5 Studies I’d Like to See

My wish list concept on green blackboard with coffee cup and paper planeImagine money is no object. Imagine you wield absolute control over the scientific community and can direct it to run whichever study you desire. If you can dream it up, they’ll get the subjects, produce the money, and make it happen. All you need to come up with is the overarching design. What would you choose? What do you wonder? What questions do you want answered once and for all?

Here’s what I’d choose:

Omega-6 From Seed Oils vs. Omega-6 From Nuts and Seeds

Linoleic acid isn’t linoleic acid. In nuts and seeds, the fragile omega-6 fats have a home. They have cellular walls and antioxidant compounds protecting them from these oxidative stressors. In theory, eating nuts is far different than consuming an equivalent amount of omega-6 through seed oils.

In a seed oil, the omega-6 fats are adrift like storm-tossed sailors, subject to oxidative stressors like heat, light, and oxygen with little protection. To make matters worse, the refining process often strips them of what few endogenous antioxidant compounds remain. They tend to arrive in your kitchen already oxidized and rancid, and if they aren’t, cooking finishes the process. Consuming these oxidized fats makes your LDL particles more vulnerable to oxidation, and oxidized LDL particles are strong candidates for primary progenitors of heart disease.

What’s more, we’re eating (well, maybe not us so much as the average Westerner) more seed oils than ever before. In observational studies, the two sources are conflated. Omega-6 from nuts might be perfectly safe and healthy, and I suspect they are, but we just don’t know. A study pitting the two against each other over a period of 6-12 months would be among the most important for public health.

If you wanted to really isolate the effect of the fatty acids alone and eliminate the variables, you’d give the seed oil group a vitamin/mineral/micronutrient supplement replicating the nutrient content of the nuts. But I don’t think this is necessary, and it may even be counterproductive; people don’t eat seed oils with complicated nutrient complexes to replace the missing nutrients they’d otherwise get from nuts. They just eat crappy refined oils. The simpler study pitting nuts against oils would be more realistic and applicable to how people actually eat.

Track: Bodyweight, lipids, oxidized LDL, inflammation, liver health/fat.

Strict Keto vs. “Keto Zone”

While staying strict when you first embark on the Keto Reset journey is highly recommended, if not downright mandatory, not everyone remains so. Hardcore keto eaters are often lifers, figuring if it worked better than anything else they’d tried early on, there’s no reason to think the benefits would slow or reverse. That may be true. But I like flexibility. I like being able to drift in and out of ketosis as needed. And from what I can tell, the beauty of going strict keto is that it unlocks and enhances your fat-burning machinery and ability to obtain energy from fat—so that you regain the metabolic flexibility to shift between sources of energy.

That’s the keto zone I often talk about—that range of macros where you have the necessary metabolic machinery to shift back and forth between ketosis and straight-up fat-burning based on the number of carbs you eat. A sweet potato doesn’t “knock you out” of ketosis for days; slipping back in just happens because you’re so accustomed to it.

I call it the keto zone because it’s exactly that: a range of carbohydrate intake that causes you to drift in and out of ketosis without even realizing it. For most, the keto zone might correlate to consuming between 20-120 grams of carbs per day. Less one day, more the next. More ketones today, fewer tomorrow. You’re constantly on the verge of either leaving or entering ketosis, and it’s okay.

Is strict keto superior to the keto zone, where you drift in and out of ketosis transiently? I have my biases, but this study would let us find out for sure.

Participants would all start on strict keto for two months, after which they’d split into two groups. One group would stay strict keto, the other would drift into the keto zone. This portion of the study would go for six months.

Track: bodyweight/composition, physical and cognitive performance, inflammatory markers, lipids.

Grilled Meat vs. Gently Cooked Meat: Long Term (5-ish Years) With Health Outcomes

I’ve written about the apparent benefits of gently cooked meat compared to high heat grilled meat. I’ve also dug into the research implicating high heat grilled meat and various diseases, and found it wanting. This would get to the bottom of it.

Except for how the meat is cooked, the diets are identical. The fatty acids are identical, so the differential effects of polyunsaturated vs saturated fat on meat carcinogenicity don’t enter. Each diet has adequate calcium, since low calcium appears to be a prerequisite for “meat-induced” colon cancer. The meat sources are identical; everything is grass-fed (or not). You compare a burger patty grilled over charcoal to a burger patty lightly simmered in some water. A pork chop over fire versus the same pork chop in the pressure cooker.

