This article was great! Definitely where I've found myself in the last few years of my experiments with chronic fatigue/hypothyroid/estrogen dominance. May I humbly suggest an add on to this energy metabolism? But I feel melatonin is also an overlooked antioxidant that we're discovering plays a HUGE role in the body's ability to repair itself from the damage of everyday living and even in cancer prevention. I say this because it was what ended up being the "cure" to my own energy disorder.
I had a nominal recovery from my chronic fatigue with vitamins and supplements back in 2016, and from reading articles on the internet I thought at first I was dealiing with copper toxicity, before finding the Weston A Price Foundation and diving headlong into their approach and saw good things at the outset, so I stopped taking most all of my vitamins and supplements in the effort to get everything from my diet and food. Needless to say it was a disaster and all of my progress evaporated in less than two years (not saying that Weston A Price isn't useful! I still follow a majority of their principles and advice with great success, but it's not the whole picture is what I'm saying), followed by me trying to reintroduce everything I had been taking and that had worked in the past, but now to no avail. To say I was beside myself in despair after having success and then losing it and not able to get it back was an understatement. I couldn't give up though and so I kept experimenting, reading the forums of other chronic fatigue sufferers. I knew the thyroid was involved, but it wasn't the whole story. I took everything; iodine, selenium, iron, tyrosine, zinc, magnesium, etc (I still do take these supplementsto be clear ). Finally, in a fit of desperation I turned to DHEA and pregnenolone when the forum said it was helpful for chronic fatigue sufferers. It was an absolute disaster, BUT it was the catalyst for finding out what was really wrong. Both of those hormones increased my estrogen in a very bad way, so I had the clue that it was hormones that were the main problem and what was dysregulated, specifically my sex hormones. It was when I was looking for a natural aromatase inhibitor that I found melatonin as an answer.
Now to go into my family history. My mom has PCOS and lost most of her hair from high testosterone and developed diabetes because of it. I had none of my mom's symptoms however and was never diagnosed with PCOS, but the more I looked into it the more it seemed that I had inherited some of its defects because in 2015 a study from China found a polymorphism or defect in the melatonin receptors in the reproductive area of women with PCOS. This seemed confirmed later in a 2019 study from Iran when they gave PCOS women 10mg of melatonin and it resolved their issues. The findings now are that we have 4x the amount of melatonin in our reproductive sites than in our blood and they found this deficiency by measuring the follicular fluid of these women. What is so crazy is that the first time I recovered I was taking 2mg of melatonin in a blend, so I didn't know it was what was having the impact and it was one of the first supplements I stopped since I didn't know if it was necessary or not. Needless to say, after reading those studies I ran out and bought 5mg of melatonin and IMMEDIATELY all of my vitamins and supplements that had worked in the past worked again like before. It was incredible!
That's why I'm writing this because I feel it fits into your framework of lifestyle/ environmental factors turning certain genes or receptors on and off and what a critical role melatonin in particular has in repairing and regulating energy in the body. Another study showed that if a woman's melatonin status is compromised during pregnancy it is passed to her children who then also manifest endocrine disorders later.
Even if you don't have the genetic defect like I do, they know that the melatonin receptors can be calcified and become defective that way, which explains the importance of vitamin K2 that you've discussed in the past Chris. :-)
The other big piece in my recovery story was getting my dopamine status back up and getting it regulated correctly. A new finding shows there's a polymorphism in dopamine regulation in bruxism (clenching and grinding of the teeth). My dad has that and I do too. It would make sense that these two dysregulations in both melatonin and dopamine could be a perfect storm for fatigue disorders since melatonin and dopamine act as each other's counter balance/ shift manager in circadian rhythms/ energy outputs. However, it seems melatonin is the master repairer in this relationship as it protects dopamine neurons even though it opposes dopamine production directly.
Anyway, sorry for the long story, but I felt I had to offer this insight as the research into melatonin is truly groundbreaking and its very essential role in energy recovery and maintenance. All of the vitamins and supplements you listed in your article haS been the backbone of my recovery, but none of them worked until I put in the true base of melatonin in place, in my case. :-) Like you said, it may look different for everyone as we all have unique factors in our genetic make up, but there are still some constants and I think melatonin may be one of them as it seems our lifestyle/environment is damaging the formation of its receptors in the body, particularly reproductively.
