Massie himself is a grass-fed off-the-grid farmer. My friend John Moody profiled his farm here.

The farm is powered by solar panels and Tesla batteries with a house the Massie family built themselves out of logs they cut from their own woods and with stone they quarried from their own land. The home is heated from the same wood, and water comes from a well that Massie dug by hand with his neighbor.

They grow peaches and apple trees, raise pastured chickens with an automatic tractor, and raise grass-fed cattle.

Massie once admitted to Moody he used Google Maps to spy on Joel Salatin to get new ideas for his farm.

No one paid me to write this. Massie has never given me any money but I have donated to his campaign.

Massie originated and championed the Processing Revival and Intrastate Meat Exemption “PRIME” Act.

Crafted by the Farm-to-Consumer Legal Defense Fund, in turn founded by Sally Fallon Morell of the Weston A. Price Foundation and others, this act is meant to remove the USDA as an impediment to small farmers.

Small, locally run custom slaughterhouses are all over the place in the United States. USDA slaughterhouses are vanishingly rare and often at great distances away from farmers. The custom slaughterhouses are used by homesteaders and hunters who eat their own meat. The PRIME Act would allow them to be used by small farmers who sell their meat to the public, provided that they comply with local health regulations and don’t sell their meat across state lines.

The regulatory burden to get a slaughterhouse inspected by the USDA is huge, and the number of USDA-inspected slaughterhouses is dwindling. Farmers often live 15 minutes from a custom slaughterhouse but have to haul cattle hours in trucks to a USDA site. Even then, USDA slaughterhouses are often booked for two years in advance.

This all favors massive producers over small, local producers. They simply set up near a USDA facility and get treated with priority. Imagine trying to start a small new farm when the slaughterhouses are booked out for two years!

After ten years of championing this bill, Massie finally got a major part of it passed by the House as part of the Farm Bill on April 30 of this year. The bill itself passed 224-220.

Massie jokingly calls this version the “Subprime Act” because it allows direct sale to consumers but not sale to restaurants and grocery stores. The Senate still has to pass its version of the Farm Bill later this year to make the PRIME Act “pilot program” law.

This is a massive step forward for decentralizing food production.

Massie led major efforts to protect the rights of local governments to regulate AI data centers.

Without Massie, you probably would have lost your ability to fight any AI data centers being put in your backyard.

Massie used his seat on the Judiciary Committee to directly kill the Protect American AI Act, which would have granted privileges to AI datacenter permits. He opposed it on the basis that no industry should get special treatment.

The original “Big Beautiful Bill” had a provision that would prevent state and local regulation of data centers. Massie exposed this on X, and that played a major role in the popular opposition that got it stripped in the Senate.

After Trump introduced an executive order making glyphosate production a matter of national security and therefore protecting it with legal immunity, Massie introduced the “No Immunity for Glyphosate Act.” That so far has gone nowhere.

Around the same time, the Farm Bill came in with provisions that struck down states’ ability to regulate pesticides inside their own borders and gave pesticide manufacturers legal liability against state-mandated warnings.

Chellie Pingree, a Democrat representing Maine, introduced the “Protect Our Health” amendment to strip these provisions. The House Rules Committee rejected it, then Massie co-sponsored it. They rejected that, then Anna Paulina Luna, a Republican representing Florida, submitted her own version that achieved the same thing. The Luna version was was allowed through committee, it was voted on and passed, and the provisions have been stripped from the Farm Bill.

Massie doesn’t own this issue the way he can claim to own the Prime Act, but he played an important role in it.

Massie was one of three people who spearheaded the legalization of hemp after 60 years of federal prohibition that occurred in several stages from 2014 to 2018, and he single-handedly obstructed the DEA from confiscating legally used hemp seeds during that period.

In addition to real wins like this, Massie is a voice for food freedom and elevates the conversation.

Ron Paul had introduced the Unpasteurized Milk Bill in 2011 to reverse the FDA’s 1987 ban on transport of raw milk between states.

Massie picked up the torch when he arrived in Congress. In 2014, he led a coalition of 20 lawmakers to introduce the Milk Freedom Act of 2014 and the Interstate Milk Freedom Act of 2014. The latter would open up transport between states that had already legalized raw milk and the former would open up transport across any state lines. He reintroduced these bills in 2015.

In 2018, he got them attached to the Farm Bill, which forced an open floor debate about raw milk. Industrial dairy groups lobbied against it hard, and it lost 331-79.

He reintroduced the bills in 2019, 2021, 2022, 2024, and 2026, but the bills have not gone anywhere and the open-floor debate in 2018 was so far its greatest achievement.

In March of 2024, in response to the Amos Miller legal battle, Massie introduced a Constitutional Amendment:

Why is there 15 million dollars trying to push Massie out today?

Because Massie co-introduced with Ro Khanna, a Democrat representing California, the Epstein Files Transparency Act in July 2025.

This bill was blocked by Republican leadership and Massie took the nuclear option.

He filed a discharge petition, which allows the House leadership to be overridden with 218 votes, something a congressman almost never does against the leadership of his own party.

The White House signaled that signing this would be “viewed as a very hostile act to the administration.” Massie was one of only four Republicans to sign, along with Marjorie Taylor Greene, Nancy Mace, and Lauren Boebert.

Exposing the Epstein files was Massie’s unforgivable sin.

The impact could endure for decades. Because he got it signed into law, the law itself would have to be reversed to end its impact. Until then, the files kept hidden are done so illegally and this can be prosecuted later. This surely is part of why his sin is so unforgivable.

The primary vote is TODAY.

Here’s what you can do:

• Donate to the Massie Money Bomb. Every last dollar counts in the early morning of the election day. That day is TODAY.

• If you live in KY-4, vote!

• If you know someone in KY-4, tell them to vote!

• If you have an audience, tell them to do all of the above!

Don’t let the Epstein billionaires take away our greatest advocate!

Epilogue

Massie lost 55/45, winning only his home county of Lewis where he got two thirds of the vote, and Mason county, where he won by a slim margin.

Based on polling, Massie likely won the 18-55 vote in a landslide, but lost the election overall due to much better turnout of the >55 vote.

Massie slightly choked up as he raised a glass of raw milk to toast his late wife.

He told the story of how in 2018 the dairy lobby went hard against his amendment to legalize transport of raw milk across state lines.

His wife had said, “I didn’t realize the lactose lobby was so intolerant!”

Crowd chants “Rhonda! Rhonda! Rhonda!” in honor of his late wife.

Massie says they need to figure out what God is telling them, and says he “won’t make any announcements” tonight.

Before and after this, repeatedly the crowd had been chanting, “2028! 2028! 2028!

The final time he says “Oh I know what you mean. You want me to run for congress again?”

They start chanting “President! President! President!”

He says “You made a compelling argument but I need a medical margarita. We’ll talk about it later.”

Mikhaila, his daughter, saw that what was ailing him was affecting so many systems of his body that it had to all be connected and began to wonder if it was a form of mitochondrial dysfunction.

In trying to research whether mitochondrial dysfunction could be driven by the turning points in his health problems like SSRI withdrawal, benzodiazepine withdrawal, and toxic mold, she found my work and reached out to me.

This is the conversation that we had:

My hypothesis is as follows.

Mikhaila shares half of Jordan’s genes and has been more detailed about her own health journey going back to childhood, so we start with her.

She had juvenile arthritis symptoms starting at 2 and a diagnosis at 7. She went on Enbrel, a “biologic” (a pseudoscientific regulatory term) that opposes the action of the inflammatory mediator tumor necrosis alpha (TNF-alpha); and on methotrexate, which inhibits folate and adenosine metabolism. Methotrexate raises adenosine, which inhibits T cell proliferation. Its inhibition of folate metabolism is thought to be more relevant to cancer but its adenosine-mediated inhibition of T cell proliferation is thought to be more relevant to autoimmune arthritis.

The next year, at age 8, she was diagnosed with depression and put on SSRIs.

My hypothesis is that she has an underlying block in mitochondrial metabolism leading to CoA sequestration, which occurs when CoA-requiring pathways fail to complete properly. This leads to secretion of TNF-alpha as part of a cellular stress response. TNF-alpha serves to increase carnitine transport into the cell. The carnitine then trades places with CoA, detoxifying the metabolic intermediates and carrying them out into the urine, allowing CoA metabolism to continue.

Blocking the TNF-alpha is a double-edged sword. On the one hand, the elevated TNF-alpha will interact with genetic predispositions to certain types of immune dysfunction and with suboptimal joint mechanics to produce an autoimmune disease. Blocking the TNF offers relief from the autoimmunity, but then in doing so makes the cells that were releasing it as a stress signal unable to mitigate their CoA sequestration. This may lead to a plethora of side effects, and for Mikhaila this was depression.

I do not discount that inhibition of folate metabolism by methotrexate could have messed with her methylation system, but Mikhaila remains very intolerant of methylfolate and thrives on a low-folate all-meat diet, and I do not think any of her health problems are explained merely by a methylation deficit.

Her first major advance was going on an elimination diet that eventually morphed into the red meat carnivore “Lion Diet.”

T cells are fueled by glucose and glutamine during active inflammation, and when they transition to resolving inflammation a major drop in glucose and glutamine is a central hallmark of the metabolic shift.

The zero-carb nature of the Lion Diet helps resolve T cell inflammation and displaces the need for methotrexate.

The large amount of red meat provides carnitine, which addresses CoA sequestration from the point of carnitine supply, relieving the need of cells to secrete TNF-alpha to signal carnitine demand. The carnitine in the red meat thereby helps relieve the need for the Enbrel.

Since her elimination diet gave her the first relief of depression she had experienced, it led her to go off the SSRIs.

Going off SSRIs produced 2.5 years of new-onset neurological dysfunction, which I contend was new-onset mitochondrial dysfunction. This may have interacted or blended with the mitochondrial dysfunction that initially led to the arthritis, or it may have just been a completely new acquired mitochondrial disorder thrown on top of the existing problems.

Throughout this story, various exposures to toxic mold occurred that made her problems worse, including one in 2022 that gave her a whole new list of problems that only moving away from the mold was able to solve. Mold toxins are mitochondrial toxins, so exposure to them would cause a third layer of mitochondrial dysfunction.

Jordan had been on SSRIs for over twelve years, but when he saw Mikhaila cure her depression with the early precursor to the Lion Diet, he followed her approach. Having gotten rid of his own depression, he too went off SSRIs around the same time as she did. This led to akathisia, a catastrophically debilitating movement disorder. I contend that this is SSRI withdrawal-induced new-onset mitochondrial dysfunction.

He then had a terrible reaction to apple cider that had sodium metabisulfite as a preservative. This led him to be unable to sleep for two or three weeks. He became green and hunched over, and couldn’t walk.

For this he was placed on clonazepam, a benzodiazepine.

Sulfite has to be converted to sulfate, which requires the mineral molybdenum and the transfer of electrons from the sulfite to the mitochondrial respiratory chain.

Mitochondrial dysfunction will prevent sulfite clearance.

Zero-carb diets will increase endogenous sulfur production and diets that lack liver and legumes are low in molybdenum.

The mitochondrial dysfunction induced by the SSRI withdrawal would inhibit sulfur clearance and the diet that helped Jordan and Mikhaila cure their depression would keep the sulfur-detoxification system maximally occupied.

If sulfite is not quickly metabolized to sulfate, it converts to S-sulfocysteine, which is a neurotransmitter that activates glutamate receptors.

Sulfite itself is mitochondrially toxic, so if it crosses a critical threshold it can elicit a storm of excess sulfur catabolism and impaired sulfur clearance that keeps S-sulfocysteine levels high. That vicious cycle could explain why the sleep loss lasted 2-3 weeks.

Clonazepam directly opposes S-sulfocysteine in that it binds to GABA receptors making GABA more powerfully activate them, which counteracts the S-sulfocyteine’s activation of glutamate receptors.

Peterson stayed on clonazepam for three years and then tried going off of it, but this caused an even worse case of akathisia than he experienced from SSRI withdrawal. It lasted three years, and it made him suicidal.

Clonazepam can alter calcium signaling in mitochondria in opposite ways depending on the preexisting state of the mitochondrial function. Possible effects of withdrawal include a catastrophic energetic supply/demand imbalance and precipitation of calcium causing damaging deposits that jam up the mitochondrial infrastructure. It is very possible that the clonazepam was causing progressive mitochondrial dysfunction the entire time he was on it and that it only became apparent once the GABA breaks on energy demand were removed by withdrawal.

He briefly restarted an SSRI during this time but it didn’t help and it made him so fatigued he needed four extra hours of sleep per day.

Ultimately, the final version of the all-meat Lion Diet helped Jordan recover from akathisia.

More recently, however, his parents died and he had been cleaning out their moldy basement preparing for a big move, and this led to an attack of pneumonia and sepsis and a return of his akathisia.

The mitochondrial toxins in the mold thus became his third acquired mitochondrial disorder, the first two from withdrawal from SSRIs and benzodiazepines.

Jordan and Mikhaila share a lot in their health history but her mom has none of these problems and has never been on SSRIs. Thus, it is very likely there are genetic predispositions to these problems that Jordan and Mikhaila share.

The Lion Diet is overall extremely helpful but could probably benefit from specific strategies around managing sulfur metabolism.

I will do what I can to help them, starting with looking at their mitochondrial function. I think more specific data will provide insights that they can use to convert the vicicous mitochondrial cycles to virtuous mitochondrial cycles and I hope and pray for Jordan’s robust and lasting recovery.

We’ve put our sights on the North Star.

We know how to know when we’re healthy.

But what do we do to get there?

If we have arrived at the promised land, how do we stay there?

How do we explore it more deeply to discover the riches of its treasures?

What Everyone Should Be Doing For Their Health is a collection of “the basics” that everyone should check in on from time to time to make sure they aren’t missing any of the foundational health strategies:

But what if you’re missing many of the basics? Where should you start? How should you narrow in your focus?

Or what if you’re hitting them all and you need a more advanced health strategy? How do you guide your search?

The Five Laws of Mitochondrial Health

The Five Laws of Mitochondrial Health are the compass you need to keep you following your North Star.

They are the lenses with which you should view the basics.

They are the guardrails that keep you on solid footing as you search for your next advanced strategy.

These are the Five Laws of Mitochondrial Health:

• The First Law: Always start with your mitochondria.

• The Second Law: Put food first and pharma last.

• The Third Law: Never put tech before nature.

• The Fourth Law: Remember your needs are your own.

• The Fifth Law: Observe your needs as they change with time.

Applying these five laws will require specific mitochondrial strategies and a plethora of mitochondrial tactics.

Our purpose in this article, however, is to understand the laws so that when we seek to apply them using strategies and tactics we do so from a position of wisdom and understanding.

This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.

This is a fundamentally philosophical article, so it focuses on articulating the philosophy rather than on substantiating claims with evidence from scientific literature.

The 1st Law: Always Start With Your Mitochondria

Mitochondria extract usable energy from the food you eat so you can use it to fuel the production, maintenance, repair, and distribution of everything in your body.

The amount of cellular energy your mitochondria produce drives the dial of health and disease.

As you produce more energy, the dial drives to the right and points to health.

As you produce less energy, it falls back to the left and points toward disease.

Within each range, the amount of cellular energy drives how ill we are or how healthy we are.

There are thousands of genetic variants and uncountable experiences and exposures that can drive what disease or health looks like for each one of us.

For one person, disease is diabetes. For another, it’s heart disease. For another, it’s cancer. For yet another, it’s a neurological disease. And for yet another, it’s chronic fatigue.

For one person, peak health is athletic achievements. For another, it’s business. For yet another, it’s leadership and the formation of harmony within a community. And for yet another, it’s contemplation of eternal truths and their articulation in art or writing or speech.

But whether we experience health or disease and how much of each we experience comes down to how much usable energy we can extract from food and to what extent we can use the top layer of abundant energy to fuel the commitment of the bulk of the energy toward our health and highest purpose.

Living in accordance with the first law can be achieved at many levels: one level applies to how we manage our own health; another applies to how a physician may manage the health of others; yet another applies to the scientists who study how the many things we could be exposed to impact our health.

For example, using or prescribing mitochondrially toxic antibiotics for acne before giving the skin enough vitamin B5 to allow its mitochondria to clear away the fatty acids that are fueling the growth of those bacteria violates the first law.

Consider high cholesterol. Training the liver’s mitochondria to produce abundant energy through fasting and intense exercise will improve the ability of the liver to fuel the energy-intensive clearance of cholesterol from the blood. To do this before resorting to strategies focused exclusively on micromanaging the production of the cholesterol transporters with fiber, ezetimibe, seed oils, and statins is to live in accordance with the first law.

A scientist trying to solve the protracted withdrawal syndromes of benzodiazepines and SSRIs by focusing exclusively on neurotransmitters does not walk in the way of the first law. To walk in its way, the scientist must consider how these drugs distribute through the entire body, entering cells in every tissue and altering their mitochondria.

The 2nd Law: Put Food First and Pharma Last

The second law does not say “never use a pharmaceutical.” Rather, it says “don’t solve with pharmaceuticals a problem that can be solved with food.”

The second law is built on respect for complexity.

The complexity of a system is proportional to the number of potential pairings of its components.

The more complex a system, the more safety there is in allowing it to freely consume and utilize the materials that naturally feed it, and the more likely it is that centralized and forceful interventions carry the danger of unintended consequences.

The position of a cell within the human body is roughly analogous to the position of a person within the global economy. To put it in perspective just how complex your own body is, the global economy has eight billion people while your body has 30 trillion cells.

There are 32 quintillion potential pairings in the global economy and 450 septillion potential pairings in the bodily economy, making your body 14 million times more complex than the global economy.

Food provides your body with the raw materials it was designed to use within that complexity. Your body knows how to extract all the useful things from your food and leave the rest to your pee and poop. It knows how to get more of one nutrient into your brain and more of another into your liver. It knows how to get some nutrients into one type of neuron and other nutrients into another.

Your body treats pharmaceuticals all the same way: oxidize them, conjugate them to make them more water-soluble, then either pee them out or let them pass into the stool. In short, get rid of them. This is why their effects often only last a matter of hours.

Why? Because it doesn’t know what to do with them and they pose a risk of toxicity.

A psychiatrist wants a benzodiazepine to get into the brain and work on a GABA receptor. But most of it winds up in fat tissue and skeletal muscle and the tiny little adrenal gland accumulates it six times faster than the brain.

The holy grail of SSRI development was to try to get rid of the 2-week lag in treatment efficacy by getting the drug to increase serotonin’s activity on its destination neuron while blocking its negative feedback on the neuron that released it. Pharma never succeeded because it simply doesn’t have the tools to make a drug do one thing on one neuron and the opposite on the one right next to it.

They wanted the cargo inside the lipid nanoparticle envelopes of COVID vaccines to stay in your shoulder at the injection site. They packaged it inside the lipid nanoparticles to evade the more immediate destruction your body would impose on an intrusively injected foreign substance. But lipid nanoparticles look and behave just like lipoproteins and get distributed to heart, lungs, muscle, mammary glands, reproductive glands, and more. Wherever the cargo landed became for some completely undetermined period of time a factory of the toxic spike protein that went around poking random holes in cell membranes.