Track: Incidence of cancer (and related biomarkers), diabetes, heart disease, and everything else they say meat will inflict upon us.

Battle Of the Carnivores: Muscle Meat Carnivore vs. Whole Animal Carnivore (e.g. organs, bones, skin) Over 5 Years

Many zero-carbers are adamant that beef muscle meat is all one needs to thrive. They’ll eat steak and nothing else. Ground beef and nothing else. They’ll drink water and sometimes coffee. They’ll salt their food, but pepper is a stretch. Obviously, there’s something to this. Meat offers nutrients you simply can’t get anywhere else, and in the most bioavailable form around. Eating a bunch of it is probably better than eating none of it.

I suspect that a whole animal carnivore would be healthier, one who ate organs, bones, skin in addition to the muscle meat. This provides a wider range of nutrients, particularly by eating nature’s multivitamin (liver). It balances the methionine (from muscle meat) and glycine (from connective tissue), a ratio that plays a role in the lifespan according to animal models. It’s also more evolutionarily congruent than discarding everything but the muscle meat.

That said, we don’t know for sure. The anecdotes are persuasive. I’d argue that their results are preliminary, and we don’t know if the effects will persist 3, 4, 5 years out. This study would give us a good idea.

It would be cool to throw in another meat-based group who also ate leafy greens and other non-starchy vegetables.

Track: Lipids, body composition/weight, metabolic health, inflammation markers, physical performance, strength, endurance, health endpoints like mortality, diabetes, cancer.

Three-Year Study Of Keto In Anaerobic Athletes (e.g. basketball or soccer)—Enough Time For Full Adaptation

Even skeptics admit that getting fat adapted can help endurance athletes excel at their sport, but what remains to be seen is if keto is good for athletes who perform above the anaerobic threshold. Traditionally, going anaerobic means burning glucose. If you don’t have glucose, either because you’re not eating it or your metabolism isn’t optimized for its utilization, your performance will suffer. That’s the story, at least. The data so far is spotty, mixed, and plagued by the fact that the perfect study hasn’t been done.

My intuition is that the keto team would do better than expected. Maybe not better than the other team, but better than the skeptics would assume, and perhaps equal. After all, fat-adaptation extends your anaerobic threshold. You can go longer and harder burning primarily fatty acids than a “normal” athlete. This should preserve glycogen for when you truly need it. And certain “intangibles” might be better in the keto team, like teamwork/cooperation/morale (from improved cognition) and injury rates (from lower inflammation).

A fun wrinkle would be to add a third team that does “keto zone.” They’d start with a strict keto adaptation period, after which they’d cycle carbs in for workouts and games. I suspect that team would be the most successful.

Track: Performance at regular intervals, both team and individual. W/L ratio, points scored, defense, overall success, injury rates. Player attributes like speed, stamina, power.

Those are the five studies I think would be the most illuminating. What about you? What would you like to investigate?

Let me know down below. Thanks for reading, everybody.

About the Author

Mark Sisson is the founder of Mark’s Daily Apple, godfather to the Primal food and lifestyle movement, and the New York Times bestselling author of The Keto Reset Diet. His latest book is Keto for Life, where he discusses how he combines the keto diet with a Primal lifestyle for optimal health and longevity. Mark is the author of numerous other books as well, including The Primal Blueprint, which was credited with turbocharging the growth of the primal/paleo movement back in 2009. After spending three decades researching and educating folks on why food is the key component to achieving and maintaining optimal wellness, Mark launched Primal Kitchen, a real-food company that creates Primal/paleo, keto, and Whole30-friendly kitchen staples.

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41 thoughts on “5 Studies I’d Like to See”

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  1. I’m interested in the healing and health benefits of periodic fasting (3 to 10 days – water only). I’d like to see more studies on real fasting as it relates to autophagy and also muscle loss or gain during fasting. So many who claim to be “fasting” are actually on a reduced calorie diet. I want to see more study on water-only fasting over several days.

    1. We need like buttons on this site, maybe not downvote buttons. I just wanted to say I agree, and there isn’t an easy way besides following up with a comment.