I hope this helps others in their journey and yours too. ❤
I'm still trying to work that one out if I'm honest, lol. 😅 I know the hormones play a big role in its regulation too, so with trying to lower my estrogen dominance and lose weight to promote a better progesterone/estrogen ratio I'm taking all of the supplements that would naturally promote it; 50 to 200mg of P-5-P depending on my cycle, 2,000 mg split dose of methylcobalamin, 25 mg of iron bisglycinate every other day, 2,000 mg of tyrosine in a split dose too. As well as just a B-complex (Emerald Lab's B-Healthy) with 690mcg of methylfolate. I take 3,000 iu of Vitamin D3, 500mg of Vitamin C with bioflavanoids. I take a copper gluconate supplement every now and then of just 2mg, but it's not very consistent. I take all of the fat soluble vitamins too along with vitamin D3, so I'm taking 200iu in a split dose of mixed tocopherols Vitamin E, 10,000 iu of Carlson's vitamin A retinyl palmitate and 500mcg every three days of vitamin K2. I take 400mg of magnesium glycinate and extra calcium citrate of about 1,000 mg. I take a zinc amino acid chelate of 22 to 44 mg depending on my cycle. I take extra choline in a sunflower lecithin supplement of 1,200mg.
And all of this with raw milk (foods rich in tyrosine, etc. lol) and raw egg yolks that I blend in a smoothie every morning with fruit and greens.
With all of that already in place I've actually started to experiment with a Velvet Bean supplement that has natural l-dopa and has clinical studies done with Parkinsons. I'm only about a week into it, but I'll let you know if it helps or not! I started at a pretty highish dose of 1,000mg of it with 20% dopa content which gives about 200mg of l-dopa supposedly, so we'll see. 🙂 I hope some of this info helps though! 😊
Great article on what should be the most central topic in nutrition.
I get to teach prsctitioners on a regular basis and, regardless of the exact topic/focus, I will invariably find myself speaking about of influence of energy availability. The patterns here:
- practitioners immediately 'get it' as to how pervasive energy metabolism is in every single condition we work with
- they struggle to integrate this way of thinking into how they assess, plan treatment, etc. ("Do we then focus on energy first and then on dealing with inflammatory problems?" "So this is actually more important than dystegulatiom of the HPAA/stress response?" etc)
For anyone who connects with these ideas but also resonates with those example questions, I would propose considering a simple equation (one that brings it together) and then to reread this article. The equation is that of relative energy availability, ie. quantifying how much every availability we have vs. how much our system wants. Energy availability = energy production (mitochondria) + energy signalling (thyroid/insulin/etc) - energy theft (inflammation). Energy desired = physical and cognitive workload + predicted demands (reflexive computation at the brain stem/PAG, based on prior experience) - indications of physical adaption (cortisol). If there is no gap between the two, there is no mobilization (stress response). If there is a gap, either because availability is low or perceived needs are high, there is a mobilization response (aka sympathetic stress response).
This is, of course, just one model to bring these important contributing factors together in a way that avoids having to choose which 'anglr' to apply when making assessments and one that applies to all and makes evidence, while also explaining why we need to tend to multiple zones in some individuals while others will respond really well from support in just one zone (if that happened to be their one limiting factor). There are other models that are just as valid but I hope that this is intuitive and outlines how we never need to worry about whether we use an 'emrgey first' stretrgy or another approach that has proved to be successful some of the time, as they are all connected. In all individuals, all of the time.
So dropping this in here in the hope that it will allow people to take these important ideas laid out in the article and immediately translate them into use on the frontline. Because energy metabolism governs everything!
On a practical level, I would view this from a low-hanging fruit vs advanced investigation perspective.
Lowest hanging fruit is good, well-rounded, adequate diet, healthy body composition, healthy lifestyle (rest, sleep, movement, outdoor, light hygiene, stress management, etc).
Higher-up fruit is looking at lab work for nutritional adequacy and most advanced stuff on the top of the tree is looking for idiosyncrasies in energy metabolism.
If you have stress or inflammation driven by something in the low-hanging fruit you should hit the low-hanging fruit first.
But I would argue that you should climb all the way up the tree before trying to modify inflammation from an unknown source with anti-inflammatories. If your body is inflamed and you don’t know why, it probably knows something you don’t.
I think its worth clarifying that I 100% agree that energy metabolism issues are best dealt with via testing. As easy as it may be to spot energy metabolism issues, it is only through testing that I would be able to know with certainty whether this is due to a lack of Carnitine, B1, mitochondrial hypoxia or something else. Equally, 100% agree that a protocol of anti-inflammatory supplements is destined to fail without further understanding of the root cause (and thus, in the early stages, the low-hanging fruit would only relate to the removal of inflammatory triggers, eg. oxalates, mould, etc).
In other words, I would use the 'energy security model' (indexed by HRV) as a starting point, from which we can 'work backwards'. This would start with the low-hanging fruit but also identify which of the four zones (energy production/mitrochondria, energy signalling/thyroid and insulin, energy theft/inflammation and energy needs/stress) call for the most attention and, through seeing them continue to play a role after tending to the low-hanging fruit, which of these zones calls for further testing (GI stool testing, fatty acids, hormonal profiles, further testing of nutrients, etc).