Your body absolutely knows how to exert exact control over the distribution of the nutrients in the foods you eat. It does this in proportion to where the nutrients need to go.

It cannot do this with drugs because it has no “knowledge” of what to do with them.

Pharma is superior in the specificity with which a drug can have a molecular target and the intensity with which that drug can impact the target, but that is the complete opposite of what you want in a system as complex as the human body.

To boast that you’ve simplified something down to one potential pairing (molecular specificity) as you direct it to become the governing force in a system of 450 septillion potential pairings is to catastrophically lose sight of the fact that complex systems do not like to be controlled by one central command.

Pharma is inferior to food in its ability to allow the body to separate and distribute each component to where it is needed most.

Pharma has at its disposal a small handful of routes of administration: oral, topical, subcutaneous, intramuscular, intravenous, intracerebral. It has a few coatings it can use to influence distribution, like slow-release, liposomes, and lipid nanoparticles. But these are blunt tools and they can’t hold a candle to the complexity with which the body handles food.

This principle also applies to training and lifestyle strategies. For example, exercise, meditation, or altitude will all impact many hundreds of targets. But which targets are altered and how they are altered can differ between tissues, and within each tissue can differ between cells and even in different compartments within a cell. We introduce one specific, simple, natural strategy, and we experience a physiological symphony of cellular and subcellular responses to it.

This is why, for example, animal studies suggest that intermittent hypobaric hypoxia training produces an anti-depressive effect 25 times more resilient than pharmaceuticals. Because the strategy works with the complexity, not against it.

As it says in the Tao te Ching, a tree that is unbending is easily broken.

Food and natural strategies give our body a simple offering and then respect its freedom to respond with a complexity we can only partly understand.

Because we only partly understand the complexity, we certainly misunderstand much of what we think we understand. And it is that incomplete and partly misunderstood complexity that Pharma uses to develop its drugs. The drug then imposes our incomplete and partly wrong understanding of that complexity with force.

Food and natural strategies bend with the rhythms of our body. Drugs are heavy-handed but easily broken.

Working with the complexity instead of against it is the way to respect the second law.

The 3rd Law: Never Put Tech Before Nature

The third law, like the second, is built on respect for complexity.

Whereas the second law is about respecting the complexity of our own body, the third law is about respecting the complexity of what we expose it to.

The “tech” in this law is not to be construed broadly as any kind of technology. The third law is not meant to make us Luddites.

Rather, the “tech” of the third law refers to the use of technology to deliver an essential exposure our body is designed to receive from nature.

As with the second law, the third law does not say, never use such technology.

Rather, it says never replace an essential natural exposure with a technological solution that substitutes for nature rather than improving your ability to access it.

The third law provides a basis for distinguishing between the many strategies that lie somewhere between food and pharma. These include technologies like supplements, naturally occurring peptides and other mitochondrial molecules, biohacking devices, and hormones.

All of the essential nutrients are critical to mitochondrial health, so the food that provides them is the most essential of all mitochondrial medicines.

The histories of infant formula, purified medical diets, and purified rodent diets all show us that food is far superior to the collection of what we in all our scientific glory believe are its most essential components. Each of these histories contains decades of health problems and even deaths from mistakes made in conceptualizing nutritional requirements. Even after the big mistakes were fixed by the evolving science, breast-fed infants are still today healthier than formula-fed infants and rodents fed food-based “chow” diets are much healthier than rodents fed purified diets. Total parenteral nutrition used in medicine is acutely life-saving but its long-term use still incurs fatalities that could be avoided by having its nutrient composition more closely resemble natural food.

Supplements can be very valuable when added to a strong dietary foundation, but reaching first for nutritional superfoods protects against imbalances. For example, too much zinc has the capacity to create deficiencies of copper, iron, molybdenum, and most other minerals. The interaction with copper is well known, iron is less well known, and the others are essentially unknown. Oysters are zinc superfoods that are balanced with all of the other minerals.

Many nutrients have toxicity profiles, but most of these are probably poorly understood imbalances with other nutrients. Toxicities of vitamins A and D are each relative deficiencies of the other. Vitamin B6 toxicity is a relative deficiency of the other nutrients involved in amino acid metabolism.

Foods are not all perfectly balanced and using food does not guarantee you never encounter a toxicity or imbalance, but their nutritional profiles are all confined within parameters laid out by the complex physiological needs of the plants or animals from which they come, and those parameters offer us strong protection against the greatest mistakes we could easily make with supplements.

Still, some of us may have genetically rooted needs to supplement with high doses of specific vitamins or minerals. This is a very important use of supplements but also requires expertise to uncover and diligent attention to the risk of long-term imbalances.

We can generalize this principle to other less well studied exposures. For example, take sunlight. The sun contains many specific wavelengths with direct and indirect benefits to mitochondrial function:

• Red and infrared light provide direct energy inputs into the mitochondria and structure mitochondrial water in a way that makes it easier to extract useful energy from food.

• Blue light in the morning signals to your brain that it is daytime and stimulates the release of serotonin, which helps mitochondria adjust to the higher energetic demands of wakefulness.

• Blue, green, and especially ultraviolet light unbind nitric oxide from proteins, which stimulates vasodilation and improves blood flow, delivering more oxygen and nutrients to mitochondria, and which reverses the effects of excessive inflammatory and hypoxic signaling, thereby liberating energy to be used towards health-promoting purposes.

• Ultraviolet light has antimicrobial effects, strengthens the skin barrier, and counteracts fungal infections, psoriasis, and eczema. This reduces unnecessary inflammation and thereby liberates energy to be used toward health-promoting purposes.

• UV-B light helps synthesize vitamin D, which helps optimize mitochondrial metabolism of iron and sulfur, which are critical to the infrastructure of the mitochondrial engines.

There is a substantial body of evidence that kids who spend more time outdoors have a lower risk of myopia. A number of Chinese trials that randomized different schools to different amounts of outdoor time suggests that spending time outdoors directly causes the improvement in eyesight. To date, the leading candidate to mediate this effect is simply the brightness of the light, which may directly regulate the growth pattern of the eyes.

There are many tools to isolate specific parts of this spectrum but none that perfectly replicate it. Morning sunshine is very enriched in red and near infrared light, and 30-90 minutes of it can provide the equivalent of 10-20 minutes in front of a red and infrared light panel. But it also has blue light that will entrain your circadian rhythm, release serotonin to adjust your mitochondria to daytime, and provide a nudge to start freeing up nitric oxide from the protein pool.

A little bit of unprotected sunshine in the afternoon will turn up the dial on the nitric oxide effect and will round all of these benefits out with vitamin D-synthesizing, skin-optimizing, and antimicrobial wavelengths.

Spending as much time as possible in indirect natural sunlight throughout the day will give your eyes the stimulus that they need.

The likelihood that we have finished delineating the beneficial wavelengths of sunlight is minimal. This is a field that just recently started waking up from its decades-long slumber in the belief that being healthy meant staying completely out of the sun.

The third law does not say “don’t buy a red light.” It says don’t substitute the red light for natural sunlight. Use it because you believe you benefit from adding more red light to a solid sun exposure regime.

We can also supplement with compounds that are not essential nutrients but are found naturally in our bodies. Some of these like CoQ10 make up part of the infrastructure of the mitochondrial engines and are not fundamentally involved in communicating something. Others, like the mitochondrial peptide MOTS-C or hormones like thyroid hormone, estrogen, or testosterone, are fundamentally involved in communication rather than infrastructure.

All of these have the capacity to break vicious cycles of declining mitochondrial energy production, declining abundance signaling, and declining maintenance of mitochondrial infrastructure, but there are reasons to think twice in each case before use and they are not all equivalent to one another.

If you choose to supplement with a component of the mitochondrial infrastructure, why aren’t you making enough in the first place? There may be genetic reasons but you probably have suboptimal status of nutrients needed to make it. Fixing those is necessary because they will cause other problems, and fixing them will impact the dose of the supplement you need, so it is better to fix them first.

When we are considering signaling molecules found in our own body, we have additional concerns. We now have to consider the fact that they are meant to communicate something specific, and if we intervene to change what they are saying, they may not be reflecting the physiological and biochemical truth occurring within our bodies. You can use hormones to “fake it till you make it,” but the window you have opened is your opportunity to create genuine abundance with your nutrition and lifestyle. Otherwise, there’s a chance you’ll be left with a surprise bill for all the energy you used during that time.

When using any technology, the goal should be to restore normal physiology in its most excellent manifestation.

For example, using high doses of a vitamin because you have a genetic mutation in an enzyme that uses it and the vitamin normalizes the function of that enzyme serves as an extension of food within the light of the third law. But using high doses of a vitamin because those high doses do something to you that amounts you could get from food would never do — for example, say they impact some receptor that lowers your cholesterol — puts that use squarely in the realm of pharma, which the second law relegates to the last position in the hierarchy of mitochondrial strategies.

Using a hormone to make up for a deficiency of that hormone that cannot be solved through more natural and root-cause approaches is closer to nature than a drug in the light of the third law, but using a hormone to achieve an unnatural or supraphysiological state is well within the category of pharma.

Challenges For the Third Law

By evoking the relationship between technology and nature, the third law wades into some murky territory where challenges arise and much debate could be had.

The third law is not about mindless subservience to nature, demonization of technology, or dogmatic rankings of good and bad technologies. Nor is it blind to the fact that all human innovation takes the form of technology and many technologies are truly ancient.

Therefore, the third law can be used as a framework for debate and discovery.

For example, is using an exercise machine substituting for nature or is it helping you get better access to the resistance of gravity and intermolecular forces that demand you summon your strength, endurance, power, speed, and agility?

The best way to look at this, in my view, is to ask whether the exercise is improving your ability to engage in natural feats that require these skills. The degree to which it translates into functionally useful movements is the degree to which it is aiding your exposure to these natural stimuli rather than hindering it.

Much could be debated about what constitutes a “functionally useful movement,” and much could be studied about which exercise technologies translate best to those movements.

Herbs are another challenge to the third law. Herbs that have drug-like effects are much closer to pharma than food. Some people steeped in modern pharmacology have fundamental skepticism toward the safety of herbs because of their complexity — they argue that they know exactly what is in a pharmaceutical and what its risk/reward profile is, and know neither for the herb — but the third law values complexity and sees it as food-like.

Traditional herbalism has more categories than we have been using here. Herbs could at least be separated into those that are tonic or medicinal, where tonic herbs could be consumed in small amounts continuously over decades to support and refine certain energies or aspects of the person, and medicinal herbs could be used in short courses for specific reasons. Various systems had additional categories and dimensions, matching herbs to constitutional differences among individuals, to the safety of specific durations of use, and to specific situations. Even the most tonic of herbs were not simply “vegetables.” Limits were acknowledged because their impacts were strong, and natural limits were imposed on the quantities people could use by availability, cost, and sometimes seasonality.

The third law neither adopts nor rejects traditional views of herbalism, and it passes in silence over debates about whether modern pharmacology does a better job classifying herbs than traditional herbalism does.

However, the third law does see thousands of years of tradition treating something that grows in the ground as if it is safe to use indefinitely within traditional parameters as being awfully close to its own definition of “food.”

Therefore, the default view that the third law takes toward herbs is to see tonic herbs as foods if they are used within the parameters of the system that defined them as tonic, and to see medicinal herbs as drugs. One can take inspiration from the third law to view medicinal herbs as safer than pharmaceuticals because of their complexity. Given that even traditional systems recognized toxicity concerns with medicinal herbs, however, the third law does not itself adopt or endorse that position. Certainly if we lack modern pharmacological studies on medicinal herbs, one should stay within the traditional framework when using them. Where we have such studies, one should either defer to them, synthesize them with the frameworks of traditional herbal medicine, or make a conscious choice to adopt the epistemology of traditional herbal medicine over and above that of modern pharmacology. These judgments do not proceed from the third law but are left to the free choice of those who follow the third law.

The 4th Law: Remember Your Needs are Your Own

Each of us is a unique individual. My needs are not yours, yours are not mine, and ours are different from those of our neighbors.

We are all impacted in small ways by common genetic variants. In some of us, many small effects will cancel each other out. In others, many small effects might add together or synergize.

Rarely, some of us may have classical genetic disorders that respond to nutritional therapies.

Nearly all of us are impacted by heterozygous rare disease mutations. While these are often dismissed as “carrier” status as if we carry the potential for a disease but no impacts of it, they represent genuine biochemical deficits approximately equal to 50% of the biochemical impact of the disease itself. We each have one or a small handful of these that have big impacts on our biochemistry and alter our requirements in a way where we might benefit from supplementing with doses of essential nutrients or endogenously synthesized infrastructure molecules at doses that we could never obtain from food.

This is very well studied in the case of heterozygous familial hypercholesterolemia. The rare, homozygous disease requires two copies of a defective gene and can cause heart disease in infants and children, with individuals having heart attacks as early as 18 months old. Having one copy of the gene instead of two is far more common and it leads to higher risks of heart disease that dominate in a person’s 40s, 50s, and 60s.

It is not well studied in any other cases, but it is certainly true. Prior to genome sequencing, the way rare disease specialists showed that a biochemical defect was heritable was to show with enzymatic analysis of each parent that they each had half the deficit of the child. There are case reports of heterozygous defects in biotin recycling causing chronic yeast infections starting in a woman’s 30s, and there are case series showing people heterozygous for Wilson’s disease have dysregulated copper metabolism in their brains.

The One Million Exome Study showed that each of us have a small handful of these heterozygous rare disease genes.

While the third law acknowledges idiosyncratic nutrient requirements as a reason to add technology (supplements) to nature (food) without replacing nature, the fourth law tells us it is almost certainly the case we will, if we look closely enough at ourselves and our responses, find at least one example that applies to us.

The fourth law takes no position on how we should go about finding our idiosyncratic needs. It simply demands recognition that we have idiosyncratic needs.

If we see that a strategy worked for someone else, assuming it will work for us is flippant disregard for the fourth law; believing it might work for us but knowing it must be tested is keeping our mind set on the fourth law.

The 5th Law: Observe Your Needs as They Change With Time

Our requirements for nutrients and natural exposures change with time.

There are a few reasons for this:

• Different stages of life have different requirements.

• As our choices change over time, we create different requirements.

• Some things in our lives are beyond our control, and events may occur that impose new demands on us. These can be major shifts to new long-term regimes, or can be acute emergencies that require a short-term resolution.

• If we are actively incorporating health strategies, they may have cumulative effects over time that are not seen in the short term.

For example, a woman may be predisposed to iron deficiency when she is young. She is missing iron from her mitochondrial engines and she is missing iron from the hemoglobin that delivers the oxygen they use to burn their fuel. She hits menopause and stops losing iron in her menstrual blood, and has a genetic predisposition to iron overload that she had never bothered looking for because her circumstantial predisposition pointed in the opposite direction. Now she is vulnerable to oxidative stress from iron overload damaging her mitochondria and inhibiting their energy consumption. Before she needed to make sure she got enough iron. Now she needs to make sure her iron stays within bounds.

Another woman could have stopped menstruating earlier because of stress, failure to eat enough food, a primary hormonal problem, or a mitochondrial deficit, and the same thing would happen to her but at a much younger age.

Stressful events could require us to operate at a higher percent body fat for a time to give our brains confidence that energy expenditure is safe.

Exercise, weight loss, or a new diet could impact our need for different nutrients if they shift us away from burning carbs and toward burning fat or vice versa.

An exercise routine could be an excellent stimulus in the short term but constitute overtraining in the medium or long term.

If we correct a deficiency rapidly with a supplement, we may wind up taking something indefinitely at much higher than our maintenance dose. We may not see the effects of imbalances until months or years down the road.

Acute events may occur in which our needs radically change, but only until the situation is resolved. This could be, for example, an injury, a life-threatening illness, a demand for greater physical or cognitive performance.

The reasons our needs could change are innumerable. The fifth law does not create a tactical prescription for finding all of them, but instead requires us to acknowledge the principle, and to incorporate it into our awareness.

To be lulled into the assumption that if something worked for you in the past it must be working for you now or will work for you in the future is to transgress the fifth law. To continue doing what is working while maintaining awareness that you may need to be flexible and change is to keep the fifth law written in your heart.

A Hierarchy of Strategies

We can synthesize these laws to form a hierarchy of what to address first. This hierarchy not only represents the sequence in which you should address problems, challenges, and goals, but also represents superiority and inferiority. If you can obtain your goals while staying toward the top of the hierarchy, your approach is better than if you need to go further down the hierarchy to get the same benefit.

Biohacking devices that provide a narrower range of a natural exposure than the natural source itself are considered the same as “supplements” in this framework.

The hierarchy assumes the first law: it organizes the types of strategies that could be used for any purpose but assumes they are used first to support mitochondrial function.

The hierarchy is applied to each circumstance in which you find yourself. These shift and change with time, as emphasized in the fifth law. You may be optimizing your health using the first level but have an acute emergency that demands a short course of something in the sixth level. This does not move you as an individual to the sixth level. It simply means that the particular circumstance demanded something from the sixth level, and when that circumstance is resolved you are back to level one.

The fourth law implies that most of us will at some point move from the first level to the third level as we learn what our idiosyncratic needs are. Whether we pass through the second level is immaterial. However, the third law does require us to address those idiosyncrasies with nutrient-rich superfoods before moving to supplements.

The fourth law may also imply for some people in rare instances a highly specific, fundamental deficit of a hormone that requires treatment with the hormone. This could move someone directly to the fifth level without necessarily passing through the others.

The fact that such needs arise only requires us to move to those levels to address the specific need. Level one remains superior to level two even if most of us get to level three for at least one nutrient and a small number of us have an idiosyncratic demand for chronic use of something from level five.

The Hierarchy

• First: Use food, exercise, and natural ancestral exposures like sunlight, fire, grounding on the natural earth or in the ocean, forrest bathing, and spending time in the mountains. Tonic herbs can be considered foods when used in a manner faithful to the traditional system that classified them as tonic.

• Second: Use supplements of essential nutrients to resolve deficiencies that food cannot, using them only at doses that can be found within nutrient-dense diets. That “food cannot” resolve the deficiency does not mean that there is no food that contains the amount needed, but rather that you do not tolerate those foods, cannot make a sustainable habit out of them, or dislike them strongly. Similarly, the second level includes the use biohacking devices to supply a stimulus that should be obtainable from nature but is not obtainable to you for similar reasons. These reasons should be compelling enough that you will consciously choose to move from the top-tier approach to a second-tier approach.

• Third: Use supplements of essential nutrients, non-essential mitochondrial infrastructure molecules (like CoQ10), or biohacking devices at doses that cannot be found in food or nature to meet idiosyncratic needs. This should be done conservatively and slowly and should be based on empirical benefit. It should be done only after trying to use natural sources of those exposures such as nutrient-dense superfoods to address the idiosyncrasy.

• Fourth: Attempt to break a vicious mitochondrial cycle by using doses of supplements or stimuli from biohacking devices above and beyond what can be found in nature for a period of time without any evidence you have a specific, genetically rooted need for such doses. By default these should be done for a limited course such as as twelve weeks unless there is a specific reason to use them for longer.