      Grok on I suppose

      1. I have been doing an 8 day water-only fast at the start of each month and then sticking to a medically-modified ketogenic diet and eating only one meal per day throughout the rest of the month. Started this eating program to heal from neurological problems which are much improved since I started eating this way. I still have symptoms, but not as bad as before. Other health issues have improved or disappeared, also. I’m my own lab-rat on this, but would like to see more scientific studies about things that are hard to monitor outside of a medical testing facility, such as the effects of exercising while fasting on muscle mass, especially after a fast of several days.

    2. Studies here would be “interesting” but why wait to live even more primally… since October 2017, wife and I have been practicing a 5-day water only fast at the beginning of each month. On day 1, we do an all out workout to simulate a failed hunt. Fasting as usual on days 2, 3 and 4; however, day 5 is another all out workout to simulate a successful hunt.

      We always lose a solid 5 to 7 lbs… the next 2 weeks we are a little bit weaker, less metabolically fit and a little less lean mass. Weeks 3 and 4 are when the magic happens… stronger, fitter and more muscle than baseline. I also see the autophagic and apoptotic benefits as the best health/ life insurance policies that money can buy.

      1. That sounds awesome – love the idea of simulating a ‘failed’ hunt and a ‘successful’ hunt. In crossfit if we’re doing a sprint-type workout I imagine a bear chasing me, or if rowing, imagine a crocodile swimming behind me to help keep me going those last few seconds. It’s surprisingly effective at making you realize you have more ‘in the tank’ than you thought! 🙂

    3. If you haven’t already seen it there’s a good documentary movie currently available on Amazon Prime (don’t know where else) called the Science of Fasting. It talks about its history in Russian and German Medical Clinics as well as current data from Southern California using it to support Cancer treatments.

      1. Found Science of Fasting on YouTube! Excellent, thank you for mentioning it.

    4. Dr. Fung has done many studies on this subject. Many of his patients are not on insulin any longer due to a strict fasting regime. Check out his books

      1. Dr. Fung has written much in support of fasting, I am encouraged by his work and results. But, it’s always good to have more scientific support concerning such a controversial subject.

  2. Yes, I knew you would list some fat-adapted performance study that you want to see. Basketball I could see benefits, but how about ultimate frisbee? I think more intense heart rates from the frequent hard sprinting there.

    I’m really looking forward to Luis Villasenor articles on how keto helps intensity and power without glycogen. I’ve got Keto Reset but have yet to read it, and I’m pretty bewildered on how anaerobic intensity can run without glycogen.

  3. Those are all great studies. The only other study I can think of is low carb/keto with varying amounts of protein. I started LC/keto with high fat, but lately I’ve been eating “high” protein and less fat. Which one leads to better weight loss? Which one leads to more retained muscle mass (or growth)? I’m particularly interested in, if you get “enough” protein per day (assuming you can determine this level), does it pay to eat more than that? Is it detrimental to do so?

    It would also be nice to take a lot of data with these studies, use ketone blood and breath meters, continuous glucose monitors. What I’ve found is that after 4+ years of LC/keto, I can get kicked out of keto (defined as BOHB of 0.5 or higher) quite easily. For instance, I can eat meat, but I can’t eat the sauce my wife makes with the meat (made with some onions or the like). I can eat relatively small quantities of vegetables or olives or pickles, otherwise I’m out. Protein seems to lower BOHB, fat seems to raise it. It seems to me it’s easier to get kicked out of ketosis when eating higher protein (which the study might help to measure), but I’m not sure that’s a bad thing. I think chasing a number, such as high BOHB levels, might not mean much, depending on the goal.

    Oh yeah, thought of another study. Determine what calorie requirements are. For one group, have them eat 500 calories less per day but keep protein the same (or higher). The other group, have them eat 500 calories less per day, including dropping protein correspondingly. Both would be LC/keto. What happens to ketones, blood sugar, basal metabolic rate, etc.? I see several people saying that you subtract 500 calories per day of fat (while keeping protein the same), and this helps you burn your own fat, but this seems like reduced calorie 2.0, and reduced calorie always fails over time.