I speak of the above not as the 'right' model, but simply as one that allows us to integrate the important concepts of how energy governs everything (without abandoning the positive effects we are seeing from tending to inflammation or stress, and without thinking that these are separate things), because I think that the ideas you speak of in this article are so important.
Awesome thoughts. My model is more focused on figuring out the ultimate root cause and resisting palliative action to get knowledge sooner whereas yours seems more in a fluid dance at different levels of the causality tree trying to get constant improvement from any part of it while slowing gaining more knowledge about which parts are limiting.
I like it. My style is a little different, and I am also often working with people who come to me with a history of too much action and not enough results from not enough knowledge, which to me skews the needs heavily towards root cause knowledge.
Thank you Chris. This is so good and so helpful. “idiosyncratic genetic impairments in energy metabolism that are rare as individual diagnosable diseases are likely to be common as heterozygous partial biochemical impairments. My suspicion is that it is very common to have one or a few “carrier status” mutations that do not lead to disease, but do form idiosyncratic bottlenecks in energy metabolism.” This is definitely my experience. Also “ A high-energy, low-entropy state allows us to maximally contract our muscles when contraction is needed, and fully relax our muscles when it is not. A low-energy, high-entropy state mixes these together and results in fatigue and muscle tension, or the rigidity, tremors, and slow movements of Parkinsonism.” I’ve been having issues with not being able to get to sleep and not entering deep sleep with one of the symptoms being leg tremors/restless legs and a mild recurrence of allergies. Finally yesterday I was able to put a stop to it with riboflavin. I guess it’s just something I’ve got to take religiously. And though sometimes it seems that high dose thiamine would be a good choice for me it always results in symptoms of riboflavin deficiency when I try it. “using imagination for sufficient hope instead of excessive worry” has been a discipline I’ve had to learn. The discipline of expecting good things instead of worrying about what bad thing might be around the corner. I imagine it as being in a room full of rats but remembering to leave the door cracked for the cat to get in. Gonna do some more reading on the ACAD enzyme you mentioned.
Okay, this article definitely helped but I can’t yet express it in your colour language. I suspected I needed thiamine because my first wow supplement that brought me back to life was Benfotiamine. But raising the dose or trying high dose thiamine caused riboflavin deficiency symptoms -( mouth cracks, sore tongue, red eyes). But after correcting these symptoms more then a small dose of riboflavin (50 mg) made me really depressed. I was never able to afford metabolic testing for myself but my son had a urinary organic acid test that showed high succinic acid calling for riboflavin and elevated beta hydroxy butyric acid (so.?). But he too became a very sad little boy taking riboflavin. I added 5mg of biotin which was a positive thing. But here is where I could not go forward until I added niacin and high dose vitamin A. At this point I safely added 100 mg of riboflavin without symptoms of depression but when I added acetyl Carnitine and Borage oil (GLA) I started having mild symptoms that were corrected by riboflavin (200 mg in the morning and 200 mg at night). The symptoms were mild allergies, restless legs and trouble sleeping and cracked lips. So far I don’t notice any feelings of depression at even this high dose and my hypoglycaemia has gone away allowing me to not tank if I don’t eat immediately at meal times. So is niacin in the teal zone, lol? I was always very intolerant to corn and if I ate too much or had something with corn starch in it I would have terrible anxiety and skin rashes. This was corrected with niacin but the niacin has been causing mild vision problems which I believe are riboflavin related. There is an article online entitled The Clinical Manifestations of Nicotinic Acid and Riboflavin Deficiency (Pellagra) Sydenstricker where he claims that Pellagra is not one nutrient deficiency. In another article The Relation of Riboflavin to the Eye from The British Journal of Opthalmology it says “The most important function of the flavoprotein enzymes so far described is the oxidation of the nicotinic acid co-enzymes.” Is this why I could not tolerate riboflavin before niacin? My blurred vision problems from niacin seem to be more like cataracts caused by riboflavin deficiency then the maculopathy caused by a need for B6 and B6 makes my hypoglycaemia worse. Maybe I will need to add the B6 or B1 after the high dose riboflavin. I will keep looking for any symptoms of deficiency.
With ketones high he was not deficient in fatty acid oxidation, at least he was not as deficient as he was in the respiratory chain as suggested by the high succinate.
So this is vaguely supportive of a riboflavin-responsive respiratory chain problem.
However, riboflavin might still wake up fatty acid oxidation faster then it wakes up the respiratory chain.
Since carnitine will enhance fatty acid oxidation and burden the respiratory chain, and it reversed the riboflavin intolerance, I am going to guess the latter was from respiratory chain activity exceeding fatty acid oxidation, perhaps driven by too high of an NAD/NADH ratio.
Niacin and vitamin A are not as clear and they aren’t on the picture because they don’t fit neatly into the model.