• Fifth: Bring hormones to natural physiological levels when levels one through four of the hierarchy have been unable to bring them to those levels on their own.

• Sixth: Use medicinal herbs or pharmaceuticals.

As an example, using a statin (level six) when your thyroid hormone levels are low without addressing those first violates the hierarchy because thyroid hormone is the central systemic regulator of cholesterol levels, but using thyroid hormone replacement (level five) before ensuring you have adequate protein, iodine, and antioxidant nutrients also violates the hierarchy. If you are deficient in any of these, using supplements (level two) before trying to address the deficiency with food (level one) violates the hierarchy, and megadosing iodine without evidence of an iodine transport defect (level four) instead of trying to get doses within food range (level three) violates it as well. Walking through the hierarchy in order would put natural foods and other natural exposures first, ensuring nutrient adequacy with supplements next, addressing idiosyncrasies after that, and after these have been done you would check whether you still need thyroid hormone. After thyroid status is optimized you would see if you still need to do anything about cholesterol.

The Spirit of the Laws, Not the Letter

These laws are not meant as dogmatic and rigid strangleholds, nor as impositions against anyone’s freedom.

They are, instead, discoverable truths that make up the parameters that guard our way through the journey of optimizing our mitochondrial energy production to give us the highest probability of optimal results.

It is important to be able to dynamically move through the hierarchy on an as-needed basis.

An emergency may justify quickly moving to level six in the hierarchy, and the demand for speed in an emergency may require doing so without thinking through whether it is absolutely necessary. It could be far more important to do something you know will work right now than to spend time figuring out if something higher on the hierarchy is just as good.

Pain and suffering can be a reason to move faster through the hierarchy when finding first-level or second-level strategies seems too difficult or takes too much time.

The laws do not demand tribute of any sort, and certainly do not accept homage in the form of pain, suffering, or failed emergency treatments. Rather, the spirit of the laws is to be forgiving to those who need speed but to be available for embrace to those who want sustainable, long-term solutions.

Seeking longevity should be done with strategies that themselves have longevity, and the strategies with longevity are those whose foundation is these five laws.

But how do you know you are healthy?

What are more specific things you look out for to verify you are on the right track?

Many of us can get lost in tactical details and proxy markers, looking at our weight, waist circumference, sleep metrics, HRV, testosterone, estrogen, ApoB, VO2max, microbiome testing, and so on.

While proxy markers are necessary in some respects and tactical details matter greatly when we are in the weeds of optimizing something, we need a North Star to govern the constellation of markers we are tracking, or to check in on when we aren’t tracking anything.

This is your North Star:

We can derive some guiding rules from this.

You Should Rarely get Sick

For example, you should rarely get sick. You can regard each sickness as docking a chunk off your energy score:

• You were likely missing energy and resources to defend against the illness.

• Your body may have purposefully become inflamed to calm you down because it didn’t have the energy to do what you were trying to make it do.

• Regardless of why you got sick, recovering from the illness will take a considerable chunk out of your energy budget.

The downtime associated with the illness has to be counted against your healthfulness through taking points out of the energy score.

The Energy-to-Anxiety Ratio

Another rule you can derive from this is that you want a high energy-to-anxiety ratio. A state that is abundant in energy is one in which the top layer of that energy is used to direct the bulk of the energy into the right places and toward the right uses. As you start to lose energy, often the first thing you may notice is that what energy is left goes into the wrong places because you lost the energy that you needed to control the rest.

If your energy is spent on worrying about things you cannot control, this is a lower energy state than if it is spent on taking charge of the things you can control.

It may feel like the same amount of energy is buzzing through your body in each case, but that is because the additional energy it takes to direct the flow of the bulk of your energy doesn’t feel like a buzz. It silently flows through you, increasing the gracefulness of the bulk energy. You may not feel more energy. You may instead feel that your energy burns more cleanly, flows more calmly, and is more available to your purpose.

Libido and Life Force Energy

You can take a broad view of “libido” to think of it as life force energy. If you are purposefully directing your life into pursuits that do not involve sex, I am not arguing that you have to be tortured with sexual desire to be healthy. But you should feel that this underlying life force is abundant and under your purposeful direction.

This life force will take different forms in different stages of life and will operate according to other natural rhythms, including for a woman the menstrual cycle.

During the bulk of life, reproduction dominates as an imperative and viewing libido literally and classically makes sense as the default.

When evaluating the health of a child you are expecting it to be amorphous and manifest in a plethora of ways but they should appear full of life.

An older person may be redirecting this energy entirely into a consolidated singular purpose or diffusing it across relationships or nostalgic connections.

You should see this vital force in abundance in anyone, and whether the light is dimming or shining brightly is an index of health.

Pain-Free Ease of Movement

You should feel comfortable in your own body, and appear to others that you are comfortable in your own body. It shouldn’t hurt to sit still or to move, and your movement should reflect your intention.

Expectation Management

Properly interpreting the North Star requires some skill in expectation management.

If you feel overwhelmed and totally unable to meet your goals, is it possible that you are just trying to do too much?

There is always an easy way to find out if you are doing too much: do a little less and see if everything gets better.

For example, suppose you are lifting weights. Your numbers keep going down. It is certainly possible that you have a new health problem and that’s to blame, but the rational thing to do in response is to vary your total effort expended in weight lifting by varying your volume, frequency, intensity, duration, or exercise selection. If increasing total effort leads to better results, you weren’t getting enough stimulus. If decreasing total effort leads to better results, you were doing too much.

Suppose you determine you were in fact doing too much, but you believe in your heart of hearts that you should be able to do more. You might be right, in which case you should make being able to do more a goal of your health and enter an optimization cycle to achieve that goal.

But you should hone your expectation management skill by discussing this with experts and peers and by doing a little research to see if you are framing the issue the right way.

For example, you might start out thinking you should be able to do more volume in the gym, but through dialogue you might arrive at the conclusion that you really want to be stronger, or faster, or be able to hike with your friends and not get tired, and that doing more volume is not the best way to achieve your true goal.

Having clarity about your problems, challenges, and goals can help improve your interpretation of your North Star.

Vet Everything Against Your North Star

All your other markers should be vetted against the North Star.

Sleeping more? That is often excellent. The way you know it is excellent is you start feeling more energetic during the day, more clear-headed, and less anxious. If you start feeling progressively more tired during the day as you sleep more, however, you’re probably sleeping more because you need more sleep, and the underlying reason could be a drop in your health.

Did a strategy increase your energy? Great — but did it lower your anxiety? If the energy-to-anxiety ratio didn’t improve, the North Star isn’t necessarily looking better.

Did a strategy lower your ApoB? Great — but what happened to the North Star? Perhaps you notice nothing and you improved a proxy marker covering one aspect of your longevity. But if it hurts more to move, something is going wrong that takes precedence. If your North Star is shining brighter in every respect, you may be genuinely on to something fantastic.

Never Forget the North Star

Carry on in your journey as far as you yearn to go.

But never forget to look up at the sky to let the North Star guide you.

Moving Forward From Here

How do you achieve the North Star?

Start with the Five Laws of Mitochondrial Health:

Widely believed to regulate the ability of the brain to relax by increasing the power of the neurotransmitter GABA, they are actually whole-body drugs with specific mitochondrial targets. Using them and quitting them both have the potential to cause mitochondrial dysfunction.

About four percent of populations in the modern West use benzos, and as many as ten percent of the US population uses them.

They include drugs like alprazolam (Xanax), diazepam (Valium), lorazepam (Ativan), clonazepam (Klonopin), temazepam (Restoril), midazolam (Versed), and oxazepam (Serax).

They also include Rohypnol (flunitrazepam), known as “roofies” or “the date-rape drug,” which is illegal in the United States and several other countries.

There are also a number of benzodiazepine “designer drugs” that are broadly illegal or controlled substances in most modernized countries, including clonazolam and flubromazolam, which can be found in preparations with names like “Xanax bars” or “liquid Xanax.”

Benzos are thought to act primarily by increasing the potency of GABA, the primary inhibitory neurotransmitter. GABA calms and relaxes us, though it plays other roles such as suppressing our attention to distractions, which helps us focus.

GABA is the primary counterbalance to glutamate, which excites our nervous system.

People who use benzodiazepines are 60% more likely to die over a given period of time than those who don’t use them, but people who quit them are 60% more likely to die than those who stay on them.

Correlation is not necessarily causation and these data do not necessarily show that using and withdrawing from these drugs causes the excess mortality, but they raise the possibility that using them is a deadly physiological trap.

As we will soon see, their use and withdrawal can both cause mitochondrial dysfunction, and since maintaining healthy mitochondrial function is the single most important driver of all health and disease, the possibility that they do create a deadly physiological trap must at least be considered.

This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.

Withdrawal from benzos often causes rebounds of the conditions the drugs were originally treating that are worse in magnitude than they had been prior to treatment.

It can also cause new-onset symptoms that are unrelated to the original reason for treatment. These can include digestive problems and food intolerances; trembling in the limbs, skin, or whole body; difficulty driving or walking; problems with balance, muscle spasms, heart palpitations, and blood pressure; difficulty swallowing; new-onset seizures; hallucinations; and akathisia, a neuromuscular disorder that can produce an inner unbearable restlessness and uncontrollable non-productive movements that persist without any relief.

While the available data seem to imply that most people get over these symptoms in a matter of weeks, some people experience a “protracted withdrawal” syndrome that can last for at least as long as one to five years.

For example, in a survey of just over 1200 people who were active on internet sites about drug withdrawal, many reported symptoms lasting over a full year: over 50% reported these including digestive problems and muscle weakness; almost 50% reported trembling in their limbs or skin, head pain, and difficulty driving or walking; over 40% reported problems with their balance, muscle spasms, heart palpitations, or blood pressure problems; 38% reported difficulty swallowing; 36% reported akathisia; 26% reported uncontrollable whole-body trembling; 22% reported seizures; and 20% reported hallucinations.

This builds on previous reports of isolated cases of tinnitus lasting 6 months to two years and one case of it lasting over five years, and on cases of numbness and burning lasting two to four years.

Most studies do not adequately follow people up in the long-term and and we have no reliable data on how common protracted withdrawal is.

The possibility that going on these drugs raises the risk of mortality by 60% and quitting them raises it another 60%, however, hints at the possibility that some degree of long-term physiological damage could be relatively common.

These data make much more sense when we realize that benzos are mitochondrial drugs and benzodiazepine withdrawal is a form of mitochondrial dysfunction.

It is never the case that what we think a drug does is exactly what it does, nor is it ever the case that our present understanding of a drug encapsulates everything it does, and it is quite often the case that whatever we think a drug does is not even its primary mechanism of action.

Psychiatric drugs, though, are unique in the degree to which they are claimed to do one thing but have powerful effects no one talks about. The reason is that psychiatry systematically claims that its drugs target the brain, yet it is totally implausible that a drug taken orally primarily goes to the brain.

Human autopsy studies show that benzos have the second lowest accumulation in the brain out of any tissue measured. As a proportion of tissue mass, their highest uptake is in the adrenal gland. As a proportion of total benzodiazepine, their greatest accumulation is in muscle and fat.

GABA receptors themselves are strongly enriched in the nervous system, but they are found ubiquitously throughout the body on the surfaces of many different types of non-neuronal cells where they carry out signaling activity just like in neurons. Many but not all of these are sensitive to benzodiazepines.

It was in the two papers outlining the very first discovery in 1977 of the ability of these drugs to impact GABA signaling in which a second receptor was discovered embedded in the mitochondrial membrane. At that time, it was wrongly thought to not be present in the brain and was named “peripheral” for its abundance outside the brain.

Thus, the very birth of our mechanistic understanding of benzodiazepines brought forth twins: a brain-dominant GABA receptor-binding site; and a mitochondrial membrane receptor dominantly distributed outside of the brain.

Somewhere in the translation of pharmacological science into the practice of psychiatric medicine, there were people who consciously buried the knowledge that benzos are whole-body mitochondrial drugs. Presumably they did this because they considered it unrelated to the reason psychiatrists would use them to treat people’s anxiety and insomnia. Or perhaps they buried it because it was an obstacle for promoting the use of benzos for these conditions.

We now know that benzos have two independent mitochondrial targets.

The GABA receptor target lies on the surfaces of cells and is accessible to the extracellular fluid.

But benzos are relatively fat-soluble and their transport into the brain is proportional to how fat-soluble they are. Once there, they primarily accumulate in cellular and intracellular membranes.

While the drugs obviously distribute into synapses to carry out their GABA-enhancing activity, their accumulation in membranes puts them in much closer vicinity to their mitochondrial targets than to their GABA receptor targets.

Their impacts on GABA absolutely impact mitochondrial function through GABA signaling itself. Withdrawal from this effect would be expected to create a severe crisis of imbalance between the supply and demand for cellular energy.

Each of them, however, has different abilities to act on the two mitochondrial targets.

Clonazepam (Klonopin) has the strongest ability out of any to assist in “switching on” mitochondrial energy production in people who need a moderate boost. Through this very same mechanism, however, it has the strongest ability to silently poison the ability to switch it on in people who already have a major deficit in mitochondrial function.

Diazepam (Valium) has the strongest ability to support the transport of cholesterol into mitochondria for the production of conventional steroids in the adrenal and reproductive glands and the production of inflammation-cooling and energetically calming neurosteroids in the brain. Through this very same mechanism, however, it also has the strongest ability to hurt the mitochondrial conversion of blue light to red light during energetic crisis and to hurt the ability of mitochondria to defend themselves against oxidative stress.

Download This Article

Masterpass members can download this article to print it out and read it in natural lighting as recommended in What Everyone Should Be Doing For Their Health here:

In This Article:

• Benzos Are Whole-Body Drugs

• Benzo Use and Withdrawal: Not A Clean GABA Picture

• Benzos Are Mitochondrial Drugs

• Messing With the Mitochondria’s Gas Pedal

• Benzodiazepine Withdrawal as an Energetic Supply/Demand Imbalance

• Benzodiazepine Withdrawal as Dramatic Energetic Failure

• Red Light, Blue Light, and Oxidative Stress

• What Concentrations Are Needed For These Effects?

• The Deadly Physiological Trap

Read more

Read more

But how do you know you’re healthy?

Look to your North Star:

One holds that she had a basket of eggs that miraculously turned blood red while she was waiting with other women at the tomb of Jesus as he arose from the dead.

The other holds that after Jesus’s ascension into heaven she greeted the emperor with “Christ is risen!” He then pointed to an egg on his table and said, “Christ is no more risen than this egg is red,” after which the egg immediately turned red.

While Easter eggs are often dyed many colors as if an array of spring flowers, in the East they are simply dyed red using vinegar and onion skins in commemoration of the blood Jesus shed on the cross.

Various Slavic traditions add more ornate patterns over the red foundation or use multi-colored artwork.

The Easter egg evokes various imagery associated both with the Christian story and with spring. For example, new life emerges from an egg, which is like an external womb, whereas Jesus arose with new life from the womb of the earth. Christians also gave up eggs for Lent and could finally eat them on Easter. More broadly, in temperate environments chickens stop laying eggs in winter as they recuperate their nutrient and energy stores and start laying them again in the spring, which coincides with Easter.

In most of the world, these are Paschal eggs. “Pascha” is the Latin and Greek derivation of the Hebrew Pesach and ties the blood Jesus shed on the cross to the blood of the Passover lamb.

“Easter,” according to the eighth century English monk Bede, is tied to an ancient goddess of that name, though nothing survives before Bede supporting this. It does have etymological roots with east as a direction, which itself is associated with the sun arising from nightly sleep. It has at least a curiously coincidental surface similarity to the name of the Biblical Jewish queen Ester. Roger Seheult has been collecting some striking similarities between her story and that of the Easter story.

Billions of people will be eating, gifting, or otherwise engaging with Easter eggs today.

About 250 million people will wait until next week, due to the use of an older and less frequently self-correcting approximation of the date of the Paschal full moon.

In honor of the Easter Egg, here are the top five insights about eggs from my 2+ decades of research into nutrition:

Boiled Eggs Are Supercharged with Biotin

Biotin prevents brain fog, supports healthy hair, skin, and nails, stabilizes blood sugar, normalizes cholesterol levels, and supports healthy pregnancies.

About one in thirty people have genetic mutations normalized by high doses of biotin.

All of the biotin is in the yolk.

The egg white, by contrast, ties up the biotin and makes it unusable.

The simplest way to render the egg white completely harmless in this respect is to boil it for four minutes or more.

Three Nutrients Where Eggs Really Shine

While liver is the king of all superfoods, eggs are the picky eater’s general superfood, and both of these really stand out as sources of biotin, choline, and arachidonic acid.

While we covered biotin above, choline and arachidonic acid are no less important.

A livestreamed 2010 USDA committee deliberating the then-upcoming dietary guidelines referred to “The Choline Problem.”

That is, USDA maintains that eggs are bad for you, but all of the data say people need more choline. Thus, “The Choline Problem” is the fact that everyone needs more choline and less eggs, but eggs are by far and away the top source of choline that modern Americans would actually want to eat.

Fatty liver runs rampant, and choline matters more to fatty liver than sugar, alcohol, or fat. In fact, get enough choline in your diet and nothing else will be able to give you fatty liver.

Saturated fat raises the need for choline: it is the ratio of choline to saturated fat that determines how much fat our livers fill up with if we eat foods like butter and cream.

The choline-to-saturated fat ratio is probably important to heart disease as well: recent research on “LDL aggregation” suggests that a high ratio prevents LDL particles from clumping up and contributing to atherosclerotic plaque.

Choline is incredibly important to methylation, being able to keep this process running even if you have that darn MTHFR gene. Methylation prevents us from ruminating too much and makes us mentally flexible, neutralizes our allergies, and pumps our muscles full of creatine.

Choline is used to support cell membranes and make our bile flow smoothly.

Choline is used to make the neurotransmitter acetylcholine, which cools inflammation, helps us rest and digest by activating our parasympathetic nervous system, and in our brains it supports learning, memory, and sustained, focused attention.

Arachidonic acid needs go up when we grow, get pregnant, heal from injuries, or start building muscle.

We use it to power our brains, to waterproof the skin, to prevent food allergies and intolerances, and to attack foreign invaders whenever we start getting sick. Waterproofing the skin is critical to the prevention of eczema, and helps keep you maximally moisturized.

Choline Without the TMAO

Some people are concerned that a compound made from choline in the gut, trimethylamine, and the product we make from that in our liver, trimethylamine oxide (TMAO), contributes to heart disease.

While I am not convinced of this, the form of choline found in eggs is the least likely to generate TMAO in the gut. If you’re worried about this, reach for the egg before the choline supplement.

A Folate Superfood?

The best sources of folate are liver, legumes, and leafy greens.

While we need more data, some analyses suggest that eggs from chickens raised on pasture, who eat leafy greens (grass) all day long, are incredibly high in folate.

The Incredible, Edible Egg Yolk

While boiling your egg can make the entire egg a powerhouse of nutritional value, if you have to throw something away it should be the white, not the yolk.