  4. These would be a great start. I’d like to add a 1-3 year study of the Dale Bredesen ReCode protocol versus the SAD.

  5. “In the old days we used to eat the guts of the buffalo, making a contest of it, two fellows getting hold of a long piece of intestines from opposite ends, starting chewing toward the middle, seeing who can get there first; that’s eating. Those buffalo guts, full of half-fermented, half-digested grass and herbs, you didn’t need any pills and vitamins when you swallowed those.” – The Great John (Fire) Lame Deer

    You don’t need a double blind RCT to tell you that which you know to be true… it’s in your heart… it’s in your brain… it’s literally in our DNA!

    1. I’ll pass on the buffalo guts, but I agree with your last paragraph. The only truly accurate “studies” are the ones that work for each of us as individuals.

  6. Excellent recommendation. Always keeping it interesting. Thank you Mark.

  7. I’d just like a simple study comparing of processed meats vs grass fed/pastured meats and no grains to put this meat causes cancer BS to bed once and for all.

  8. Sounds like your next business opportunity: Primal Research! You practically have your grant proposals here…Set up a non-profit, tackle the Ancestral Health topics! I’m in on the KS campaign!

    1. ‘Primal Research’ – what a fantastic idea! I would sponsor that.

  9. Would like to see a study involving a Primal Diet and prostate health. Sorry for the gender bias. 🙂

    1. No need to apologise for the gender bias – I was reading somewhere just recently how the most common form(s) of prostate enlargement equate to PCOS in women – so your study could happily cover both genders.

  10. All of these sound good, Mark. Related to the first comment, I’d like to see a comparison of, say, 6 weeks of keto per year and then low carb, with periodic water fasts and then low carb over year.

  11. All are interesting but I am more excited about Strict Keto vs. “Keto Zone”.
    I’ll be waiting for your update.
    Thank you!

  12. The strict keto v keto zone would be very relevant at the moment, but my favourite would be the battle of the carnivores because I have had quite an interest in the zero-carb movement since I first read about it two years ago.

  13. …and gut microbiome, equal numbers of men and women, and all participants should have their genetic polymorphisms identified. It’s well past time when research could assume that every human being will respond the same.

  14. Thank you, Mark. I would like to see a study on the impact on cognitive health and performance on “smart drugs.” I would be nervous putting people on the study for longer than a year.

    1. Eat more brain! Grass Feb Brain provides whole brain extract along with brain derived glandulars including the pituitary, hypothalamus and pineal glands to further nourish, balance and support neurological health. Included in whole brain extract is sphingomyelin which plays a central role in the myelin sheath, cell signaling and apoptosis, as well as neurotrophic factors such as brain-derived neurotrophic factor (BDNF) that support the survival of existing neurons and encourages the growth of new neurons.

      I can pick up a whole lamb brain for about $13 bucks here in Houston, TX… getting wife to cook it for family is whole different story!

  15. Hi Mark, thanks for asking. I’d like to see most studies that I’ve read about from you over the last six plus years redone on people NOT eating a SAD. I think the results of most health and nutrition studies are ridiculously skewed because of the SAD. Since I’ve been eating progressively Primal, then Paleo, then Keto, and now part-time Carnivore, I tend to blow off most studies anymore because I think those folks are still eating sugar and grains, and therefore not truly healthy or valid subjects. But then, if that were to happen, we wouldn’t need studies, because most people wouldn’t be sick anymore. I’d like to see ANY legitimate study done on Primal/Paleo/Keto diet eaters who have bounced back to robust health and ditched their meds, not just anecdotes and success stories. Please do start Primal Research!

  16. Would love to see a study of a gluten-free diet in people with Hashimoto’s thyroiditis. And a nightshade-free diet for people with psoriasis or rheumatoid arthritis. (In general, more autoimmune research!)

  17. I know I’m late to respond to this blog post, but I’d like to see, if not a study, just more investigation into the neurotransmitter/hormone cocktail that is responsible for the sensation we call “infatuation”. This has consistently been more effective for me as an antidepressant — not over-the-top happy, but just feeling normal, and able to handle errands, go about my day and generally function in ways I often can’t otherwise — than any prescribed drug I’ve ever taken. Unfortunately chasing this sensation has the undesired side effect of wrecking relationships so I’m hoping one day researchers will be able to isolate the components, tweak the amounts for the desired antidepressant effect and make it a marketable prescription antidepressant. Major Depressive Disorder might become a thing of the past…

  18. I would like a study on how carb diets effect folks that have to have knee and hip replacements . A lot of my friends have had replacements and my theory is it is diet related. For some reason I do not see articles on this.