However, I’m going to guess that they were increasing NADH (red zone activity in the diagram) if they were helping the riboflavin intolerance, but this is mainly for parsimony, which doesn’t guarantee accuracy.
So the other marker was extremely high oxalate levels which we did find relief from by eating low oxalate. Riboflavin is necessary for the conversion of tryptophan to niacin and for Pyridoxine as PLP. I’m just wondering how thiamine fits into all of this as a deficiency can also lead to high oxalate levels. I tried to add B6 to the mix yesterday and it was much more tolerable in that it didn’t cause immediate hypoglycaemia now that I’m on high dose riboflavin but it did cause a noticeable burning in my esophagus . B6 seems to lower calcium which is never a good thing for me. But without it the riboflavin at 200 mg made me feel good but tired. B6 gave me my umph back. Gonna see if thiamine is a better choice.
I have been looking at Sequencing.com and Nebulagenomics also. I have run my 23andMe and Ancestry dot com and FTDNA results through Promethease and seen a few interesting things on Strategene (note these DNA results providers can be inaccurate so not used for diagnosis, just for further research). I think I have a metabolic smoking gun somewhere though, that will turn up on whole exome or whole genome sequencing eventually. I've been using DNA for genealogy for quite a few years and there are quite a few early deaths on my dad's side including suicides. A deep dive into the family tree can be instructive.
I meant to say the raw genetics results from Ancestry, 23andMe and FTDNA are not validated and some errors do show up in their reporting (Promethease notes some of these; there are false negatives and false positives from these companies). Dante, Sequencing and Nebula use a different method as far as I can tell with more reads. I am currrently waiting on results for WES from TovanaHealth avg 80x, which will be reviewed by their geneticist Gidon Akler, MD and includes genetic counseling and reporting that is periodically updated. I actually signed up for it a few years ago through FTDNA (no longer offered there) and when I timed out trying to fill out the medical history form, I didn't have the mojo to start over right then. And then I totally forgot about it until recently. I may have other family members test there or elsewhere. Once I have my data I'll be able to run it through Sequencing's or Nebula's reports (they allow uploads) or consult with you on how to manage the bottleneck or bottlenecks.
Nebula is the kit/lab provider for Sequencing dot com but their reports are different. Nebula was recently acquired by a publicly held company so you can look at the ownership and their plans to further bring down the cost and increase market visibility and accessibility of WGS while addressing orphan disease drug development. For me I’d like to see nutritional interventions first.
Yes, of course! Energy metabolism trumps everything! I believe this is why the carnivore diet fixes nearly everything for nearly everyone! It did for me. Except for a few seasonal allergies here and there... for which I'll try your riboflavin trick asap as it is still May! For some of my carnivore years the allergies have been better than others (sometimes nonexistent), but I haven't been eating eggs this year and it's worse... and I'm homozygous MTHFR C677 on a high fat diet so ... riboflavin is not a bad idea.
I think you are generalizing too much from your own experience and those you pay the most attention to. “Nearly everyone” has never gone within ten miles of a carnivore diet, let alone tried it and had it fix everything for them.
Yes, I meant "nearly everyone who has tried it". (Based on my years of hanging around carnivore internet groups, and seeing so many amazing results.) Much more than say, Morley Robbins' Magnesium group. There you sometimes find people saying they've decreased such and such symptoms by 50%, but in the carnivore groups so many people say they have "completely healed" all, or almost all, of their issues, while any remaining ones are 80% better. Except for weight-loss... seems to be the one thing that doesn't happen for some subset of people, though other symptoms get better. I mean I think it's a combination of improved nutrition (so many more B vitamins?), and no plant toxins. Speaking of which, I'm trying to learn more about plant sterols... seems to me they are highly suspect. Why would the body be so interested in eliminating them that it is willing to get rid of perfectly good real cholesterol in order to do so?
I don’t doubt your experience in the forums, though I have several carnivore clients who have lots of residual stuff to work on, and I don’t think it’s always about plant toxins, for some it’s eliminating carbs.
But RCP is a very simple program that is bizarrely focused on one nutrient so it isn’t surprising that you don’t see the dramatic effects you find in people who cut out the entire plant kingdom.
I just don’t think you would see this generalize to a random sample of people they say you see it in those who have self-selected to spend time in these forums.
The body makes its own cholesterol so is not obsessed with holding on to every last drop from food and has no particular need for plant sterols.
This is a great comprehensive overview. I’m interested if you’ve looked at Morley Robbins theories around iron and iron deficiency. Also, your thoughts on mitochondrial function and nutritional support for improving it.
The latter question is exactly what is answered above, though “mitochondrial function” is simply the majority of energy metabolism and otherwise a distraction as a distinction from energy metabolism outside the mitochondria.