The yolk contains all of the arachidonic acid, choline, and biotin, as well as 100% of the carotenoids, vitamins A, E, D, and K (8 items). The white does not contain 100% of any nutrient.

The yolk contains more than 90% of the calcium, iron, phosphorus, zinc, thiamin, B6, folate, and B12, and 89% of the panthothenic acid (9 items). The white does not contain more than 90% of any nutrient, but contains over 80% of the magnesium, sodium, and niacin (3 items).

The yolk contains between 50% and 80% of the copper, manganese, and selenium, while the white contains between 50% and 80% of the potassium, riboflavin, and protein.

If you aren’t going to fully cook the white, you are probably better off throwing it out, and if you are going to throw out one or the other, your vitamins, minerals, and fatty acids will be best off throwing out the white.

But, boil that white for four minutes or longer and you’re good to go on all the nutrients.

Happy Easter!

With that, enjoy your Easter Eggs, and Happy Easter!

The idea behind these trials was that the polyunsaturated fatty acids (PUFAs) in seed oils will lower cholesterol levels in the blood and thereby prevent heart disease.

Detractors from this idea focus on PUFAs making our tissues highly vulnerable to oxidative damage — very similar to the rust that accumulates on metal objects kept outdoors over time — and maintain that these fats could worsen the risk of heart disease by making the lipoproteins that carry cholesterol in the blood, such as LDL, more vulnerable to oxidative damage.

The failure of the seed oil trials to show a convincing reduction in heart disease and their worrisome finding that they may increase the risk of cancer suggests that this vulnerability to tissue damage is the mechanism that wins out in the long run.

One of the criticisms of these trials is that they are confounded by the use of trans fats in the seed oil groups.

While there are some trans fatty acids that occur in nature, such as in beef or dairy fat, there are specific trans fatty acids that occur in massive amounts in partially hydrogenated vegetable oils that do not occur in nature.

Hydrogenation itself is done to make liquid oils harder. When carried to completion, it turns all of the monounsaturated and polyunsaturated fatty acids to saturated fatty acids.

However, the path from a polyunsaturated fatty acid to a saturated fatty acid involves a monounsaturated fatty acid as an intermediate.

The definitional chemical characteristic of a saturated fatty acid is that it contains only single bonds and no double bonds, whereas monounsaturated fatty acids contain one double bond and polyunsaturated fatty acids contain more than one. The path from a natural double bond found in an unsaturated fatty acid to the single bond of a saturated fatty acid involves the formation of an unnatural trans double bond.

Thus, partial hydrogenation causes a loss of PUFA, but an increase in both monounsaturated and saturated fats, and the unique production of unnatural trans fats that are not found in any other foods.

Partially hydrogenated oils have been effectively banned in the United States and various other countries, but were widespread during the time of the classic seed oil trials.

Were these trials truly confounded by these unnatural trans fats?

We start our analysis with the longest seed oil trial ever conducted, the eight-year LA Veterans Administration Hospital Study.

The claim that it is confounded by trans fats relates to the use of a margarine in the seed oil group. There were actually two margarines used, one which was free of trans fats and one which contained trans fats. Here, we dig into historical sources such as advertising materials, preserved boxes with ingredient labels, patent infringement lawsuits, and scientific papers of the era. We blend this with direct analyses of the margarines and foods made with them and physiological biomarkers of trans fat consumption to narrow in on the best answer.

But first, why was this trial so incredibly important?

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What the LA Vet Trial Tested

The LA Veterans Administration Hospital Study was just over eight years long. It enrolled its subjects between 1959 and 1967, completed in 1968, and had its major publication published in 1969.

Most of the subjects were enrolled in the first two years of the trial, so most of the subjects who survived were in the trial for 6-8 years.

856 male veterans ages 55 or older staying at the Los Angeles home for disabled veterans were randomized to one of two diets that each provided 40% of calories from fat: either a control diet or a diet involving “a replacement of [two thirds of] the saturated animal fats and hydrogenated shortenings of the conventional diet by equal quantities of unsaturated fat in the form of vegetable oils.”

Apart from this change, the diets were nearly identical.

Men under 55 years old were excluded because they tended to have short stays at the home and heart disease takes a long time to develop.

The major importance of this trial lies in these three points:

1. It is one of only two double-blind trials, the other being the Minnesota Coronary Survey, that made a specific substitution of seed oils for traditional fats.

2. It is the longest of any of these trials, most of which were only five years long.

3. It is the only trial with a mean age above 65, which allows us to see the impact of seed oils on cancer.

There were two dining halls, one providing the control diet and one providing the seed oil diet.

The subjects were randomized to receive punch cards that only worked at one or the other dining hall.

The punch cards were used to track how many meals they ate, as they were allowed to leave the home and eat elsewhere.

In order to best preserve blinding, the institutional diet was changed from its historical diet and everyone was told they were on a special diet. Using this new, altered diet as a base, the two dining halls fed the exact same foods except that seed oils replaced traditional fats in one of the halls and only one egg per day was allowed in that hall.

In the first two years of the trial, over 130 people withdrew and there were 53 more withdrawals in the seed oil group than the control group. However, in the last six years of the trial there were only a few withdrawals per year and they were evenly distributed between groups.

The chief complaints in the excess of people withdrawing from the seed oil group in the first two years were disliking the flavor of the milk and complaining about the restriction of eggs. The milk had its fat removed and replaced with seed oils. The investigators improved this process after the first two years to generate a better flavor and people stopped complaining about it.

It appears the people who hated the restriction of eggs most all left during this time and were effectively weeded out. Either the same thing happened to the people who disliked the flavor of the milk or the investigators genuinely closed the gap between the taste of the seed oil-filled milk and regular milk.

Overall, this suggests there was a minor problem with the blinding of the subjects in the first two years but it was subsequently resolved.

The physicians were surveyed in the seventh year to see if they could guess which group the subjects were in. From 229 attempts, they got the control group right 49% of the time and the seed oil group 54% of the time, which is indistinguishable from a coin flip. So, the physicians were well blinded.

While the subjects were living in the home, they ate on average 80% of their meals there.

Because many of the subjects had stopped living there before they died or the study terminated, the total number of meals eaten in the halls was 56% for the control group and 49% for the seed oil group.

Since roughly half of the usual diet was replaced by the seed oil diet in the seed oil group, and since the seed oil diet replaced two-thirds of the traditional fat with seed oils, this is best described as a highly effective randomization to replace one third of the total traditional fat the person ate with seed oils.

At each meal, they took one representative tray and saved it for analysis. Once a week they pooled together the saved trays, homogenized them, and performed chemical analysis of the nutrition. This allowed exquisite characterization of the nutritional content of the diets.

They had originally planned to weigh the food left over, but they found that the amount thrown out was trivial so they stopped doing this. When people asked for second helpings, they gave them foods that were low in fat. This helped preserve the rigor of the quantitative difference in fats between the two groups.

What the LA Vet Trial Found

In the graphs below, “experimental” or “EXP.” refers to the seed oil group.

This graph shows survival from fatal atherosclerotic events over the eight years of the study:

Because the graph shows survival, the line being higher means more people survived and is good.

There are fewer fatal atherosclerotic events in the seed oil group, but the difference is not statistically significant.

The difference begins emerging after the first year, gets wider over time, and spreads apart most in the last two years of the trial.

Statistical significance could be achieved by grouping together the incidence of all “hard endpoints” including definite heart attack, sudden death due to coronary heart disease, stroke, ruptured aneurysm, and amputation due to peripheral artery disease. This brought the p value down to 0.02.

They also achieved statistical significance for fatal atherosclerotic events by separating those between the ages of 54 and 65 from those older than 65.

The benefit was largely confined to the younger group:

Statistical significance is a completely arbitrary cutoff. The p value is best understood as a continuous variable that tells us the probability we would see a difference this large or larger produced by random chance alone. A p value of 0.02 means this probability is 2%.

If we take the finding that seed oils prevent heart disease in young people but not old people at face value, this suggests one of two things are true:

• You need to intervene with seed oils early enough in the course of disease to impact it.
  
  OR
  

• As people get older, everyone will become vulnerable to heart disease and seed oils can’t do anything about it. However, they can prevent someone from getting heart disease much younger than they otherwise would.

The other double-blind trial, the Minnesota Coronary Survey, shows that seed oils make heart disease worse, not better. We will cover that trial in the next article.

The incidence of fatal cancers was higher in the seed oil group:

Because this graph shows the incidence of fatal cancer, the line going up further means more people died of cancer and is bad.

The difference didn’t even start to emerge until year two and really took off in years 5-8. It just barely missed statistical significance at p=0.06. This means the chance of observing a difference this large or larger if seed oils don’t really raise the risk of cancer is 6%.

While there were more deaths from atherosclerosis than from cancer (70 in the control group and 48 in the seed oil group), the relative difference was almost twice as large for cancer deaths: 31 in the seed oil group and 17 in the control group. That’s 46% more atherosclerotic death in the control group but 82% more cancer deaths in the seed oil group.

Taking both findings at face value, seed oils saved 22 people from dying of atherosclerosis but killed 14 people with cancer.

Critics point out that people in the seed oil group who died of cancer had lower adherence than others, but “adherence” was defined as meals eaten, and cancer decreases appetite.

Examining adherence is also an observational study nested inside the trial and leaves the realm of strong causal inferences made from randomization because people weren’t randomized to adhere more or less strongly.

The greater cancer deaths in the seed oil group is especially remarkable because randomization failed to distribute smokers evenly. The control group had twice as many heavy smokers and 60% more moderate smokers!

In fact, the excess atherosclerotic death was found exclusively among those in the control diet smoking more than ten cigarettes per day:

Smoking raises the need for vitamin E, and the control diet was remarkably deficient in vitamin E.

The only clear role of vitamin E in the body is to protect delicate polyunsaturated fats (PUFA) in our cell membranes from being damaged by metabolism or from toxic exposures such as cigarette smoke. It is best evaluated by its ratio to the PUFA it is protecting.

Seed oils have much more PUFA than other fats, so have more vitamin E. However, since the seeds that seed oils come from are not metabolically active, the vitamin E does not have to work very hard. Once these fats accumulate in human tissues, the vitamin E gets used up faster due to the damaging byproducts of human metabolism.

The control diet had barely more than a third of what is found in run-of-the-mill commercial butter and far less than what is found in grass-fed butter, while the seed oil diet was just below the optimal ratio of 0.6 milligrams alpha-tocopherol per gram of PUFA.

Smoking raises the requirement for vitamin E, so the excess of atherosclerosis is best attributed to an interaction between cigarette smoking and vitamin E deficiency.

These should have also biased toward greater cancer, yet the fatal cancer was almost doubled in the seed oil group.

There was no difference at all in total mortality:

However, it seems like the total survival might be starting to diverge after the eighth year, with a higher death rate in the seed oil group emerging.

The beginnings of divergence after the 8-year mark represents a three-month period during which everyone was on the control diet while undergoing final examinations. If this is a real divergence, it is likely a result of 6-8 years of seed oil consumption increasing tissue PUFA content and thereby increasing the vitamin E requirement, while the vitamin E intake was suddenly dropped to the deficient level of the control diet.

However, the excess of non-atherosclerotic death starts diverging in year 7, not after the trial was done:

The reason this doesn’t show up in the total survival graph is because the seed oil group’s advantage for atherosclerotic death is increasing at the same time. Thus, one for one, every person that the seed oil diet saved from an atherosclerotic death was balanced by someone who died of something else.

The most rigorous causal inference from the randomization is that seed oils decreased death from atherosclerosis, increased death from cancer, and had no impact on total mortality.

However, other important observations include that the difference in fatal cancer and non-atherosclerotic death takes years to show up and gets worse as time goes on, and that the putative beneficial effect on heart disease is probably a mirage created by the interaction between smoking and vitamin E deficiency.

The interaction between smoking and vitamin E deficiency should have biased the trial toward worse outcomes in the control group. That total mortality simply broke even suggests the PUFA load in the seed oil group killed people to the same extent as smoking and vitamin E deficiency killed people in the control group.

While not fatal, the seed oil diet also caused a 2.4-fold increase in the the risk of gallstones.

The height of bias would be to reject the cancer finding and accept the heart disease finding at face value.

The level of bias required to do this is extraordinary, for the following reasons:

• First, statistical significance was only found for atherosclerotic death by p-hacking and data mining, either by grouping “hard endpoints” that weren’t fatal with actual fatalities or by subgrouping the atherosclerosis fatalities by age. The non-hacked p value for atherosclerosis fatalities was 0.26, 4.3-fold worse than the non-hacked p value for cancer. The effect size for cancer is almost twice as big.

• Second, the increase in non-atherosclerotic death is, while not straightforwardly “statistically significant,” every bit as statistically powerful as needed to completely abolish any benefit toward atherosclerotic death.

• If the total mortality is identical, you cannot rationally claim a net benefit.

One of the major conclusions of the authors was that they had shown that these trials need to be even longer than eight years, not shorter:

This small excess of nonatherosclerotic mortality in the late years of the study raises the very important and difficult question of whether future clinical trials of diets rich in unsaturated fat must be planned for periods well in excess of eight years rather than for the five-year periods that have been the usual goal.

They considered it “unresolved” whether seed oils have “toxicity” and took the lack of an effect on total mortality to leave their usefulness for heart disease prevention a question without a definitive answer:

Total longevity was not affected favorably in any measurable or significant degree. . . . For this reason, and because of the unresolved question concerning toxicity, we consider our own trial, with or without the support of other published data, to have fallen short of providing a definitive and final answer concerning dietary prevention of heart disease.

Was the LA Veterans Administration Hospital Study Confounded by Trans Fats?

According to the authors, what they were testing was “a replacement of the saturated animal fats and hydrogenated shortenings of the conventional diet by equal quantities of unsaturated fat in the form of vegetable oils in the experimental diet.”

Taken at face value, this suggests the trans fats would be higher in the control diet due to the hydrogenated shortening.

However, there was a margarine used in the seed oil diet that may have increased trans fat consumption in this group.

The following quote from the primary 1969 paper shows the authors themselves considered both diets to be low in trans fats:

We did not analyze our diets or tissue lipids for trans fatty acids. Presumably both diets contained some trans fatty acids from partially hydrogenated fats, but such fats were only minor components of both diets. Therefore, the cholesterol-elevating⁵⁹ and triglyceride-elevating⁶⁰ effects of unnatural fatty acids cannot have been an important factor in this trial.

But is there more to the story?

As they detailed in a 1962 paper, approximately 32 grams of fat per day in the seed oil diet — 28.5% of the total fat — came from an “unsaturated margarine.” 75% of this was used as a table spread, while the rest was used to bake deserts or cook potatoes.

This margarine is the putative source of trans fats in the seed oil group.

But did it contain trans fats?

If it did, how much?

Was it enough to exceed the partially hydrogenated shortening that was explicitly used in the control group?

Let’s dig in.

What Was the “Margarine Based on Unhydrogenated Corn Oil”?

They reported about this table spread that “during the major part of this study, a margarine based on unhydrogenated corn oil has been used.”

According to the footnotes, “this term is used to describe a margarine in which the major component is unaltered vegetable oil, with a small amount of hydrogenated fat added as a hardening agent” and in “the major part” of the study up through at least 1962 the margarine used was Mazola by Corn Products Company.

The funding and gifts statement includes both Mazola Margarine provided by Corn Products Company and Emdee Margarine donated by the Pitman-Moore Company.

Corn Products Company had recently been formed by a merger between the Corn Products Refining Company and Best Foods, while Pitman-Moore was a pharmaceutical company that was a division of Allied Labs, which became part of Dow Chemical in 1961.

The authors wrote two 1962 papers, one on diet and one on “preliminary observations.” They also published a study on the vitamin E status of subjects in the trial in 1965. All three of these papers as well as the primary paper from 1969 refer to both of these margarines, but none of them clarify how much of each was used, whether they were used at the same time, or whether they transitioned from one to the other and when.

We will try to cut at this from several angles later, but first we look at how much trans fat we can expect to be in each of these margarines.

Emdee Margarine Was Free of Trans Fats

It is easiest to show that Emdee margarine did NOT contain any meaningful trans fats, so we start with Emdee.

According to an early advertisement in the Archives of Internal Medicine, the patent-pending margarine was produced by a “special process” that does “not alter the natural characteristics of corn oil.” It consisted of 80% “nonhydrogenated corn oil which has been specially processed to preserve its original content of unsaturated fatty acids” and was fortified with vitamins A and D. It was sold over-the-counter, but was only available in pharmacies. It was marketed as an “effective substitute for animal fats and hydrogenated vegetable oils.”

According to a documents from a patent lawsuit that mentioned Emdee’s composition by way of evaluating a dispute between Mazola and Fleichman’s, the other 20% of Emdee was “fully hydrogenated coconut oil.” This matches the listing of “hardened coconut oil” in the ingredients list of the last ad picture above.

Emdee was associated with US Patent 2,890,959, granted to Robert A Phillips and assigned to Allied Laboratories.

This Emdee can being sold on eBay explicitly references this patent:

Emdee ads started referencing the patent as soon as it was granted in 1959.

The patent itself does not explicitly require full hydrogenation, but it does require melting points so high that they can only be achieved with full hydrogenation, so it effectively requires full hydrogenation of the coconut oil.

While the patent prefers coconut oil, it does not require it. It explicitly gives the example of using fully hydrogenated soybean oil as an alternative and states that any other vegetable oil with a melting point in the correct range could be used.

Fully hydrogenated oil by definition contains no trans fats, because all of the unsaturated fats are converted to saturated fats. It is only partially hydrogenated oil that contains trans fats.

Clearly, the Emdee margarine used in the LA Vet trial was free of any meaningful trans fat.

There is one piece of major uncertainty here: while there is no evidence that coconut oil was ever removed from their ingredients, there is also no evidence that its use persisted past 1962. The ad showing the can with the ingredients cannot be found after 1958. No date can be safely attributed to the can above being sold on eBay, which shows coconut oil in the ingredients. The materials in the Mazola/Fleichman’s suit were submitted in 1962, despite being referenced in the final appeal decision in 1965.

The reason this is important is that coconut oil contains a highly unique fatty acid, lauric acid, that is not found in many other foods and is largely limited to coconut and tropical foods highly related to coconut. This can act as a “fingerprint” of Emdee consumption in the LA Vet trial, but until and unless evidence for the Emdee ingredients between 1963 and 1968 show up we cannot assume the fingerprint will work after 1962.

Mazola Margarine Was Consistently Marketed as Unhydrogenated

Now let’s tackle the slightly less straightforward question of whether Mazola margarine had trans fat.

Mazola consistently emphasized that lack of hydrogenation was one of the major virtues of its margarine. Listen to the woman in this 1961 Mazola Margarine TV commercial explain it:

“I used to buy a corn oil margarine which I thought gave me the same benefits as Mazola, but at a recent food demonstration I learned that the ordinary corn oil margarine I had put such faith in is hydrogenated. So most of its natural liquid corn oil nutrition is lost! But the corn oil in Mazola margarine is never hydrogenated, so you get the full nutritional benefit of Mazola’s liquid corn oil.”

