bottleneck for fat loss.

    I kept getting mixed reactions and weird symptoms when I took T3 thyroid. Then I took it and did 20min of hypercapnic breathing – and it began working correctly!

    I know you are big on PUFA and reductive stress, but how about managing endotoxin and stress hormones too?
    They seem to be very important for obesity.
    You no doubt know that pigs automatically fatten when winter time comes – no PUFA necessary, the stress from the cold is enough.
    Jon Gabriel has written a lot about this in his book, these aptly named FAT (Famine And Temperature) programs, triggered by all sorts of stressors.

      1. I think doctors have an aversion to most measurements that they cannot see and control themselves.
        Either that or they are vampires who just love sucking blood out of people.

        On another note, temperature is not always perfectly accurate. I had hypothyroid symptoms with 37C. Taking thyroid gives me a permanent fever of 38C, but I feel way better. This is likely caused by high stress hormones, artificially raising temperature because oxidative metabolism does not provide sufficient energy.

        It might be useful to also measure resting waking heart rate, and resting waking Body Oxygen Level Test (BOLT) score.
        The latter gives you an idea of CO2 retention, and I found that the most useful.
        The lower CO2 retention, the higher glycolytic stress metabolism, and the lower oxidative metabolism as a result.

    1. I link to what ISAK said, and I would like some feedback because in this study they seem to indicate that saturated fats worsen insulin resistance while PUFAs improve it:

      https://pubmed.ncbi.nlm.nih.gov/27434027/

      Furthermore, PUFAs appear to be PPAR gamma activators and / or agonists and inhibit GSK3B (an enzyme you really need to watch out for).

      It is not controversial or critical … you and Ray Peat have done a lot to improve my health and that of other people as well (I am ill with juvenile ALS, I am 32 years old.

      ISAK on CO2 is exactly what I noticed because you create a hypoventilation environment but always remember that you are in an acidic environment … if you start to feel dizzy, prepare yourself with bicarbonate.

      1. The problem with a lot of these short term feeding trials (the average in the paper was 28 days) is that they are not tracking what happens to the glucose. PUFA makes you very insulin sensitive in the sense that blood glucose comes down quickly after a meal. Where did it go? Glycogen, De Novo Lipogenesis or did you actually burn it? Feeding trials show that PUFA inhibit pyruvate dehydrogenase, which means that they prevent you from burning glucose.

        PUFA DO activate PPAR gamma. Rosiglitazone activates PPAR gamma, causes insulin sensitivity and weight gain. What happened to the glucose in response to PPAR gamma and insulin? You made it into fat.

    2. As to endotoxins: lipopolysaccharide is a cause of Reductive Stress. https://fireinabottle.net/cd38-links-obesity-bacterial-induced-inflammation-and-reductive-stress/

      As to stress hormones, cortisol is probably bad, but I’m not a expert on its causes. As to CO2… Ray Peat says that high CO2 in cells helps with electron flow and therefore kind of “lubricates” (my term) metabolism. I don’t know this to be true, but it’s interesting. If this is indeed the case, the higher carbon to energy ratio of carbs versus fat would argue towards carbs as a leaner burning fuel.

      Brad

      1. I know you love biochemistry, but if you leave out the perspective of hormones, I fear you might not assimilate a complete model of obesity.

        I mean, look at people who are treated with cortisol medications for auto-immune diseases.
        They blow up like air balloons!
        No PUFA needed; these people were naturally lean before.
        Isn’t this also what triggers pigs to become fat when winter comes?
        The cold causes stress/cortisol to rise, thus causing fat gain by upregulating appetite and fat storage.

  16. I’m so excited to try this! However I am concerned about the elevated temp and sweating. I work with the public and have to check Temps daily. How long does it last? Is this just something I’d have to do on weekends only? Thanks for your time and all the great info!

    1. Yeah, it could be a problem. The elevated temps last for hours. I just checked, mine is 99.0 at the moment. I would try it on weekends and see how it goes. The good news is that the half life of new mitochondria is 1-2 weeks, so mitochondria built on weekends can help you all week.

      Brad

  17. Hey Brad,
    Thank you for a very interesting post.
    A couple of questions:
    1. When you talk about the dosage, are you talking about Pyruvate or Calcium Pyruvate. Seems the paper talks about the latter, and it seems approximately 85% is Pyruvate and 15% Calcium.
    2. Should this supplements best be taken:
    – a: with food?
    – b: fasted?
    – c: once a day?
    – d: divided over 2 or 3 times?