I have listened to Robbins’s book and referenced it in the May AMA.
Could psoriasis be caused by a retinyl esters toxicity?
In 1947, the New Enlgland Journal of Medicine published a study in which 11 severe psoriasis patient were put on a diet low in vitamin A and carotene: 7 complete clearing of lesions, 2 marked improvement, 1 slight improvement, 1 no improvement.
Another study shows that psoriasis patients have slightly low retinol-binding protein (RBP) and high dehydroretinol, along with other vitamin A related abnormalities.
Perhaps. Certainly vitamin A toxicity involves skin lesions that seem related in some way. And it is interesting that sun helps in part through D metabolites.
I really wish that Chris Masterjohn had taken time out of his busy 24/7 schedule to tell us how to lower retinyl esters without hurting vitamin A status. I haven't had time to research this question but I have been questioning if lowing vitamin A intake would help. Zinc could be part of the puzzle.
Another interesting aspect of psoriasis is that under stress, cortiso. levels in people with psoriasis drop. However, the adrenals function just fine in test, they produce cortisol when stimulated with ATCH. This suggest that understress, there are biological changes that prevent the adrenals from making cortisone, which I suspect is a lack of an unknown substrate.
If nothing else works for you psoriasis, I would suggest trying strontium. I would use high doses for a few weeks, and if it works I would continue with caution. A short-term high dose is safe, and but long term high dosing should be done with intelligence. Read my blog on strontium for more info. Start with this post. https://joeanstett.substack.com/p/benefits-of-strontium
I went to see Mazin AlKafaji,considered an expert in treating skin condition via Chinese medicine, this was 2003,in fact for perhaps the first time my P cleared to within 3% and I felt marvellous,unfortunately after about 18 months it slowly returned but it was truly a wonderful 18 months.just recalled I got a lot of sun last year and also took sacromyces boulardi and until winter was almost clear so a much shorter period.
Thanks again I’ll definitely look into your post .
Because not everyone needs a pharmacological boost to NAD, and even though NAD declines in aging and disease states you can easily fix that with moderate dietary improvements.
At the population level you will cause glycine and methyl group depletion in many people.
I’m someone who benefits so much from niacin and glycine and methyl groups send me to a bad place. The other day I was reading an article on how cats have low conversion of tryptophan to niacin, lower delta 6 desaturase levels and need to stay away from oxalate. It seems I am a cat, lol. I think I saw an image once of St. Christopher with a dog’s head ;) I wonder if dogs benefit from more glycine, lol. This is why cats should not be fed dog food ;) Anyways, my point in all this silly nonsense is that I agree that we can’t be suggesting everyone take niacin or glycine as a general rule.
Amazing!! This article is well thought out. Chris is many leagues above most of the nutrition gurus in the space at the moment, thank you for your work. W/ regards to energy metabolism, the most recent change I have made in my health has been vitamin B1 megadosing for my IBS. It has massively reduced bloating, gas, indigestion and as a side effect has improved my energy levels! I'm not sure of the effects on my blood sugar though which would be interesting. Thanks to Eliot Overton for making me aware of this as well.
That is under negotiation, but currently it is only accessible in a consultation context and until the negotiations are finished clients are not being charged directly.
Hey- so much great information! There’s so much testing here. When people work with you, can you narrow down which tests are most relevant? Or, do you still suggest doing everything listed above?
Definitely food for thought (pun unintended)... Interesting to see a kind of grand unified theory for wellness, based on energy metabolism. However, your earlier remarks in the article suggested another important dimension, that of entropy. The article does not appear to address directly the question of entropy reduction.
This might be the point where a novice like me might ask questions about inflammation, for example, or even psychoneuroendocrinoimmunology. There may be a grand unified theory, but it appears to this layperson to lie in the interaction among several critical systems. I'd appreciate your thoughts. Thanks!
It does address that. The role of energy is to reduce entropy. I linked to my first two lessons in energy metabolism where this is discussed in more detail, and this is also basic science in, for example, Chem 101.
Yes, I am proposing the grand underlying foundation on top of which all systems operate. Its sort of like operating system vs program or app.
Thanks, Chris, for a prompt reply. I am going to compare your essay with a fascinating introduction to PNEI on MDPI here: https://www.mdpi.com/2673-396X/2/3/22
Great article. Just signed up on the 101 course, I actually got the cliff notes last year. Just wondering if you've looked into how caffeine can affect micronutrients absorption, specifically vitamin D? I drink a few cups of black and green tea throughout the day, sometimes with meals. Really appreciate your research, and can't wait to get my lessons from the 101 course!
Interesting question. I think if you take it separate from the D it should be fine, and it's probably not caffeine that has the biggest impact of coffee but rather other components.