Or take it from the man in this earlier 1960 TV commercial:

“Mazola Margarine — because its major ingredient, pure corn oil, has less saturated fat than the hydrogenated corn oils used in other leading margarines. Less saturated fat because its corn oil is never hydrogenated.”

In a 1960 ad in the Journal of the Medical Society of New Jersey, they had bolded “non-hydrogenated” and used all-caps to say again that its corn oil was “NOT hydrogenated.” This version was also repeated in 1960 issues of the Rhode Island Medical Journal, the Bulletin of the New York Academy of Medicine, and the Illinois Medical Journal; and in 1961 issues of the Journal of the American Osteopathic Association, Industrial Medicine and Surgery, Geriatrics, The Modern Hospital, and Hospital Management.

They used italics to emphasize that the corn oil is never hydrogenated in 1962 issues of Time, the New Yorker, Good Housekeeping, and Ladies’ Home Journal; and in 1963 issues of Better Homes and Gardens, American Home, and Ladies Home Journal.

A 1963 ad in an Ohio newspaper and a California newspaper used italics to emphasize that the “major ingredient” in Mazola margarine is never hydrogenated, and even offered a raffle to win $20,000 that required the person to use their knowledge from the first page to complete this sentence on the second page: “The corn oil in Mazola Margarine has ________ ________ ________ than the hydrogenated oil most other margarines use.”

A brief “History of the Corn Products Company” in a 1961 issue of the Journal of the American Oil Chemists Society says that “Mazola margarine” was “developed in response to demands for new foods containing unhydrogenated corn oil, as a source of the linoleic acid now known to be so important in human nutrition.”

Despite Its Marketing, Mazola Was Made with Partially Hydrogenated Seed Oils

According to a 1961 article about the upcoming “Cholesterol War on TV” in the programming magazine Sponsor, the composition of Mazola margarine was as follows:

This Corn Products spread is 47% corn oil and 53% combination cotton seed and soybean oil. The latter two are hydrogenated until they form irregular walls inside which the liquid corn oil is trapped.

This echoes an earlier 1960 blurb in the journal Food Processing:

Seeming paradox of a firm liquid-oil-containing product is result of revolutionary process whereby a matrix of partially hydrogenated oils holds sub-microscopic droplets of liquid Mazola Corn Oil, much as a honeycomb holds liquid honey.

A holder of the patent connected to Mazola Margarine, Daniel Melnick, published a paper in 1964 that described how it is made. While he didn’t name it as Mazola, he directly tied it to the Mazola patent and his description about the “major ingredient” strongly echoes the marketing of Mazola:

The first, hereafter called blended corn oil margarine fat (BCOMF) is a liquid oil margarine (27) made with non-hydrogenated corn oil as its major ingredient; other components of the blend are a lightly hydrogenated cottonseed oil and a partially hydrogenated soybean oil. The corn oil in this product provides about 90% of the total linoleic acid; the remaining 10% is contributed by lightly hydrogenated cottonseed oil.

The Main Mazola Patent Implies It Has Trans Fats

The main patent that we know is tied to Mazola Margarine, the one Melnick cited, is consistent with all of the above evidence that it contained trans fats.

A 1961 article in Advertising Age gives important background to what we know about the main patent.

Mazola Margarine was originally branded as Cornette in 1959 when it was tested on six markets but then released to the broad market in late 1960 as Mazola.

Fleichman’s beat them to the punch with a corn oil-based margarine, which they released several months before Corn Products started testing Cornette. By 1961, Fleichman’s had double the market share as Mazola.

Fleichman’s made the claim to be 100% corn oil, but all of its corn oil was partially hydrogenated, making it lower in natural polyunsaturated fatty acids.

Mazola made the claim that their corn oil was pure and unaltered, making it higher in these fatty acids.

Fleichman’s second product, however, was just as high in polyunsaturates as Mazola. Hence Mazola had lost their differentiator.

The dilemma at Corn Products is: How can they reach the consumer with the message that Mazola is a superior product, from the polyunsaturate point of view, to the salted Fleichman’s brand?

By 1962, the answer had become clear: sue them for patent infringement.

The lawsuit claimed that both Mazola Margarine and a new reformulation of the older Nucoa Margarine, also made by Corn Products, were covered by the Melnick and Luckmann Patent, No. 2,955,039, which was filed in February of 1959 and granted in October of 1960. The Fleichman’s Regular and Fleichman’s Unsalted margarines were claimed to infringe the patent.

Mazola Margarine ads began in October of 1960 emphasizing this patent:

That ad is from the October 11, 1960 Stamford, CT newspaper the Stamford Advocate.

Ads bearing the patent were repeated throughout 1961, including in a full-page ad in the Time magazine issue that featured Ancel Keys on the cover, in issues of McCall’s, the Saturday Evening Post and in a bulk mailer, and in at least 50 newspaper ads.

Mazola advertisements after 1961 never reference this patent, most likely because the litigation started with pretrial conferences in January of 1962.

The patent infringement claim was ultimately rejected by an appeals court in 1965 on the basis that the technology wasn’t actually novel and that the claims were far too broad.

Good Luck margarine had used a blend of liquid and hydrogenated oil from 1937-1942, and Emdee had made a margarine based on unhydrogenated corn oil in 1958, prior to both Fleichman’s and Cornette in 1959 and Mazola in 1960.

The court ruled that it was clear that Emdee was “the spark” that drove the subsequent development of both Fleichman’s and Mazola.

While the patent was ruled invalid, the patent itself still tells us how the margarine was made and how Melnick, Luckmann, and Corn Products Company viewed the importance of the technology they used.

According to the patent, the novelty of the covered margarine was that it was high in essential fatty acids and had a high ratio of essential fatty acids to saturated fatty acids.

It doesn’t mention anything about trans fats.

The process described involves using 30-70% unhydrogenated liquid oil with the remainder a hydrogenated oil. The hydrogenation used settings that would cause it to yield “substantially complete” hydrogenation of linoleic acid and “selectivity” that would bias it to hydrogenate polyunsaturated fats like linoleic acid rather than monounsaturated fats like oleic acid.

The fact that the linoleic acid was expected to completely convert to saturated fatty acids while the oleic acid was not suggests that the oil would be particularly high in elaidic acid, the trans isomer of oleic acid.

The hydrogenation described is indeed partial hydrogenation, which generates trans fats, consistent with early descriptions in the press and Melnick’s description in the science literature.

Mazola Ingredient Labels of the Era Consistently List “Partially Hardened” Oils

Mazola ads almost never show the ingredients and never show the ingredients clearly. Usually, the Mazola box appears as stylized art that readjusts the logo to occupy the space where the ingredients would be so they could be removed without showing any dead space.

Nevertheless, with a little craftiness we can get our hands on clear ingredients lists from that era.

This is the label of the original 1960 release printed in the journal Modern Packaging:

The second ingredient is “partially hardened soybean and cottonseed oils.”

This Instagram post shows this image, bearing the exact same ingredients list, from a set of grocery store posters from 1964. The account holder messaged me a picture of the box the posters came in, which reads “Brand Names Week May 21-31, 1964 Display Ads.”

This is almost certainly the actual box in circulation in 1964. The original 1960 box showed the corn cob facing up-and-to-the-left, not straight-up. The up-and-to-the-left position persists through 1963, but the straight-up position is found at least as early as 1965.

However, beginning in 1965, the Mazola margarine box read “New! See the Difference! Visibly Better! Definitely More Delicious” when it was “now made by a special process so that it doesn’t burn, blacken, or smoke at normal frying temperatures.”

The package remained like this through 1967.

Thus, 1964 is the only year where the corn cob could have been turned straight up before the new formula was announced on the box.

Jason Liebig (Instagram, LinkedIn) the lead storyteller for the History Channel’s “The Food That Built America,” “The Mega-Brands That Built America” and “Hazardous History with Henry Winkler,” is a collector of vintage brand memorabilia and sent me this image of a 1966 Mazola carton:

The ingredients are identical, except that instead of just using isopropyl citrate to protect the flavor, they had then started using calcium disodium EDTA to protect the flavor as well.

The use of isopropyl citrate and EDTA together to protect the flavor was submitted as a Corn Products Company/Daniel Melnick patent in 1959 and granted in 1961 as US Patent 2,983,615.

An eBay seller claims this is a 1960s-era box:

This is, however, most likely a 1970s-era box.

When I asked for a more precise year, the seller told me they had no idea except that it was from before the advent of bar codes. But the first bar code was scanned on June 26, 1974, so the absence of a bar code does not necessarily isolate it to the 60s.

The corporate office of Best Foods is listed on this box as Englewood Cliffs, NJ, whereas the earlier boxes all list it in New York, NY. An article from Long Beach, CA’s Press Telegram from November 6, 1968 refers to an open house for the new corporate office in Englewood Cliffs. This dates the box to late 1968 at earliest.

I cannot find the phrase “contains golden corn oil” in Mazola Margarine ads prior to 1973.

Another differentiator of this box from earlier ones is that it has a picture that zooms in to show a section of the corn rather than the whole cob and there is a stick of margarine sliced into pats with one of the pats melting on the corn.

Yet another is that the box is a rectangle instead of a square.

All of this imagery can be found in the 1970s-era “We Call It Maize” television campaign.

According to the November 5, 1979 issue of the Oakland Tribune, the New Mexican Apache Tenaya Torres struck a deal for this series in 1976.

All of the boxes in all of these commercials have the sliced margarine stick with one pat melting on the zoomed-in section of corn, and all have the “contains golden corn oil” droplet. I cannot find the rectangular box in any extant videos, but this Facebook post has images of Torres using a rectangular one in some of the ads.

Thus, this box almost certainly comes from the 1970s, not the 1960s.

And yet, its ingredients are exactly the same as they were in 1966, which were the same as from 1960-1965 with the sole exception of added EDTA.

This confirms that throughout the entire LA Veterans Administration Hospital Study, Mazola Margarine listed “partially hardened soybean and cottonseed oils” as its second ingredient.

While “partially hardened” is not a chemically specific term and would no longer be allowed on ingredient labels, FDA guidance at the time was wishy washy. In 1971 FDA increased the specificity required on labels above the regime that had prevailed since 1940 by making the industry be specific about what oil was used and always expressing some type of processing word for hydrogenated oils rather than simply calling them “shortening.” Nevertheless, it stated that the choice between “hydrogenated,” “partially hydrogenated” and “hardened” could be made based on whatever was “factual and desirable” without defining those qualities in any way.

“Partially hardened” should be interpreted in the light of the evidence from the patent, early press, and scientific literature, combined with common sense, to mean “partially hydrogenated.” This suggests that Mazola margarine contained trans fats throughout the entire length of the LA Vet trial.

How Misleading Was the Mazola Advertising?

All of the Mazola marketing focuses on the positive characteristic of having natural polyunsaturated fatty acids rather than the absence of the negative characteristic of having trans fats. It consistently prides itself on being higher in “polyunsaturates” or “linoleates,” and having a high ratio of these to saturated fat.

This can be seen visually in the early television ads, where the cups of corn oil are shown disappearing as the hydrogenation is said to deplete their nutrition.

The 1961 history of the company said the demand for unhydrogenated oil was due to its richness in “the linoleic acid now know to be so important to human nutrition.”

In its late 1960s marketing, it starts comparing itself to protein and vitamins. The “plus” of lobster or steak is “protein,” orange juice’s is “vitamin C,” and that of carrots is “vitamin A,” while Mazola’s “plus” is “polyunsaturates.”

The Mazola brand was so obsessed with increasing intake of polyunsaturated fat that it tried turning “polyunsaturating” into a sexy verb.

1969:

1969:

1970:

They even implied Ringo would be polyunsaturating Beatles tunes in the family den:

It was the embarrassing thing you catch your husband doing with himself in the middle of the night:

What you do with your girlfriends on girls’ nights:

And what you vow to the man you love and honor:

This can explain how Mazola must have internally justified its quiet sleight of hand, where it constantly emphasized the fact that its corn oil or its major ingredient was non-hydrogenated, never even mentioning in the ad copy that it had cottonseed and soybean oil that was hydrogenated, and never showing the ingredients list that bore the incriminating evidence in those ads.

If the whole point was, in the Mazola view, that hydrogenation destroys the “plus” of the natural polyunsaturates, then there’s nothing particularly misleading about this.

Once we become concerned about the “minus” of trans fats, however, this suddenly becomes deeply misleading.

Mazola Patented A Trans Fat-Free Margarine in 1960 But Never Used It

While Mazola as a brand was exclusively interested in getting more polyunsaturated fatty acids into people’s diets, their oil chemist product developers were indeed interested in reducing people’s intakes of trans fats.

Daniel Melnick and Chester Gooding filed a Corn Products Company patent on June 19, 1957 (granted Jan 19, 1960) aimed at using interesterification to produce a margarine with “relatively low trans fatty acid content.”

Interesterification rearranges the three fatty acids on the glycerol backbone of a triglyceride to make them pack together better or give them some other desirable property.

“Hydrogenated fats,” they wrote, “have been subject to frequent criticism in both the scientific and lay press since there is a decrease in essential fatty acid content and a development of isomers of fatty acids, e.g. trans oleic acid, as a result of hydrogenation of oil.”

The specific goal was to get trans fat down below 10%.

The account Melnick submitted to the court in the Mazola/Fleichman’s patent suit was that this patent was never commercialized because it wasn’t “successful,” which presumably means it didn’t produce a margarine that they thought would sell well.

Melnick told the court that his “three prongs” were “reduce saturates, eliminate all isomers of fatty acids, and increase the polyunsaturates.”

“Eliminate all isomers” means to produce a margarine that had zero trans fats.

Chester Gooding filed a second Corn Products Company patent later that year in August of 1960 (granted in mid-1963) with the explicit rationale to replace partially hydrogenated margarines and shortenings with healthier versions that are rich in essential fatty acids and have no trans fats.

This “invention” was a “novel fat” that could be used to produce “margarines and shortenings” that are “characterized by having a high essential fatty acid content” and have “the physical characteristics of fats prepared by partial hydrogenation but which, unlike the latter, contain no partially hydrogenated fats and therefore no glycerides containing isomers of natural unsaturated fatty acids.”

The rationale from the Melnick-Gooding patent was repeated: “Hydrogenated fats . . . have been subject to frequent criticism in both the scientific and lay press since there is a decrease in essential fatty acid content and a development of isomers of fatty acids, e.g., trans oleic acid, as a result of hydrogenation of the vegetable oil.”

The patent covers eight blends. Seven of them use 60, 70, or 80% cottonseed stearine, which is a largely saturated product derived from the refining of cottonseed oil. Blend eight is the exception, and is over 74% corn oil.

The remainder was one of eight different mixtures of fully hydrogenated “interesterified base fat” that could be mixed and matched with the main blend.

The various base fat combinations were made from coconut and cottonseed, palm kernel (very similar to coconut oil) alone, coconut and palm kernel, palm kernel and cottonseed, or coconut and soybean.

Blend 8 using 74% corn oil with the fully hydrogenated and interesterified coconut oil and/or palm kernel oil base fat would have produced a margarine that would be both remarkably similar in its composition to Emdee and consistent with the Mazola marketing that the major ingredient is liquid golden pure unhydrogenated Mazola corn oil, yet would be free of trans fats.

Nevertheless, this patent seems to have languished unused.

No reference to it occurs in the scientific literature until one paper in 1974 and two papers in the 1990s reference it purely to note that it is possible to produce a trans fat-free margarine and that methods to do so have already been patented.

The one time we know they changed their formula, they acted on a five-year-old patent, listed the change in the ingredients list, and introduced it with fanfare on the box label. The absence of any of this for a margarine free of trans fats strongly supports that they never acted on the Gooding patent.

Despite Gooding and Melnick being aware of “frequent criticism in both the scientific and lay press,” public awareness and interest in trans fats was subdued until the mid-1990s. The overwhelming push during the 1960s was to increase intake of PUFA and decrease intake of saturated fat to lower plasma cholesterol levels, and this was where Mazola staked their brand reputation.

Direct Analysis of Mazola Margarine

A 1962 study analyzed seven commercially available margarines. Their seventh was 20.8% linoleic acid and 50.2% trans fat. Since partial hydrogenation destroys linoleic acid and creates trans fat, and since most margarines at the time were low in linoleic acid and high in trans fat, the high linoleic acid content made them speculate that it was based on US Patent 2,983,615. This is the Melnick/Luckmann patent tied to Mazola and Nucoa. This margarine was 50% trans fat.

Daniel Melnick, named on US Patent 2,983,615, co-authored a 1964 paper analyzing a margarine that they directly stated was based on this patent. They strongly echoed the Mazola margarine advertising by saying it was made with “non-hydrogenated corn oil as its major ingredient.” The “other components of the blend,” they wrote, were “lightly hydrogenated cottonseed oil and a partially hydrogenated soybean oil.” This matches the marketing, ingredients, and descriptions of Mazola margarine and it was 25% trans fat.

These two groups used the same methodology to measure trans fats but the first margarine had double the trans fat content of the second, so it is very unlikely these are the same margarine.

The first paper probably refers to Nucoa. It was published in June of 1962, so probably submitted a few months earlier. This was after the 1961 Mazola ads explicitly tying US Patent 2,983,615 to Mazola, but before anything about the 1962 patent suit was made public that would have tied Nucoa to the patent. This would explain why they would use speculative language even though they knew what they bought in the grocery store: Nucoa was made by Corn Products Company and plausibly made according to the Corn Products patent, but wasn’t known to be tied to the patent yet the way Mazola was.

Thus, our best estimate is that Melnick measured Mazola margarine in 1964 as being 25% trans fat.

Which Margarine Was Used In Most of the Trial? Emdee or Mazola?

The LA Vet Trial investigators acknowledged using both Emdee and Mazola margarines in at least four of their papers, none of which explicitly state how much of each was used and whether they transitioned at any point to choosing one or the other.

This is critical, because Emdee Margarine did not have trans fats and Mazola Margarine did.

As such, this question makes or breaks the case of whether trans fats were in the diet of the seed oil group.

We now look at several forms of evidence: textual evidence, historical availability, dietary analysis, and biomarkers.

What the Trial Investigators Actually Said

We start first with the LA Vet trial authors comment that trans fats were “minor components of both diets.”

We then turn to their statements about the use of Mazola rather than Emdee “during the major part of the study” up through 1962.

What Does Trans Fats Being “Minor Components” Mean?

The following quote from the primary 1969 paper shows the authors themselves considered both diets to be low in trans fats:

We did not analyze our diets or tissue lipids for trans fatty acids. Presumably both diets contained some trans fatty acids from partially hydrogenated fats, but such fats were only minor components of both diets. Therefore, the cholesterol-elevating⁵⁹ and triglyceride-elevating⁶⁰ effects of unnatural fatty acids cannot have been an important factor in this trial.

What is a reasonable definition of “minor” here?

Since the next sentence situates this statement with respect to whether trans fats could have had impacts on the trial participants discussed in references 59 and 60, our minimum definition of “minor” has to be “well below what increased cholesterol and triglycerides in those studies.”

Reference 60 is an abstract of an experiment where 1.6-3.9-fold increases in plasma triglycerides were produced by feeding five people diets that were 20-40% of total calories as trans fats. As such, it is not useful for drawing a lower bound beneath which we could consider something “minor.”