    1. I think it’s best to divide the doses over 2-3 times per day. The study used 12g calcium pyruvate. You are correct that 12g of pyruvate is about 9g pyruvate/3g calcium. That’s probably plenty of pyruvate. Pyruvate seems well absorbed without food. The carnitine I think is better taken with a meal, but you’ll get some on an empty stomach with pyruvate.

  18. Brad but if Acetyl Carnitine is high, why should plain L Carnitine help? just because it’s not acetylated? I can’t understand, it seems controversial.

    1. Acetyl-carnitine shuttles the acetyl groups out of the mitochondria where there are out of harms way.

  19. Back in my early 20’s when I had a knockoff Total Gym machine, I remember testing acetyl-L-carnitine and having favorable results in my endurance when exercising. That’s the acetylated version, but I was working pretty hard so I wonder if the L-carnitine effect was in there somewhere. I never did test L-carnitine by itself.

    I don’t have that gadget anymore, but I do have a latex rubber band system I haven’t used in almost a year. I should get back into that & see how it goes with L-carnitine in the system.

  20. One thing I’m curious about here, just an intuition more or less, is whether a defining factor of obese individuals is Reductive stress in the Liver, normal/maybe reductive/maybe oxidative/don’t know stress elsewhere in the body. It seems to me that introducing L-carnitine and pyruvate, especially if it exports the “calories” as Lactate, would act to force the liver, as it’s usually 1st in line to receive calories from the portal vein, to give up its calorie overload in a different chemical form to the rest of the body. Is the process of resolving metabolic syndrome merely one of “tricking the liver into sharing its burden wider across the body so more tissues can burn off the excess calories including the brain/hypothalamus which can then properly respond to the newly corrected metabolic state”?

    1. The thought here is that, the liver is also 1st in line to receive excess calories from visceral fat, which means its reductive stress burden never ends, day or night – never really ends at all until you’re skinny, in fact.

  21. Any advice for dealing with the digestive upset? Smaller pyruvate doses at a time? Drink with food? Tried 2g l-carnitine, 8g pyruvate and got diarrhea.

    1. Yes, lactate can be laxative. I would recommend more smaller doses rather than one big dose.

  22. Hi Brad,

    Forgive my ignorance if this seems obvious and I just haven’t registered it correctly yet.

    So am I right in thinking that Pyruvate is like the Succinate of the Carb burning world?? As in if your on a higher fat / lower carb diet (Focused on Saturated Fats of course) then Succinate is probably the best way to go?? While if your on a higher carb / lower fat diet then Pyruvate is the way to go??

    Or am I taking it in completely wrongly where Succinate and Pyruvate would actually help either diet style really well as they assist with different complexes of the transport chain (2 for succinate and 4 is it for Pyruvate??)

    Thanks again for the amazing work that you do!! I love that your more than prepared to evolve your mindset on things as you learn new ideas along the way.

    1. I don’t think that either one is necessarily geared at fat or carbs. Burning too much fat tends to result in reductive stress, which blocks carbohydrate metabolism by inhibiting pyruvate dehydrogenase. Pyruvate eliminates the reductive stress (by being converted to lactate by lactate dehydrogenase), allowing carbs to burn, but also allowing fat to burn more easily when there are no carbs around. Basically, pyruvate increases metabolic flexibilty and metabolic rate.

      Succinate, OTOH, targets ROS generation (and therefore thermogenesis) at complex II (succinate dehydrogenase). This should increase metabolic rate nomatter what you’re burning. The only catch is that for succinate to work, succinate dehydrogenase has to be active. It is acetylated and turned off in obesity. Pyruvate and carnitine should help get complex II deactylated so that succinate can do its thing.

      Brad

  23. I did a quick experiment with 12g of calcium pyruvate and 2g of l-carnitine for three days. Unfortunately didn’t seem to have any outwardly noticeable thermogenic effect (I didn’t measure my temperature). I’ll give it a few days break and probably will try again with measuring. I might have had some more satiety after eating carby foods, but that’s really hard to quantify, so not sure.

    1. Did try again. This time with actual temperature measurements.

      Did one dose of 4g calcium pyruvate and 1g l-carnitine first thing in the morning. Measured temperature 30 minutes, 60 minutes, 90 minutes and 2 hours after. No change in temperature. In the late afternoon, tried again with 8g calcium pyruvate and 1g l-carnitine. Again the same temperature measurements afterwards with no change in temperature.