  19. Would love to see studies comparing Primal vegetarian diets to “normal” veg, as well as to omnivorous Primal! Sure it’ll never happen, but I can dream…

    1. I vote for “Grilled Meat vs. Gently Cooked Meat”. Not only because it is highly like that humans had plenty of time to adapt their detox biology to cooking over fire. I actually looked into the science, and learned that the mice in the studies of putative carcinogens (HCA, PAH, acrylamide) produced by charring lack the detox enzymes (CYP3A4, Phase II detox enzymes) and supporting pathways that are highly expressed in humans, And mice don’t cook their meat over fire, right? Other primates also have much lower expression of these enzymes:


      1. The one I’m interested in is the actual #3, grilled meat versus gently cooked meat. At one time I spent quite a while trying to find out if exogenous advanced glycation endproducts (AGEs) cause elevated AGEs in the body; I found no good information. AGEs are a Bad Thing. Like previous thinking about cholesterol and eating egg yolks, the assumption in the mainstream has been that exogenous AGEs lead to elevated AGEs. The mainstream, of course, has since backed off on the cholesterol question. I suspect (actually, I hope, since I like my meat charred) the same might be true of AGEs.

  20. Definitely more large scale population studies on HDL particle size and CVD risk a la (https://www.ncbi.nlm.nih.gov/pubmed/19268944) but with multiple arms using realistic dietary interventions that every day folks could use. Of course this also would require insurers covering more detailed blood assessments. Right now most health plans don’t even cover basic HbA1c testing much less HDL particle size and number..

    1. You can buy an NMR test with particle sizes for less than $100, so insurance isn’t really an excuse not to get one. I just bought on on sale at Life Extension for $58.

  21. All of these would be interesting though I wonder and would hope to investigate how my children’s teeth are improved as paleo children (our family has been eating paleo/real food for 7 years now). My children have wide palates and pretty good teeth (my husband and I not!) and facial structures. Is this just luck or is it because they have eaten real food for most of their lives. Or is it also because they were never spoon-fed baby purees, they did baby-led weaning with lots of chewing and swallowing? Could we get a whole lot of paleo children together and compare their teeth to the general population of the same age?

  22. I’m unaware if I have been a catalyst at all for any officially recognized studies – probably not, though that’d be cool as I enjoy influencing stuff, like a small stone starting an avalanche – (however I am sometimes on the gutter front lines as a currently ex-homeless person [in a sorta ghetto room] who still lives like a bit of a scavenging savage, so I learn from experience and draw conclusions via common sense and intuition sometimes (I do my own studies, lemme tell you somethin’), but just before walking back to the library after a break during which I enjoyed a two-breath roach that I found on the way to get free drop-in center coffee, with some liquid amber already, and enjoyed some of those all at once and was politely ranting near the city hall that they should plant apple trees, tomatoes, chives etc. rather than high-maintenance flower plots and spending money and hurting the environment cutting grass excessively in so-called parks (all it takes in this city is a bench and a garbage can and they call it a park). not very literate, huh? I don’t have much inclination to edit further (last edit). Many plants get annihilated around here – they cut down bushes and trees just so people have nowhere to hide, when the city’s park or whatever-they-call-it budget could be going to something awesome, such as I recommended above.
    They got a bunch of money for a “bike lane budget”. Yeah, too late, since apparently the original city planners were careless and negligent regarding bicyclists so there isn’t much room for bike lanes, unfortunately. I heard on the radio that they’re considering a new trail somewhere. I’d prefer “town bicycles” (and if it’s not too expensive I’d recommend tracking beacons inside the frames).
    I wonder if Mark and Forrest Griffin have ever met. I found Forrest’s “Be Ready when the Sh*t Goes Down” in a thrift store, purchased it for 10 cents like everything else costs there (get maximum of 10 items simultaneously, even pots, pans, and a coffee maker! – good deal!) and since I have no internet access in my room (lack of tech – last computer I had, which was a cheap hand-me-down laptop, got destroyed by a leaking can of beer in a backpack) I’ve reread it and still flip through sometimes for entertainment, even this morning.

  23. Thanks for a great share Mark! Amazing recommendations. It’s important to know how to make balance between the omega 3 and omega 6 and other subtopics of the article. Worth sharing.