On the other hand, reference 59 is very useful for this purpose.

This is a 1961 paper by Ancel Keys and colleagues reporting three controlled experiments, each using 23-27 institutionalized psychotic men, showing the impact of trans fats on serum cholesterol. These experiments used either 30 grams or 100 grams per day of partially hydrogenated oil and compared them to the same amount of the same oil in its natural form, or compared them to blends of other fats and oils that were richer in monounsaturated or saturated fats.

The partially hydrogenated oils were 33-37% trans fat, so the lower bound is 9.9 grams of trans fat per day and the upper bound is 37 grams of trans fat per day.

30 grams of partially hydrogenated safflower oil containing between 9.9 and 11.1 grams of trans fat per day increased serum cholesterol by 10 mg/dL compared to unhydrogenated safflower oil, but this was similar to what would have been predicted by the increased saturated fat in the partially hydrogenated oil. This made it impossible to attribute a specific rise to the trans fats.

By contrast, 100 grams of partially hydrogenated safflower or corn oil providing 33-37 grams per day of trans fats raised serum cholesterol by 25 mg/dL, and this was unambiguously more than what could be attributed to their saturated fat.

These experiments led to the preliminary conclusion that each increase of 1% of total calories in the diet from saturated fats with 12-18 carbons (later revised to exclude the 18-carbon stearic acid) predicts an increase of 2.68 mg/dL serum cholesterol, whereas the same increase in trans monounsaturated fat would predict a rise of 2.1 mg/dL.

The 30 grams of partially hydrogenated safflower oil provided trans fat at 2.7-3% of calories, which the prediction equation derived from the second experiment suggests should have caused a 5.7-6.4-mg/dL rise in serum cholesterol.

This indicates that the trans fats were not failing to increase the serum cholesterol in the first experiment. Rather, the fact that the partially hydrogenated oil had similar amounts of saturated and trans fats made it hard to mathematically tease their impact apart.

“Minor” could mean many things to many people, but here it is meant to dismiss a potential confounder, so it means “we can ignore this because its impact, if any, would be trivial.”

In the context of a randomized controlled trial, it also means “we can assume this was sufficiently distributed across the two groups that it could not have created a meaningful inaccuracy in the estimation of the difference in outcomes between the two groups.”

To satisfy the first definition, the trans fats should have been under 1% of total calories. It is below this point that it would be difficult to detect any impact even under very rigorously controlled conditions. In the LA Vet trial, where the average energy intake was 2496 Calories per day, this would amount to 2.8 grams of trans fat per day.

However, I could see them rationalizing the sloppier definition of less than 30 grams per day of partially hydrogenated oil or less than 10 grams per day of trans fat because this is the lower dose fed in the Keys paper that on the surface was claimed to not show an impact.

In the context of the caloric intake in the LA Vet trial, according to the Keys paper, 10 grams of trans fat per day would translate to a 7.6-mg/dL difference in cholesterol levels. This could only be considered “minor” if it was thought to be spread equally across the two groups.

The average difference in serum cholesterol between the two groups in the LA Vet trial was 29.5 mg/dL. A 7.6-mg/dL theoretical difference is 26% of the actual difference, which is not a “minor” portion of it.

On the other hand, if a 7.6-mg/dL increase was distributed into both groups evenly, to one through shortening and to the other through margarine, I could see them saying that it didn’t matter because the seed oils still created a 29.5-mg/dL difference between groups.

In other words, the confounder would blend into the sameness of the two groups, and the difference that rises above this sameness is what is important.

Therefore, I could see two possible definitions of “minor” here:

• Trans fats were less than 2.8 grams per day in both groups, in which case the difference between the two groups doesn’t matter.

• Trans fats are close to 10 grams per day, but they are evenly distributed between the two groups.

What Does Using Mazola “During The Major Part of the Study” Up Through 1962 Really Mean?

At least four papers from the LA Vet trial reference the use of both Emdee and Mazola margarines.

The only statement indicating the dominance of Mazola is from the 1962 diet paper:

During the major part of this study, a margarine⁷ based on unhydrogenated corn oil has been used.

Footnote 7 then says “Mazola Margarine, Corn Products Company.”

“The major part” implies that Emdee was used in “the minor part.”

However, papers published in the mid-1960s and 1969 simply list both margarines without making any reference to one being more dominant than the other.

The 1962 paper does not tell us whether they started with Emdee and switched to Mazola rather early on or started with Mazola and switched to Emdee rather recently.

By the time the trial was complete, whatever they used from 1963 onward was “the major part” and whatever was “major” in 1962 could have been rendered irrelevant.

The Historical Availability of Mazola and Emdee Margarines

Recruitment for the LA Vet trial began in the summer of 1959, and the first man was assigned to a diet in September of 1959. Everyone was switched onto the control diet eight years later in September of 1967 during a 3-month final observation period.

Thus, the seed oil diet had a margarine demand from September of 1959 to September of 1967.

Emdee was available at least as early as April of 1958.

Emdee almost immediately was used for scientific research. A major early study they boasted about in their advertising was published in the May 16, 1959 edition of JAMA. Emdee was fed to 300 institutionalized psychotics for five months, during which it reduced plasma cholesterol by 23% from an average of 250 mg/dL to 193 mg/dL.

Ads for Emdee continued running in newspapers through late 1968, as shown by this drug store ad from the November 18, 1968 edition of the New Orleans-based The Times-Picayune:

Emdee Margarine completely disappears from newspaper ads after November of 1968. It lingers into the 1970s in catalogs of drugs, manufacturers, and trade names, and it makes its way into a 1990 book about companies and their brands and a 2013 book and its 2021 edition about the politics of nutrition. There is no evidence it was ever sold after November of 1968.

Mazola was released into six markets as “Cornette Margarine” in 1959. The first newspaper ad I can find for this margarine is in the October 13, 1959 issue of The Times Record (Brunswick, Maine).

Cornette had its name changed to Mazola as it was released into the broad market in September of 1960.

Mazola was available throughout the rest of the trial period and is still available today.

In 1970, the year after the LA Vet trial had its main paper published, Daniel Melnick, who was named on the main Mazola Margarine patent, co-wrote an article titled Dynamic utilization of recent nutritional findings: Diet and cardiovascular disease that takes a dig at Emdee:

The first so-called “liquid oil” margarine on the market⁸ was a blend of corn oil with hydrogenated coconut oil. This was a soft, shortening-like product packaged in a tin can for sale in drugstores. Although rich in polyunsaturated fatty acids, it lacked the form, texture, and other sensory characteristics of margarine and, in addition, contained an undesirably high level of the saturated fatty acids from hydrogenated coconut oil.

The next sentence references Mazola:

The first margarine in stick form having a relatively high polyunsaturated and low saturated fatty acid content was introduced in 1959.⁹ Other brands soon became available, giving the consumer considerable choice among products meeting the criteria of the American Medical Association.

The paper has a long accounting of the LA Vet trial itself. It does cover their use of margarine, but doesn’t take the opportunity to tie it to Emdee or Mazola.

While Melnick could be taken to imply that Emdee went out of business because consumers didn’t like it, a more plausible reason is found in the writings of Myra Waldo, a food writer of the era.

Waldo was an early advocate of these margarines. Her cake recipes appeared in the March 12, 1959 New York Post and the March 18, 1959 Dallas Morning News using exclusively Emdee margarine. Her 1961 cookbook, Cooking for Your Heart Health, however, had abandoned Emdee in favor of Mazola because Emdee was “much more expensive and available only in drug stores.”

Since Emdee was available before Mazola, this should lean us toward Emdee being used during the first year until Mazola became available in late 1960.

Analysis of the LA Vet Trial Diets

As a blend of 80% corn oil and 20% fully hydrogenated coconut oil, values for these foods in the USDA database predict that Emdee should be 31% saturated, 24% monounsaturated, and 45% polyunsaturated.

The Mazola/Fleichman’s patent lawsuit materials include a reference to a direct chemical analysis that Melnick had done on Emdee showing it to be 28% saturated fat, a little lower than predicted from the USDA database.

Approximately half of the fully hydrogenated coconut oil should be lauric acid, a 12-carbon saturated fatty acid that is found almost exclusively in coconut and some closely related tropical fats. That should make Emdee 10% lauric acid.

Mazola advertised their margarine as being 19% saturated, 53% monounsaturated, and 28% polyunsaturated.

Based on the production method in the Mazola patent, nearly all of the trans fat should be monounsaturated, and according to Melnick’s analysis it is 25% of the total. Thus, the Mazola breakdown is more precisely 19% saturated, 25% trans fat, 28% natural monounsaturated, and 28% polyunsaturated.

Based on 32 grams of margarine being consumed per day:

• Emdee would provide 3.2 grams of lauric acid per day, while Mazola would provide none.

• Mazola would provide 8 grams of trans fat, while Emdee would provide none.

• Emdee would provide 9-10 grams of saturated fat per day, while Mazola would provide 6.

• Emdee would provide 14 grams of polyunsaturated fat per day, while Mazola would provide 9.

• Emdee would provide 8 grams of monounsaturated fats per day, while Mazola would provide 17 grams, but 47% of Mazola’s monos would be trans fat.

The trial investigators aimed to keep the “iodine value” of the diet constant. The iodine value is a measure of the number of fatty acid double bonds and is based on the ability of these double bonds to absorb iodine. If we calculate a simplified version of this as (monounsaturated fat x 1)+(polyunsaturated fat x 2), Emdee is 36 and Mazola is 35, nearly identical.

This means a change from one to the other would not necessitate a meaningful adjustment to the amount of margarine or to the amounts of other oils to maintain a constant iodine value, so should show up as a change in the fatty acid subtypes of the overall diet:

• If they changed from Emdee to Mazola, saturated fat should have gone down by 3-4 grams, polyunsaturated fat down by 5 grams, and monounsaturated fat up by 9 grams.

• If they changed from Mazola to Emdee, the reverse changes should have happened: saturated fat up 3-4 grams, polyunsaturated fat up 5 grams, and monounsaturated fat down 9 grams.

The LA Vet trial published these distributions of dietary fatty acids.

1962:

1964:

1965:

1966:

1969:

In no case where the 12:0 (lauric acid) is reported does it show up beyond a trace level, and a little blip is consistently shown in the control diet but not in the seed oil diet. There is thus no sign of coconut oil consumption in the seed oil group from 1962 through the end of the trial.

This would seem to rule out the use of Emdee after 1962.

It is uncertain that Emdee used coconut oil 1963-1968, but Emdee was definitely using coconut oil from 1959-1962, so it would seem from the 1962 papers that Emdee had already been cut loose.

Now, suppose also that Emdee did change their formula to use a different fully hydrogenated fat, or that Mazola acted on the Chester Gooding patent to make a margarine free of trans fat. Even if neither were marketing these fats publicly it is at least conceivable that they could have issued a special product for the trial. The resulting margarine would be relatively close to Emdee in its composition, so we would expect to see the same types of changes, just without any lauric acid.

A change toward this type of margarine would mostly show up as an increase of 18:0 and 18:2 at the expense of 18:1.

However, there is no indication that there is any sudden change or any drift in the fatty acid composition at all. This makes it incredibly unlikely that any kind of formula change was made after the publication of the 1962 diet paper.

This suggests that Emdee had been cut loose prior to 1962 and Mazola was used exclusively thereafter.

Biomarker Analysis

In 1962, the “preliminary observations” paper reported that lauric acid was 1% of subcutaneous fat prior to randomization; it dropped to “trace” in the control group after one year and to zero by the second year, but in the seed oil group it stayed at 1% after one year and didn’t drop to zero until the second year.

This suggests that the pre-study “regular” diets of the people contained small amounts of coconut, while the trial diets contained little or no coconut, but that something was sustaining the lauric acid content of the subjects in the seed oil group for the first year of the study that had stopped sustaining it by the second year.

Serum and adipose fatty acids were reported for each year up through year five in 1966, but lauric acid was not included.

In the 1969 main paper, lauric acid is described as “identified inconstantly” both at baseline and at the end of the trial in both groups.

The change from 1% to “identified inconstantly” in the baseline measurements likely reflects the expansion of tissue biopsies from 75 people to 240 people and may reflect the fact that prior to the study some people ate coconut and others didn’t.

The 1969 paper does not report an expanded selection of year-one biopsies and therefore never claims that that first-year reporting of 1% lauric acid in the subcutaneous fat of the seed oil group should be revised.

Nevertheless, the year-one biopsies were only reported for six people in each group in 1962 and therefore could have been strongly influenced by sampling error.

Still, they are consistent with a persistent presence of lauric acid in the seed oil diet but not the control diet for the first year of the study.

Together with the dietary analysis suggesting Emdee had been cut loose by 1962, this suggests that Emdee was the margarine of choice during the first year of the trial but was not used thereafter.

Together with the data on historical availability, this suggests that Emdee was used in the first year because it was the only margarine based on unhydrogenated corn oil on the market in September of 1959, while they switched to Mazola in September of 1960 when it became available.

As to why they made the switch, cost does not make sense because the margarine was provided as a gift.

Either they thought the Mazola Margarine had better sensory characteristics and was better for blinding the subjects, Mazola was simply better at supplying the volume they needed, or they did it because they valued their relationship with Mazola, who was also providing the liquid corn oil that constituted the top oil ingredient of the seed oil diet.

Which Group Had More Trans Fat? Seed Oil or Control?

Since the margarine in the seed oil group appears to have been 25% trans fat after Emdee was abandoned one year into the study, we can quantify the trans fat in the seed oil diet as zero during year one and as eight grams per day years two through eight.

So it was confounded?

Hold your horses.

They do not tell us how much partially hydrogenated shortening was used in the control group, but we need to estimate this before we can even speculate whether there was more trans fat in the seed oil group or the control group.

We now take two approaches:

• textual analysis: what makes sense given how the diets were described, and what comports with their definition of “minor”?

• biomarker analysis: what do the changes in serum cholesterol indicate could have been the “trans fat gap” between the two groups?

Taking a Look at the Diet

Here is a breakdown of the seed oil diet, where the “added vegetable oil” and “added unsaturated margarine” would be replaced by natural animal fats and some portion of partially hydrogenated shortening in the control group.

The main foods I could see them using partially hydrogenated shortening in would be deserts, potatoes, and vegetables.

Deserts accounted for 9% of the fat, potatoes and their substitutes 7%, and vegetables 11%.

If all of these foods were cooked in shortening, shortening would have supplied 27% of the fat. The total fat was 111.2 grams per day, and 27% of this is about 30 grams per day.

The deserts definitely contain some dairy fat, especially in ice cream, so the total shortening should be less than this.

I would say some one-third to two-thirds of deserts were probably foods like pie crusts and pastries where you would expect shortening to be used, so the lower bound is about 3-4 grams of fat from shortening per day (just a third of the desert fat) and the upper bound is about 27 grams per day (these three categories minus a third of the desert fat).

What Fits the Definition of “Minor”?

Because now we are forced to reject the definition of “minor” that no more than 2.8 grams of trans fat were used in each group, we now need to shift to the more liberal definition of “minor” that up to ten grams of trans fats could have been used in each group, but they would have to be distributed equally between the two groups.

This definition is not consistent with 3-4 grams of shortening per day being used in the control group, but it is consistent with around 27 grams per day being used.

We do not have an analysis of the shortening available, but it could easily have been as low as 20% trans fat or as high as 40% trans fat, so there are quite a range of amounts of shortening that could plausibly supply similar amounts of trans fats as used in the control group.

Analyzing the “Trans Fat Gap” Implied by Serum Cholesterol

We now turn to the best biomarker we can use: the difference between groups in serum cholesterol.

This cannot tell us the absolute amount of trans fat consumed by either group, but it can give us an indication of the difference between the two groups.

The preliminary suggestion by Keys that each 1% of calories increase in trans monounsaturated fat would raise serum cholesterol by 2.1 mg/dL has been revised by subsequent research meta-analyzed in 2001 and 2003. The revised prediction is that a 1% increase of calories from trans monounsaturated fat raises cholesterol by 0.31 mmol/L, which is 1.19863 mg/dL.

According to the main 1969 LA Vet trial paper, the Keys equation would have predicted a difference of 36.5 mg/dL between groups, while the observed difference was 29.5 mg/dL.

The authors pointed out that they observed difference is 81% of the predicted difference, and that this is very close to the 78% “adherence” to the diet during the period in which people were living in the home. They therefore suggested that the 22% of the meals that were not eaten at the home (which may or may not have been replaced by a meal outside the home) could have been the reason for the discrepancy.

This makes no sense at all, because in the preceding paragraphs they describe at length how they could not model “adherence” as an explanation of serum cholesterol that achieved a correlation coefficient higher than 0.31. The square of this coefficient represents the explanatory power of one variable for the other. This means that “adherence” to the diet explained 9.6% of the serum cholesterol.

If “adherence” explained less than 10% of serum cholesterol, how could the 78% “adherence” explain why the difference in cholesterol was only 81% of what was predicted by the Keys equation?

The closeness of 78% to 81% is obviously a coincidence.

What we rather have, here, is a 7-mg/dL gap between the difference predicted by the Keys equation and that observed in the study.

Before we consider whether trans fat could account for this, we should also take into account that the LA Vet trial investigators used the equation Keys published in 1965, which attributed the cholesterol-raising effect of saturated fat to be primarily due to lauric (C12:0), myristic (C14:0), and palmitic (C16:0) acids, but did not differentiate between the ability of each of those three fatty acids to raise cholesterol.

A more modern version of the Keys equation by Müller, 2001 attributes a much stronger cholesterol-raising effect to myristic acid than to palmitic acid and attributes a modest lowering effect to oleic acid (C18:1) rather than dismissing it. In this version, the change in total cholesterol is expressed as the following, where each fatty acid is in units of a 1% change in total calories:

My reanalysis of the LA Vet trial data using this equation leads to a prediction of a 25.7 mg/dL difference.

This is actually closer to the observed effect than the 1965 Keys equation, but, critically, the difference is in the opposite direction.

Specifically, “my” 25.7 mg/dL prediction (by simply plugging in numbers into the Müller 2001 equation) is 87% of the observed 29.5 mg/dL difference, whereas the Keys equation is 123% of it. “My” prediction falling 13% below the observed difference is barely more than half the difference of the Keys 1965 prediction rising 23% above it.

This supports the improvements made to the Keys equation over time.

None of these equations are perfect, however, because in the context of a full diet, there could be many other things impacting the cholesterol, so there could be specific food effects in the trial diet that biased the net impact in one direction or another.

For example, cheese consistently lowers total cholesterol relative to butter providing the same amount of milkfat, which might be an effect of the food matrix or mineral content.

Nevertheless, the gap between the predicted and observed difference in serum cholesterol could easily be explained by the difference in trans fat consumption.

Since this gap could be explained by other effects such as food matrix and micronutrients, and since there is certainly some component of random error, this should be viewed as the upper bound of the “trans fat gap.”

The prediction being lower than observed suggests there was more trans fat in the control group.