      Hopefully others will have better luck with this, but for whatever reason it doesn’t seem like it’s producing any thermogenic effect for me 🙁

        1. Not following any specific restricted diet at the moment apart from avoiding PUFAs. Eating to hunger with no specific calorie restriction. Mostly avoid eating any highly sugary things (desserts), but do have carbs in my diet in the form of bread, sugar used in cooking, etc..

          1. On and off, probably for about a year now. Though, for most of it, it has not been strict adhering to no PUFAs, but selecting saturated fat choices always when possible. For the duration of the experiments with pyruvate, I tried to be as strict as I could.

          2. Hm, I wonder if that might have something to do with it? Totally not sure though, but I know Brad’s been largely avoiding pufas for quite a few yrs, as have I. Not zero, but very infrequent (holidays, occasional meals out etc). I wonder if one has to “work through” the pufa buildup a bit before it works? Or maybe it’s just individual variability 🤷🏻‍♀️

  24. I take Acetyl L-Carnitine, 2g/day, for a different disorder (migraine-spectrum). I’m a bit afraid to stop taking it, as it does help. Do you think it would be better to try taking non-acetyl L-Carnitine on top of that (or might that be too much?), or try switching to non-acetyl L-Carnitine instead of that?

    1. Oh no, there’s no reason to stop acetyl-carnitine in that case! keep doing what you’re doing, it’s fine!

      Brad

      1. Thanks for your response. I actually didn’t see it right away, and so I tried the non-acetylated L-Carnitine. I found I can’t take all 4 500-mg tabs of it, or I get symptoms, but 3 non-acetyl and 1 acetyl are borderline ok. I think I will try taking 2 of each until the bottle of non-acetylated is done. It’s been interesting.
        I don’t get any thermogenesis from the pyruvate, either, except possibly once, and just a fleeting rush of heat for a few minutes, then. I’m taking sterculia oil and waiting patiently for succinade to be back in stock. Thanks again.

  25. Jsut got my bulksupplements delivery. And sorry. I’ve looked here but can’t find something. Could someone pls tell me how much L Carnitine and how much Calcium pyruvate to take — but in tea (or table) spoons — NOT grams.

    So how many teaspoons of each should I take daily? I understand I may need to break a day dosage for each into 2 or 3 servings.

    Thank you!

    1. A level teaspoon of calcium pyruvate is ~5g. I think l-carnitine is similar, but I’ll clarify this.

  26. Almost a week in, one thing I’m noticing- Increased testosterone, or the feeling of it. More… “swagger” when I think about how I’m acting around everyone.

    From what others have said above, it’s probably the L-carnitine doing this. I like it!
    It does seem calcium pyruvate has a somewhat time-delayed (I’m using it in capsule form for now, easier to manage w/ kids around asking questions) “sweat-surge” effect.

    I’ve also noticed the woozy feeling once – tbh it reminds me of how I feel sometimes when I’m truly fasting, getting the sense that I’m about to get lightheaded (w/o actually getting lightheaded). I was walking around when this happened.

  27. Hey Brad,
    Have you measured your blood lactate levels after taking the calcium pyruvate using your blood lactate tester? What do you see?

  28. Started noticing a fishy smell, mostly down below.. possibly in the urine. Seems L-carnitine supplementation is known to trigger TMA/TMAO-
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037757/#:~:text=In%20this%20study%2C%20we%20confirmed,subjects%20performed%20regular%20physical%20activity.

    Haven’t had any lipid panels done recently but I’m a bit concerned with the TMAO association with CVD, so I’m stopping that for now. I noticed positive results with the L-carnitine & general “testosterone behavior” so I am partial to the thought that I should take L-carnitine, but maybe only once a week or at some lower dose. Still using Pyruvate.

  29. Has anyone noticed that they get tired from this combination? I tried ALA on its own and it seemed to make me really tired so I stopped and the tiredness went away. Getting a similar effect now with this. What could cause this? I’m getting quite lean, if that’s relevant to the question. Been eating SA and avoiding PUFA for about a year.

    1. The tired/swimmy-head feeling has been widely discuseed about ALA. I’ve also noticed it with ALA if I overdo it, but not with pyruvate/l-carnitine. People have reported increased energy.

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