Awesome, you're right that there's a lot of compounds in tea that can interact with other nutrients. Btw LOVE the vitamin a lesson and can't wait for B1 tomorrow!! 😍😍
😨 didn't know about this! most conventional advice says tea is good for you with antioxidant and all that, and just watch for caffeine past certain time of day. Would love to know more about what could be negatively impacting nutrient absorption. Btw fascinating lesson on riboflavin, time to liver it up!
This article was great! Definitely where I've found myself in the last few years of my experiments with chronic fatigue/hypothyroid/estrogen dominance. May I humbly suggest an add on to this energy metabolism? But I feel melatonin is also an overlooked antioxidant that we're discovering plays a HUGE role in the body's ability to repair itself from the damage of everyday living and even in cancer prevention. I say this because it was what ended up being the "cure" to my own energy disorder.
I had a nominal recovery from my chronic fatigue with vitamins and supplements back in 2016, and from reading articles on the internet I thought at first I was dealiing with copper toxicity, before finding the Weston A Price Foundation and diving headlong into their approach and saw good things at the outset, so I stopped taking most all of my vitamins and supplements in the effort to get everything from my diet and food. Needless to say it was a disaster and all of my progress evaporated in less than two years (not saying that Weston A Price isn't useful! I still follow a majority of their principles and advice with great success, but it's not the whole picture is what I'm saying), followed by me trying to reintroduce everything I had been taking and that had worked in the past, but now to no avail. To say I was beside myself in despair after having success and then losing it and not able to get it back was an understatement. I couldn't give up though and so I kept experimenting, reading the forums of other chronic fatigue sufferers. I knew the thyroid was involved, but it wasn't the whole story. I took everything; iodine, selenium, iron, tyrosine, zinc, magnesium, etc (I still do take these supplementsto be clear ). Finally, in a fit of desperation I turned to DHEA and pregnenolone when the forum said it was helpful for chronic fatigue sufferers. It was an absolute disaster, BUT it was the catalyst for finding out what was really wrong. Both of those hormones increased my estrogen in a very bad way, so I had the clue that it was hormones that were the main problem and what was dysregulated, specifically my sex hormones. It was when I was looking for a natural aromatase inhibitor that I found melatonin as an answer.
Now to go into my family history. My mom has PCOS and lost most of her hair from high testosterone and developed diabetes because of it. I had none of my mom's symptoms however and was never diagnosed with PCOS, but the more I looked into it the more it seemed that I had inherited some of its defects because in 2015 a study from China found a polymorphism or defect in the melatonin receptors in the reproductive area of women with PCOS. This seemed confirmed later in a 2019 study from Iran when they gave PCOS women 10mg of melatonin and it resolved their issues. The findings now are that we have 4x the amount of melatonin in our reproductive sites than in our blood and they found this deficiency by measuring the follicular fluid of these women. What is so crazy is that the first time I recovered I was taking 2mg of melatonin in a blend, so I didn't know it was what was having the impact and it was one of the first supplements I stopped since I didn't know if it was necessary or not. Needless to say, after reading those studies I ran out and bought 5mg of melatonin and IMMEDIATELY all of my vitamins and supplements that had worked in the past worked again like before. It was incredible!
That's why I'm writing this because I feel it fits into your framework of lifestyle/ environmental factors turning certain genes or receptors on and off and what a critical role melatonin in particular has in repairing and regulating energy in the body. Another study showed that if a woman's melatonin status is compromised during pregnancy it is passed to her children who then also manifest endocrine disorders later.
Even if you don't have the genetic defect like I do, they know that the melatonin receptors can be calcified and become defective that way, which explains the importance of vitamin K2 that you've discussed in the past Chris. :-)
The other big piece in my recovery story was getting my dopamine status back up and getting it regulated correctly. A new finding shows there's a polymorphism in dopamine regulation in bruxism (clenching and grinding of the teeth). My dad has that and I do too. It would make sense that these two dysregulations in both melatonin and dopamine could be a perfect storm for fatigue disorders since melatonin and dopamine act as each other's counter balance/ shift manager in circadian rhythms/ energy outputs. However, it seems melatonin is the master repairer in this relationship as it protects dopamine neurons even though it opposes dopamine production directly.
Anyway, sorry for the long story, but I felt I had to offer this insight as the research into melatonin is truly groundbreaking and its very essential role in energy recovery and maintenance. All of the vitamins and supplements you listed in your article haS been the backbone of my recovery, but none of them worked until I put in the true base of melatonin in place, in my case. :-) Like you said, it may look different for everyone as we all have unique factors in our genetic make up, but there are still some constants and I think melatonin may be one of them as it seems our lifestyle/environment is damaging the formation of its receptors in the body, particularly reproductively.
I hope this helps others in their journey and yours too. ❤
Thanks for sharing your story! I’ll do some more research on melatonin.