It means that the seed oils were more effective than expected at reducing serum cholesterol because the control group was more cholesterol-raising than expected due to some of its “oleic acid” actually being the trans isomer, known as elaidic acid.

According to the Müller, 2001 equation, switching from oleic acid to elaidic acid switches the coefficient from -0.170128 to +1.19863 mg/dL, resulting in a 1.368758-mg/dL rise in cholesterol for each 1% of calories making the shift.

Therefore, the 6.2-mg/dL difference in total cholesterol observed versus predicted could be explained by the control group consuming an extra 4.5% of calories as trans fat, which would be an extra 13 grams per day.

There is definitely uncertainty around these calculations and we should not put too much trust in this as an exact estimate. However, I looked through the papers published since Müller, 2001 and I do not see any that challenged the equation as inadequate or provided a better one. The fact that it predicts the observed cholesterol difference with hardly more than half the gap as the Keys, 1965 equation supports its improved utility, which in turn supports the flipped direction toward greater trans fat in the control group.

However, using the Keys papers from 1961 and 1965, we would flip to attributing 3.3% more calories from trans fat to the seed oil group and conclude that they were eating 9.2 grams of extra trans fat per day.

The case to use Müller, 2001 is uncertain but solidly rooted in objective arguments: improvement over time with a larger base of research, unchallenged since, and tighter agreement to the observed results.

The best conclusion is that we should not rule out either difference but we should consider it more likely there was more trans fat in the control group than in the seed oil group.

One way to put this is that our range of possibilities is 9 extra grams in the seed oil group to 13 extra grams in the control group, with probability being toward more in the control group and the exact amount being very uncertain but almost definitely less than these boundary amounts.

Since we should value the Müller, 2001 equation over the Keys 1961/1965 equations, we should be biased toward the right side of the estimate: more trans fat in the control group.

Since the total meals eaten in the home were approximately half of the meals eaten during the study period, we should cut the outer boundaries in half: more likely that there were 6-7 extra grams in the control group than that there were 4-5 extra grams in the seed oil group.

If we give weight to the investigators’ comment that these were “minor” constituents of both diets, this should bias us toward the middle of this estimate rather than the boundary.

This leads me to the tentative conclusion that there was more trans fat in the control group, but not that much more.

Does the Trans Fat Matter?

If I am right that there was more trans fat in the control group, but not that much more, then the trans fats largely fade into the “sameness” across the two groups and the few grams per day pales in comparison to the deliberate randomization of one-third of the fat, to the accidental distribution of twice as many heavy smokers to the control group, and to the poor selection of fats in the control group that rendered them having ten times less vitamin E and almost three times less vitamin E per gram of PUFA.

Another way to look at this would be to ask the question, how much extra trans fat would we expect to need to consume to generate the outcomes observed?

The problem with this is that the outcomes need to be analyzed in the context of the other trials because the benefit to heart disease in this trial is an anomaly.

We therefore turn next to whether trans fats confounded the Minnesota Coronary Survey, the only other double-blind trial, and the one that is distinguished for being largest in size despite not being as long as the LA Vet trial.

Our conclusion here, for now, is that there was probably more trans fat in the control group of the LA Vet trial, but not that much more, and as a result it probably didn’t matter.

Read more

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• Nutrients to focus on for immunity

• At the first sign of a suspicious sneeze

• If you get sick, what to do: week 1, week 2

If you’ve gotten sick and are not recovering like you should, go to my guide on “How to Finally Get Rid of Your Lingering Cough”

For the science on how to leverage nutrients to keep from getting sick, see my course, Nutrition and Immunity.

Gordon Guyatt coined the term “Evidence-Based Medicine” in 1991 and together with David Sackett and others he founded the EBM movement, formally proclaimed in the Journal of the American Medical Association (JAMA) in 1992.

He cofounded the GRADE Working Group in 2000, which has now become embedded in the World Health Organization, Cochrane, and other institutions as the authoritative distribution of EBM’s influence in the world’s institutions.

He started the authoritative textbook on EBM, Users Guide to the Medical Literature, in 2001, which reached its third edition in 2014 and remains the authority of the field.

As such there is no one else alive who speaks more authoritatively on what Evidence-Based Medicine truly means.

You may then be surprised that the familiar “pyramid” of the “evidence hierarchy,” which appears to have been created by an entirely unknown reference librarian at SUNY Downstate in 1997, is, according to Guyatt “totally confused.”

Among other reasons, properly conducted n=1 self-experiments belong at the TOP of the hierarchy, where they have appeared in the EBM textbook since 2001, remaining so in the 2014 edition. Guyatt told me that if he ever produced a fourth edition, n=1 trials would remain right at the top.

We looked together at my own randomized n=1 self-experiment comparing the impact of corn vs quinoa on my sleep and energy.

You may also be quite surprised at how Guyatt described the importance of mechanistic reasoning in interpreting the generalizability of human outcome studies. In some cases, it’s “crucial.”

We talked about how I synthesize mechanistic reasoning, animal studies, and human trials to interpret the way choline status should impact the effect of seed oils on fatty liver and Guyatt weighs in with his verdict on my reasoning.

In this interview, Guyatt and I discuss how to apply the principles of EBM to medicine, health and nutrition, and daily life, paying special attention to the less appreciated aspects of EBM, like the importance of individual values and choice, recognizing what we don’t know, understanding the limits of generalizing from RCTs, weighing mechanistic reasoning against observational studies as means of navigating uncertainty, and how Guyatt responds to critiques from public health and to John Ioannidis’s claim that EBM has been hijacked.

0:29 What was medicine based on before it was based on evidence?
3:29 What is EBM?
5:38 How individual choice is core to EBM but remains underappreciated, and how it took time for it to become a core part of EBM.
10:50 Why the “hierarchy of evidnce” pyramid is “totally confused.”
19:08 Why n=1 trials are at the TOP of the evidence hierarchy
25:09 What might change his mind on statins?
29:15 My own n=1 randomized experiment of corn vs quinoa
33:27 Do randomized controlled trials apply to individual people?
36:06 What is the role of “try it and see if it works” in EBM?
37:38 What is the role of mechanistic reasoning in extrapolating from randomized trials?
46:51 Guyatt evaluates how I synthesize mechanistic reasoning and animal experiments with human trial results to interpret the likely impact of choline status on how seed oils versus saturated fats impact fatty liver disease.
56:08 Does the fact that RCTs aren’t long enough mean that long observational studies can be high-quality evidence?
1:01:08 Whether the upcoming revisions to the GRADE framework are inappropriately reducing skepticism toward observational studies
1:07:31 How he responds to criticisms from public health
1:09:39 Is EBM in “crisis” and has it been “hijacked”?

VO2max is the maximum rate at which you are able to take up oxygen from your lungs and transfer it out of your blood to the tissues that need it.

You can test your VO2max at an exercise science lab for some $75-250 a pop, or you can get a device like a VO2Master for just under $8000, and then you can predict your lifespan or optimize your workout for VO2max to lengthen your life.

There’s just one problem: none of the studies used to make this claim have measured VO2max. In fact, they don’t even claim to have predicted VO2max.

This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.

In This Article

• The Short Answer

• What The Studies Actually Measured

• How Do These Tests Relate to VO2max?

• What the Mortality Papers Actually Show

• Do These Papers Even Claim to Measure or Predict VO2max?

• Why Does It Matter?

• Why Does Bad Data Generate Stronger Correlations?

• Other Mortality Data

• So What Do We Do With This?

This Article Is Reserved for Masterpass Members

This article will is reserved for Masterpass members (learn more about the Masterpass here).

Download This Article

Masterpass members can download this article to print it out and read it in natural lighting as recommended in What Everyone Should Be Doing For Their Health here:

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Mitochondria convert your food to usable energy in the form of ATP, which is used to produce, maintain, repair, distribute, and organize everything in your body.

Abundant health right now, and preserving your health throughout the lifespan toward your longevity, all depends on your mitochondria.

In fact the best explanation for aging is that its a vicious cycle of declining mitochondrial function.

We should always be thinking of mitochondria first. SSRIs, acne treatments, and statins are given as examples. Targeting mitochondria without proper testing has its own set of problems.

This video covers the top things we should all be doing for our mitochondria and how to figure out our own mitochondria’s unique needs.

This is not medical advice and is for educational purposes only.

1:20 Mitochondria govern everything because they convert food into usable energy
7:25 Mitochondrial dysfunction drives aging
10:43 Depression starts with your mitochondria
17:26 The problem with SSRIs
21:59 Acne should start with vitamin A, zinc, B5, and mitochondrial function
28:00 Cardiovascular disease starts with mitochondrial dysfunction
40:26 Statins are mitochondrial toxins
54:00 Targeting mitochondria without testing can be dangerous: three examples.
59:45 CoQ10: no one dose and no one supplement for everyone.
1:04:30 Methylene blue can make your mitochondria worse if you don’t need it.
1:07:48 The power of mitochondrial testing: three examples
1:15:14 Mitochondrial biology
1:17:32 Your mitochondria are pointless if you don’t have creatine
1:18:20 What Mitome is testing
1:20:42 What Mitome reports look like
1:21:57 Energetic bottlenecks are like traffic jams
1:25:01 Organic acid testing of mitochondrial function
1:26:53 Other mitochondrial tests
1:27:44 Five things everyone should do for their mitochondria right now.
1:40:48 We all have unique mitochondrial needs

If you want clarity instead of guesswork, start with the pathway that produces your energy.

Mitome is the first at-home test that measures your cellular energy directly and gives you a personalized roadmap to optimize energy, slow aging, and protect against disease.

Find it here at mito.me
@mitometest

Blood cholesterol levels, along with LDL particle count, ApoB concentration, LDL particle size, LDL pattern, and the ratio of cholesterol between LDL and HDL are all governed centrally by the LDL receptor.

Genetic mutations in LDLR cause familial hypercholesterolemia by lowering LDL receptor expression. One in a million people are born with homozygous mutations, and this can cause heart attacks as young as 18 months old. One in 300 people are born with heterozygous mutations, which shifts heart disease forward from a phenomenon that primarily kills between the age of 60 to 80 to one that primarily kills between the ages of 35 and 60.

The LDL receptor is the main way you bring cholesterol from outside the cell to inside the cell. While the liver only makes about 16% of the body's cholesterol, it is overwhelmingly responsible for controlling the concentration of cholesterol in the blood by taking it up using the LDL receptor. That cholesterol can then be put to productive use, especially for the synthesis of bile acids to support digestion.

However, there are two primary governors of LDL receptor production:

• Thyroid hormone governs it by signaling abundance. This causes the liver to take up more cholesterol than it needs to meet its basic needs, and this is what drives bile acid production to support digestion.

• Cholesterol deficiency within the liver cell governs it by signaling scarcity. The liver takes up cholesterol from the blood not to put it to productive use but simply to replenish its own stores.

Statins work by inducing a cholesterol deficiency in the liver. The liver responds to this by taking up more from the blood to bring its stores back up to normal.

In his 1976 book, Solved: The Riddle of Heart Attacks, Broda Barnes reviewed the history of using thyroid hormone to control both cholesterol levels and heart disease risk. It worked extremely well, but it was discontinued due to what Barnes describes as irresponsible dosing that had killed a few people.

It is important to understand here that you do not need to be “hypothyroid” for thyroid hormone to lower your cholesterol. It will work at any dose. Practitioners using it did not realize they were playing with fire by using a hormone to signal a degree of abundance that was not present in the body. Thus, some of them let the dosing get out of hand because it had nothing necessarily to do with correcting a thyroid deficiency.

Nevertheless, their approach was the same as using statins because both thyroid hormone and statins increase the LDL receptor.

On the other hand, it was the opposite, because thyroid signals abundance while statins signal scarcity.

What everyone involved fails to fundamentally understand is that your LDL receptor does not work in a vacuum. It is powered by mitochondrial ATP production.

If your mitochondria are not working well, your LDL receptor simply will not work.

Doctors who use a pharma-first approach have little respect for nature and doctors who use a statin-first, mitochondria-never approach do so because they do not understand the most basic elements of cellular biology.

As covered in What Everyone Should Be Doing For Their Health, everyone must use a food-first, pharma-last approach, which means everyone needs their doctor to follow the same approach. Do your research until you find a good one.

How Mitochondria Power Your LDL Receptor

As shown in this diagram from Alberts, Molecular Biology of the Cell, the “Bible” of molecular and cellular biology, the LDL receptor clears cholesterol from the blood by binding to LDL particles on the cell surface.

They are present in the membrane bound to the green protein, clathrin, which helps facilitate the membrane invaginating and pinching off to form a vesicle. The protein coat must then be removed, and the vesicle fuses with an organelle known as the endosome, which then uses the digestive organelle known as the lysosome to eat up the contents, digest them, and release the cholesterol.

The figure below shows more detail:

The protein dynamin squeezes the invagination to pinch it off from the cell membrane.

Have you ever tried to squeeze anything without investing energy into it? Here’s something you could try: buy a dynamometer and see what your grip strength is when you feel most awake and energetic. Then try it just before you go to bed, immediately upon waking, or after you finish a grueling workout.

No energy? No squeeze.

Dynamin is powered by the hydrolysis of GTP, ATP’s close cousin. In fact, GTP production is directly fueled by ATP, so without mitochondrial ATP production dynamin won’t function.

Put all the LDL receptors in your membrane you want. If the vesicle can’t squeeze off, the cholesterol is staying in your blood.

Contrary to what some of us learned in high school biology, cells are not sacs of fluid. Things don’t come in and then just float around. They are highly organized microcosms of civilization, with several classes of proteins making up their structural infrastructure and transport superhighways known as the “cytoskeleton.”

The two major cytoskeletal proteins involved in LDL uptake are actin (red) and microtubules (blue).

Actin filaments organize themselves around the invagination to provide structural support to it. They interact with it using myosin VI. This protein is in the same family as the myosin II that performs skeletal muscle contraction. It is directly powered by ATP.

The microtubules make up the transport superhighway network within the cell that, in this case, facilitates the newly formed vesicle moving toward the endosome. The motor proteins that power movement along the microtubules are dynein and various kinesins, which are directly powered by ATP.

Not shown in the figure, the uncoating of the vesicle is performed by heat-shock protein 70 (HSP70), which, like every other heat-shock protein, is directly powered by ATP.

Thus, every LDL receptor that brings an LDL particle in from your blood requires five different classes of ATP-dependent protein to actually move it from the blood into the cell.

No mitochondrial ATP?

No LDL receptor activity.

How Mitochondria Power Your Thyroid Hormone

As I covered in Hormones Are Never In Charge, thyroid hormone is primarily regulated by mitochondrial ATP production.

Caloric intake, especially carbohydrate, drives the pancreas to make insulin and the adipose tissue to make leptin. Adipose production of leptin is at baseline proportional to the total fat stored, so insulin is a gauge of short-term energy status and leptin is primarily a gauge of long-term energy status.

However, these hormones are not directly stimulated by carbs and calories. They are stimulated instead by mitochondrial conversion of food to ATP.

Insulin and leptin both act on the hypothalamus to increase thyroid hormone-releasing hormone (TRH). They do so by increasing ATP production in the hypothalamus.

Insulin and TRH both act together on the thyroid gland to increase the output of thyroid hormone.

Thus, any impairment in mitochondrial ATP production will hurt thyroid hormone production.

Conversely, efficient mitochondrial conversion of food to ATP will drive thyroid hormone secretion because it serves as a highly accurate signal of true energetic abundance.

Optimal Mitochondrial Function Optimizes Blood Lipids

Thus, optimal mitochondrial ATP production exerts a concerted effect on thyroid hormone to increase the LDL receptor and on the five ATP-dependent motor proteins that help bring the LDL particles into the cell.

What happens when you intervene to pump up the LDL receptor without creating the actual abundance necessary for its proper function?

On the one hand, it will not work as well as it would if ATP were abundant.

On the other hand, more LDL receptors will try to use up more ATP, so they will take it from what is available, which will make less available for other things.

Such a solution is like seeing an oil shortage and solving it by importing more cars. Will you incentivize more driving? Yes, you will. Most likely, more people will get from A to B. But now you’ve driven up home heating prices for people who heat their homes with oil, so now you’ll have more people with hypothermia, hypertension, cardiovascular and respiratory problems, and misery.

In other words, you are definitely causing cholesterol to move from your blood to your cells. But at what cost? You are draining your ATP supply and problems are just going to pop up somewhere else.

Statins Are Mitochondrial Toxins

Statins induce cholesterol deficiency in liver cells by impairing the production of mevalonate, a compound far upstream from cholesterol.

Mevalonate is used to produce many different compounds, but two that are central to mitochondrial function are CoQ10 and heme A.

Heme A is the specific iron-based protein that facilitates the use of the oxygen to convert food to ATP in the mitochondria.

By decreasing ATP production, statins hurt methylation. This is because ATP is used to make methylfolate and to activate methionine to S-adenosyl-methionine, the universal methyl donor.

Methylation is needed to produce all mitochondrial proteins. Since methylation is needed to make ATP and ATP is needed for methylation, a decline in methylation that feeds back on mitochondrial ATP production will initiate a vicious cycle.

Methylation is needed to produce creatine, and this is probably why statins decrease creatine synthesis.

Creatine is the mitochondrial power grid. It spreads the impact of mitochondrial ATP production throughout the cell, especially in the general area of the cell known as the cytosol.

It is in the cytosol where S-adenosyl-methionine is made, so creatine supports its production and a decline in creatine status will compromise methylation in a vicious cycle.

Thus, by the time low ATP is hurting methylation beyond a certain threshold, you’ve locked in a vicious supercycle composed of multiple vicious cycles that will cause perpetually declining mitochondrial function.

You now have less ATP and less creatine, which are two hits against LDL receptor activity, even though you have increased the production of that receptor.

To take this back to our oil analogy, this is worse than importing cars to deal with an oil shortage. Rather, this is denying drilling permits so that the supply of oil gets cut in half, then diverting half the oil left over into importing those cars. Now you increase demand after you’ve already decreased supply. You still get more people getting from A to B, but your heating oil shortage has gotten a lot worse and you should probably prepare for a popular revolt among the poor whose children are frostbit and whose grandparents are dying.

In other words, you are hurting the total supply of ATP but diverting what ATP you have toward LDL receptor function. It works to lower cholesterol, but at the cost of other processes that need cellular energy, which is… all of them.

CoQ10 Is Not Sufficient to Prevent or Reverse Statin Myopathy

Statins can cause muscle pain and cramps that can get bad enough in a small number of people to cause exercise intolerance and even rhabdomyolysis. “Rhabdo” is a result of muscle damage that causes muscle proteins to turn the urine a dark color.

As reviewed here, clinical trials only show this happening in 1.5-3% of people, whereas observational studies show that it occurs in 7-38% of people.

The discrepancy can be explained by the fact that people who sign up for clinical trials are healthier than the general population, the trials screen for vulnerability to side effects far more strictly than doctors do for their patients, and you can control the incidence by how strictly you define myopathy. For example, if you count people who have an increase in unexplained cramping, you will get a large number, and if you only count people whose rhabdo put them in the ER you will get a small number.

Meta-analyses conflict as to whether CoQ10 does absolutely nothing or helps substantially with statin-induced myopathy. For example, a 2022 meta-analysis concluded CoQ10 does nothing, and a 2025 meta-analysis concluded that 100-600 milligrams per day has a very helpful effect.

Although the 2025 analysis is more recent, only a single 2022 trial contributing to 16% of the result was published after the 2022 meta-analysis was prepared. The primary difference between the two is that the 2022 meta-analysis required creatine kinase data to verify the myopathy and only included placebo-controlled trials whereas the 2025 meta-analysis required only a survey of muscle pain and included trials that were not placebo-controlled.

Regardless, even if we treat the 2025 analysis charitably, it indicates that CoQ10 is only partially effective. For example, if the subjects reported a muscle pain score of 5-6, CoQ10 would reduce this by 2.5 points, which indicates it could roughly cut the muscle pain in half.

Cutting it in half is good, but if that’s where the result ends, it isn’t a resolution. Moreover, if the vicious supercycle of declining mitochondrial function has not been reversed, it is likely to keep getting worse after the trial is over.

Creatine supplementation has led to the complete resolution of statin myopathy in some cases, but has only been studied in 13 people, published in a case series and a case report.

Metabolomic analysis of statin-associated myopathy cases shows that there are broad shifts in energy metabolism that cannot be attributed to any one single cause and are idiosyncratic between patients. For example, there is a broad shift away from branched-chain amino acid metabolism and toward arginine and proline metabolism, which I suspect reflects impairment in the conversion of pantothenic acid (vitamin B5) to the energy carrier coenzyme A (CoA) as a secondary side effect of the vicious supercycle. There is a broad shift toward altered glycine and serine metabolism, which I suspect reflects impaired methylation. Some people have increased carnitine synthesis and others have decreased carnitine synthesis, showing that the mitochondrial dysfunction is idiosyncratic.

It is possible that some interventions like CoQ10 and creatine can in some people break one or two of the vicious cycles enough to interrupt the vicious supercycle, but neither of these are going to normalize the production of heme A.

There is no supplement that can reverse the inhibition of heme A synthesis, which means nothing can resolve the fact that statins will impair your mitochondrial utilization of oxygen to produce ATP.

Mitome Can Examine What Is Unique to You

As the Founder and Scientific Director of Mitome, I embedded in the reporting the ability to differentiate between impairments in CoQ10-mediated processes, signatures that methylation deficiency is impairing mitochondrial function, and the impact of inadequate complex IV activity that would be caused by a disruption in heme A.

Mitome directly tests the respiratory chain components, where disruptions of CoQ10 and heme A synthesis would first be found, and thus looks at the root cause of the mitochondrial vicious supercycle.

If removal of statins and supplementation with CoQ10 and creatine do not resolve statin myopathy, Mitome could determine what is still missing and what to do about it.

Mitome is not meant to diagnose or treat disease and has not been clinically tested in statin-associated myopathy.

However, it can reveal what the unique limitation in your mitochondrial function is and provide you with an actionable protocol to address it with food and supplements.

Why Mitochondria Must Come First

If you optimize your mitochondrial function, you promote robust thyroid hormone activity to increase your LDL receptor production, and you promote robust supply of mitochondrial ATP production to make the five motor proteins needed for LDL receptor activity do their job.

You also need to be eating enough protein, iodine, and antioxidant nutrients to support your thyroid.

To examine your diet, use the guidelines in What Everyone Should Be Doing For Their Health, track your micronutrients in Cronometer, and run the Comprehensive Nutritional Screening.

If your cholesterol or LDL-C or ApoB or whatever you are measuring remains concerningly high despite adequate micronutrients, and you have also followed the guidelines in What Everyone Should Be Doing For Their Health regarding body composition and stress management, you should experiment with fiber, your fat-to-carbohydrate ratio, and your intake of saturated fat and cholesterol.

In general you need to get your BMI to 18-25 or more precisely optimize your body fat, and, in that context, push your carbohydrates up to a point that does not destabilize your glucose and lactate numbers or make you regain body fat.

More fiber will, in general, help lower cholesterol, but your fiber intake should also be adjusted to what promotes optimal digestion and stool function.

If you have chronic inflammation that is not attributable to excess body fat, you can try a short 12-week course of any of the following, alone or combined: 3 capsules of cod liver oil and 6 capsules of fish oil for high-dose omega-3s; boswellia; 250-2500 milligrams of Specialized Pro-Resolving Mediators; 1000 milligrams once or twice per day of black seed oil; or 1.2 grams (3 capsules) of curcumin as Biocurcumax; or the lactoferrin protocol.

If these do not resolve your blood lipid problem you can try restricting saturated fat, focused on the foods that provide you with the least important micronutrients. You can compare this to restricting cholesterol, again focused on restricting the foods with the least important micronutrients. You can combine these if they both seem to work. While replacing saturated fat with polyunsaturated fat will work, I do not consider it wise.

If after all this you still need to work on your blood lipids you could consider a statin. It may in fact be optimal in certain extreme cases.

However, you should always use a food-first, pharma-last approach to everything, and you should always use a mitochondria-first, statin-last approach to blood lipids.

If you optimize your mitochondria first and you still need more LDL receptor activity, then by the time you intervene, the LDL receptor will be using the most abundant supply of ATP you were able to provide it with.

If instead you use statins — unambiguous mitochondrial toxins — as your first approach, you are killing the ATP supply and then making the LDL receptor take what little there is from the rest of your functions that need it.

It is unlikely that even the most rose-colored clinical trials and case reports are telling the full story. On average, you lose 1% of your mitochondrial function per year. While 100-600 milligrams of CoQ10 or 5 grams of creatine per day may be very helpful in statin-associated myopathy, will that be true ten years after the study was completed when mitochondrial function has another decade worth of decline under its belt? I doubt it.

Age only explains 25% of mitochondrial function, which means that 75% is in your power to optimize.

Focus on getting incredible mitochondria first so you don’t have to try figuring out the cause of mitochondrial failure later.

SSRIs can cause sexual dysfunction and emotional blunting in up to half of people, an unclear incidence of sleep disruption, and a rare risk of suicidality, self-harm, and new-onset psychosis.

Getting off SSRIs can cause discontinuation syndrome in 20-50% of people. It is more common, more severe, and lasts longer when people have been SSRIs for years instead of weeks or months. Many of the discontinuation symptoms represent new-onset dysfunction that cannot be explained by the withdrawal of an effective treatment for the pre-existing depression, such as headache, derealization, depersonalization, cramps, gait abnormalities, and “brain zaps.”

This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.

My SSRI series led to the conclusion that serotonin’s primary role in the entire body is to coordinate mitochondrial energy production according to shifts in oxygen demand, that SSRIs are primarily mitochondrial drugs, that SSRIs can cause direct and severe mitochondrial toxicity in a small number of people, and that SSRI withdrawal causes new-onset mitochondrial dysfunction in a large number of people.

Many people asked how to transition from SSRIs to using my Depression Protocol, which is a drug-free approach to depression.

What to Do About SSRI Withdrawal Mitochondrial Dysfunction was meant for helping people who experience SSRI discontinuation syndrome or have been experiencing it for a very protracted length. One of its points, however, was that, as long as you’ve been on the drug for more than six to eight weeks, you want the taper to be as slow as possible.

While I am not a medical doctor and cannot manage anyone’s medications, here are some insights derived from the literature about how to make the taper slow, and, most importantly, hyperbolic. Hyperbolic means you don’t go down the same number of milligrams each time; instead, you go down in smaller and smaller increments as you go on.

Mark Horowitz of the Prince of Wales Hospital in Sydney, Australia, and David Taylor of Kings College London Institute of Pharmaceutical Science published a paper on this topic in 2019.

They pointed out that as the dose of an SSRI goes up, the modeled occupancy of the serotonin transporter levels off:

The figure below shows the impact of a linear dose reduction on the top and a hyperbolic dose reduction on the bottom.

When you reduce the dose linearly, your early reductions have a very small impact on transporter occupancy and your later dose reductions have a massive impact.

If you want to achieve a smooth, even reduction in transporter inhibition, you need to make large dose reductions at first, and then progressively smaller and smaller dose reductions as you move on in the taper.

They modeled the range of speeds that could be used, where ten percent of people can taper off in six weeks or fewer, 10 percent of people take longer than eight months, and the median person takes 18 weeks.

In the hypothetical case they gave, the person starts on the median trajectory, but experiences discontinuation symptoms after several dose reductions, so she shifts over to the slower trajectory meant for the 70th percentile.

Henricus Ruhe and colleagues of the Dutch Discontinuation of Antidepressants Task Force replied to their paper with a useful table that models 9- and 10-step taper protocols representing 10% reductions in transporter inhibition per step for the various SSRI and SNRIs:

They suggested that one could start with one week per step instead of the slower approach suggested by Horowitz and Taylor. If the patient reports discontinuation symptoms emerging, they can go back to the previous dose and taper more slowly.

Anecdotally, I have heard of some people taking six months per step, dragging out the taper protocol to five years.

Here is my suspicion:

Take up to as long in the taper as you spent on the drug.

This is based on the literature I reviewed strongly suggesting that incidence, severity, and duration of discontinuation symptoms is driven by the time spent on the drug.

Here is a simple way to approach this. I do not give out medical advice so this is an idea you can bring to your physician to help you get off these drugs if you decide to get off them:

• Follow the dose reduction pattern in the table.

• Make an initial plan for each step to take two weeks.

• If you experience new-onset problems as a result of the taper, go back to the dose prior to the emergence of those problems, and switch to a slower taper.

• You can also make the increment even smaller. For example, you could model the dose reduction after the next, smaller step. Or if you get to “0” in the table, you can replace it with half of the previous dose.

• If you switch to a slower taper you can at first expand it to three weeks, but you should strongly consider taking the entire time you spent on the SSRIs and dividing it by ten. For example, if you have been on SSRIs for eight years, this would be 416 weeks; divided by ten, this makes each step take 41.6 weeks. You could make it simpler by rounding up to 42 weeks, or even just go down one step per year.

If you require a slow taper, you could try the suggestions in What to Do About SSRI Withdrawal Mitochondrial Dysfunction to see if they can improve taper tolerance and allow you to go more quickly.

If you experience a return of depression but not other new problems, you can then use my Depression Protocol for a drug-free approach. In general, it is not contraindicated to mix SSRIs with anything in that protocol, but you should exercise caution with anything else impacting serotonin (e.g. 5-HTP) or monoamine oxidase (dodder, pomegranate, ellagic acid). If you require an extended taper, you should use the the “optimize it” version of the protocol with the assistance of medical supervision as you likely have idiosyncratic mitochondrial dysfunction as either a background vulnerability or as caused by the SSRIs themselves.

Have experience with a successful taper? Post in the comments!

One underappreciated way in which the entire pharmaceutic industry is completely at odds with nature is the concept of the “steady state.” When you dose a drug, you want to find the dose and frequency of administration that leads to a steady plasma level that neither rises nor falls because the drug is replaced at the rate it is leaving the body. This helps maintain it within a therapeutic window that is effective without being overtly toxic.

The problem is that nearly everything in nature is meant to be rhythmic and cyclical, not steady.

This probably underlies why SSRI withdrawal causes mitochondrial dysfunction: SSRIs press the gas pedal of adaptive mechanisms inside cells like sigma-1 receptor activation but they never let go. These are supposed to be stimulated rhythmically to allow for a cycle of stimulus and adaptation, just like exercise and recovery. The steady state pressure put on these systems causes a completely unnatural dependence of mitochondria on the drug that then holds people as captive prisoners.

You don’t need to put the pedal to the metal to cause harm. Just step on the gas pedal a little. If you keep your foot in the same place indefinitely, you have a 100% chance of getting into an accident.

This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.

This Week’s Food Experiment

This week I’ve been testing: are lima beans the mitochondria’s friend or foe?

On the one hand, lima beans are overwhelmingly the richest food source of molybdenum, at least according to the scant literature. In Missing From the Databases: Molybdenum, I include data showing a shockingly low five grams of lima beans per day contain the official requirement for molybdenum. Liver, the only organ meat tested and the only animal food shown to be a good source of this mineral, requires 35 grams to provide the same amount.

Molybdenum gets rid of sulfite, which you make yourself from the protein you eat. Sulfite is a mitochondrial toxin that inhibits numerous enzymes involved in mitochondrial energy production and poisons the mitochondria’s import/export infrastructure, causing them to lose control of what they take in and let out.

On the other hand, lima beans contain linamarin, a cyanogenic glycoside, meaning a sugar-bound molecule that releases cyanide. Cyanide binds to complex IV of the mitochondrial respiratory chain, preventing the mitochondria from using oxygen to produce ATP. This causes a backup in energy utilization that can raise blood glucose. Linamarin, in fact, has been shown to cause diabetes in undernourished dogs.

Worse, inhibiting complex IV can increase sulfite production since this is part of the hypoxia response, thereby nullifying the benefit of the molybdenum.

Further, cyanide is detoxified to thiocyanate, which inhibits iodine uptake into the thyroid gland and thereby hurts mitochondrial energy production by means of downregulating it.

I had been supplementing with 600 micrograms of molybdenum as Mo-Zyme for over a year, and I recently decided to test how much I would need from food alone to prevent my startle reflex from rising, which for me is a sign of molybdenum deficiency. This is driven by sulfite accumulation leading to the formation of S-sulfocysteine, an excitatory neurotransmitter that is relevant to everyone yet totally absent from neuroscience textbooks due to the completely erroneous but universal superstition that it is only relevant to rare diseases.

My experiment on the startle reflex is not over, but my preliminary results suggest that a quarter pound per day of US Wellness 75% Ground Beef With Heart, Kidney, and Liver keeps it normalized. When I reduced this to an eighth pound, below the threshold of startle reflex normalization, I titrated up lima beans in 5-gram-per-day increments, taking just under a month to increase from 5 to 35 grams per day. While each increase seemed to reduce my startle reflex, it felt like I was chasing it upward, having to eat more and more lima beans to keep it down as time went on.

My fasting blood glucose (measured with a KetoMojo) was 87 the day I first added 5 grams of lima beans. My blood glucose rose from 87 to a peak of 118 on 35 grams of lima beans, with the 3-day average reaching 110 the next day, and then it dropped to 89 in my second day after eliminating lima beans.

My lima bean dose during this period correlated to my blood glucose, explaining a whopping 43% of the variation, with a rise of 1 milligram per deciliter for every two grams of lima beans.

If I eliminate the first day of having removed lima beans, where the glucose had fallen to 102, and consider this day still “under the influence of lima beans,” the explanatory power rises from 43% to 50%.

Given that finger prick glucose is intrinsically variable, explanatory power of 43-50% is astronomical.

I conclude that, for me, lima beans are a net mitochondrial toxin.

For more information on lima beans and other sources of cyanogenic glycosides, see Thyroid Toxins: Double-Edged Swords of the Kingdom Plantae.

Coolest Paper I Read This Week

Are common problems driven by rare bottlenecks?

Common Diseases In Clinical Cohorts — Not Always What They Seem is a paper in New England Journal of Medicine where genome sequencing was used in the UK Biobank and five randomized controlled trials to look for rare diseases in people already diagnosed and treated for common diseases like multiple sclerosis, inflammatory bowel disease, and atopic dermatitis.

In 2.86% of multiple sclerosis cases, their multiple sclerosis symptoms could be explained by a monogenic rare disease instead. Further, in these cases there was a 15-fold greater incidence of dementia than expected and a 3.5-fold greater incidence of convulsions.

1.12% of IBD cases could be explained by rare monogenic diseases that hurt intestinal function, and 2.5% of atopic dermatitis could be explained by monogenic rare diseases that cause skin problems.

They uncovered some preliminary evidence that failing to diagnose the rare diseases may account for some failure of the patient to respond to treatments in randomized controlled trials.

This paper is really just uncovering the tip of the ice berg. It doesn’t consider synergistic heterozygosity, complex patterns of inheritance, or the fact that Energy Metabolism Governs Everything and therefore heterozygous bottlenecks in energy metabolism will by the laws of physics necessarily contribute to all diseases.

It suggests that 1-3% of common diagnoses are misdiagnoses but what it’s really hinting at is that all diagnoses are just models to predict treatment response and trying to overcategorize everything into a mirage of binary factual truth is useful until it isn’t, and its usefulness has already been exhausted.

The path foward to understanding unsolved or inadequately treated health problems will be to see them as complex patchworks of biochemical bottlenecks where fixing the weakest link in the biochemical chain will provide the greatest results on the path toward better health. That will always mean maximizing cellular energy production.

Worst Scientific Practice I Found This Week

This is a case of hiding the control group.

This Egyptian paper testing whether Jarrow lactoferrin improves diabetes wins the award for this week. I like Jarrow as a brand, and it isn’t clear that they had any role in the study other than providing the product. At the special request of the investigators, they made a lactoferrin derived from camel milk, presumably to make it culturally relevant in Egypt. This makes it of unclear relevance to the US-sold Jarrow product but isn’t otherwise a bad practice.

The bad practice is this. They claim to have randomly allocated 60 obese children with diabetes to standard therapy with or without the Jarrow product while comparing their values to a set of 50 healthy controls.

Their tables show comparisons of values in 30 diabetics before lactoferrin, the same 30 after lactoferrin, and 30 controls. The result is that we wind up comparing the pre and post values in the 30 diabetics given lactoferrin. This is a very common form of statistical malpractice: the correct comparison in a randomized controlled trial is always the ending value between the treatment and control. This ensures you don’t wind up with conclusions fueled by statistical artifacts like regression to the mean.

But the problem is worse than usual. Are the 30 controls in the table the other 30 diabetics? Probably not, as we don’t have pre and post values for them. But if they are the healthy controls, why are there 30 and not 50 as stated? If they are the 30 diabetics not given lactoferrin, where did the 50 healthy controls go?

Results like these show researchers are just cherry picking whatever will present their data in the best light, presumably because they didn’t like the way it looked when they analyzed it properly.

When reading a paper, always make sure the full populations the authors claim to have studied have their data presented, that the comparisons are the ending values between the treatment and control rather than pre and post, and that any other adjustments or analyses are done after presenting the raw results in the most rigorous manner.

Mitome Story of the Week

I recently talked to a Mitome customer who thought he might have started bonking at marathons because he was getting older. But his Mitome results showed his mitochondria were better fueled with fat than carbohydrate. This allowed him to think through his past results in new light. When he had used chocolate for his intra-marathon fuel, he never bonked. Only after transitioning to carb gels did he stop bonking. It turned out after this analysis his primary problem was a food science problem: how to get chocolate not to melt in his pocket during a marathon.

On the one hand, you might consider this a standard low-carb argument: if you train yourself to burn fat, you don’t have a problem running out of glycogen. But as I covered in Carbs and Sports Performance: The Principles and The Evidence, there are good reasons to think carbs are important to peak performance.

Athletes that succeed on any given diet are self-selected, and the ones who self-select the wrong diet don’t win and get selected out of our attention.

The ability of mitochondria to run better on carbs versus fat is idiosyncratic, and using Mitome to learn which one best describes you can help you choose the fuel on which you can best perform.