Looking forward to your findings’
super interesting! what did you do for your dopamine problem?
I'm still trying to work that one out if I'm honest, lol. 😅 I know the hormones play a big role in its regulation too, so with trying to lower my estrogen dominance and lose weight to promote a better progesterone/estrogen ratio I'm taking all of the supplements that would naturally promote it; 50 to 200mg of P-5-P depending on my cycle, 2,000 mg split dose of methylcobalamin, 25 mg of iron bisglycinate every other day, 2,000 mg of tyrosine in a split dose too. As well as just a B-complex (Emerald Lab's B-Healthy) with 690mcg of methylfolate. I take 3,000 iu of Vitamin D3, 500mg of Vitamin C with bioflavanoids. I take a copper gluconate supplement every now and then of just 2mg, but it's not very consistent. I take all of the fat soluble vitamins too along with vitamin D3, so I'm taking 200iu in a split dose of mixed tocopherols Vitamin E, 10,000 iu of Carlson's vitamin A retinyl palmitate and 500mcg every three days of vitamin K2. I take 400mg of magnesium glycinate and extra calcium citrate of about 1,000 mg. I take a zinc amino acid chelate of 22 to 44 mg depending on my cycle. I take extra choline in a sunflower lecithin supplement of 1,200mg.
And all of this with raw milk (foods rich in tyrosine, etc. lol) and raw egg yolks that I blend in a smoothie every morning with fruit and greens.
With all of that already in place I've actually started to experiment with a Velvet Bean supplement that has natural l-dopa and has clinical studies done with Parkinsons. I'm only about a week into it, but I'll let you know if it helps or not! I started at a pretty highish dose of 1,000mg of it with 20% dopa content which gives about 200mg of l-dopa supposedly, so we'll see. 🙂 I hope some of this info helps though! 😊
have you thought to check your omega ratios? too high omega 6? blocking the cellular membrane uptake? of other nutrients as well?
Sorry, that should be 2,000 mcg of methylcobalamin not mg! 😅
Great article on what should be the most central topic in nutrition.
I get to teach prsctitioners on a regular basis and, regardless of the exact topic/focus, I will invariably find myself speaking about of influence of energy availability. The patterns here:
- practitioners immediately 'get it' as to how pervasive energy metabolism is in every single condition we work with
- they struggle to integrate this way of thinking into how they assess, plan treatment, etc. ("Do we then focus on energy first and then on dealing with inflammatory problems?" "So this is actually more important than dystegulatiom of the HPAA/stress response?" etc)
For anyone who connects with these ideas but also resonates with those example questions, I would propose considering a simple equation (one that brings it together) and then to reread this article. The equation is that of relative energy availability, ie. quantifying how much every availability we have vs. how much our system wants. Energy availability = energy production (mitochondria) + energy signalling (thyroid/insulin/etc) - energy theft (inflammation). Energy desired = physical and cognitive workload + predicted demands (reflexive computation at the brain stem/PAG, based on prior experience) - indications of physical adaption (cortisol). If there is no gap between the two, there is no mobilization (stress response). If there is a gap, either because availability is low or perceived needs are high, there is a mobilization response (aka sympathetic stress response).
This is, of course, just one model to bring these important contributing factors together in a way that avoids having to choose which 'anglr' to apply when making assessments and one that applies to all and makes evidence, while also explaining why we need to tend to multiple zones in some individuals while others will respond really well from support in just one zone (if that happened to be their one limiting factor). There are other models that are just as valid but I hope that this is intuitive and outlines how we never need to worry about whether we use an 'emrgey first' stretrgy or another approach that has proved to be successful some of the time, as they are all connected. In all individuals, all of the time.
So dropping this in here in the hope that it will allow people to take these important ideas laid out in the article and immediately translate them into use on the frontline. Because energy metabolism governs everything!
Great thinking.
On a practical level, I would view this from a low-hanging fruit vs advanced investigation perspective.
Lowest hanging fruit is good, well-rounded, adequate diet, healthy body composition, healthy lifestyle (rest, sleep, movement, outdoor, light hygiene, stress management, etc).
Higher-up fruit is looking at lab work for nutritional adequacy and most advanced stuff on the top of the tree is looking for idiosyncrasies in energy metabolism.
If you have stress or inflammation driven by something in the low-hanging fruit you should hit the low-hanging fruit first.
But I would argue that you should climb all the way up the tree before trying to modify inflammation from an unknown source with anti-inflammatories. If your body is inflamed and you don’t know why, it probably knows something you don’t.
I think its worth clarifying that I 100% agree that energy metabolism issues are best dealt with via testing. As easy as it may be to spot energy metabolism issues, it is only through testing that I would be able to know with certainty whether this is due to a lack of Carnitine, B1, mitochondrial hypoxia or something else. Equally, 100% agree that a protocol of anti-inflammatory supplements is destined to fail without further understanding of the root cause (and thus, in the early stages, the low-hanging fruit would only relate to the removal of inflammatory triggers, eg. oxalates, mould, etc).
In other words, I would use the 'energy security model' (indexed by HRV) as a starting point, from which we can 'work backwards'. This would start with the low-hanging fruit but also identify which of the four zones (energy production/mitrochondria, energy signalling/thyroid and insulin, energy theft/inflammation and energy needs/stress) call for the most attention and, through seeing them continue to play a role after tending to the low-hanging fruit, which of these zones calls for further testing (GI stool testing, fatty acids, hormonal profiles, further testing of nutrients, etc).
I speak of the above not as the 'right' model, but simply as one that allows us to integrate the important concepts of how energy governs everything (without abandoning the positive effects we are seeing from tending to inflammation or stress, and without thinking that these are separate things), because I think that the ideas you speak of in this article are so important.
Awesome thoughts. My model is more focused on figuring out the ultimate root cause and resisting palliative action to get knowledge sooner whereas yours seems more in a fluid dance at different levels of the causality tree trying to get constant improvement from any part of it while slowing gaining more knowledge about which parts are limiting.
I like it. My style is a little different, and I am also often working with people who come to me with a history of too much action and not enough results from not enough knowledge, which to me skews the needs heavily towards root cause knowledge.
A primer on HRV, it's connection to energy availability and how to use it here: https://marekdoyle.substack.com/p/heart-variability-and-stress-explained for those who who are interested
Thank you Chris. This is so good and so helpful. “idiosyncratic genetic impairments in energy metabolism that are rare as individual diagnosable diseases are likely to be common as heterozygous partial biochemical impairments. My suspicion is that it is very common to have one or a few “carrier status” mutations that do not lead to disease, but do form idiosyncratic bottlenecks in energy metabolism.” This is definitely my experience. Also “ A high-energy, low-entropy state allows us to maximally contract our muscles when contraction is needed, and fully relax our muscles when it is not. A low-energy, high-entropy state mixes these together and results in fatigue and muscle tension, or the rigidity, tremors, and slow movements of Parkinsonism.” I’ve been having issues with not being able to get to sleep and not entering deep sleep with one of the symptoms being leg tremors/restless legs and a mild recurrence of allergies. Finally yesterday I was able to put a stop to it with riboflavin. I guess it’s just something I’ve got to take religiously. And though sometimes it seems that high dose thiamine would be a good choice for me it always results in symptoms of riboflavin deficiency when I try it. “using imagination for sufficient hope instead of excessive worry” has been a discipline I’ve had to learn. The discipline of expecting good things instead of worrying about what bad thing might be around the corner. I imagine it as being in a room full of rats but remembering to leave the door cracked for the cat to get in. Gonna do some more reading on the ACAD enzyme you mentioned.
Glad you found in helpful!
Regarding riboflavin and thiamin, I would take a look at the diagram in the lactate/pyruvate ketone ratio article.
Okay, I’ll be sure to do that.
Great. Let me know if it helps.
Okay, this article definitely helped but I can’t yet express it in your colour language. I suspected I needed thiamine because my first wow supplement that brought me back to life was Benfotiamine. But raising the dose or trying high dose thiamine caused riboflavin deficiency symptoms -( mouth cracks, sore tongue, red eyes). But after correcting these symptoms more then a small dose of riboflavin (50 mg) made me really depressed. I was never able to afford metabolic testing for myself but my son had a urinary organic acid test that showed high succinic acid calling for riboflavin and elevated beta hydroxy butyric acid (so.?). But he too became a very sad little boy taking riboflavin. I added 5mg of biotin which was a positive thing. But here is where I could not go forward until I added niacin and high dose vitamin A. At this point I safely added 100 mg of riboflavin without symptoms of depression but when I added acetyl Carnitine and Borage oil (GLA) I started having mild symptoms that were corrected by riboflavin (200 mg in the morning and 200 mg at night). The symptoms were mild allergies, restless legs and trouble sleeping and cracked lips. So far I don’t notice any feelings of depression at even this high dose and my hypoglycaemia has gone away allowing me to not tank if I don’t eat immediately at meal times. So is niacin in the teal zone, lol? I was always very intolerant to corn and if I ate too much or had something with corn starch in it I would have terrible anxiety and skin rashes. This was corrected with niacin but the niacin has been causing mild vision problems which I believe are riboflavin related. There is an article online entitled The Clinical Manifestations of Nicotinic Acid and Riboflavin Deficiency (Pellagra) Sydenstricker where he claims that Pellagra is not one nutrient deficiency. In another article The Relation of Riboflavin to the Eye from The British Journal of Opthalmology it says “The most important function of the flavoprotein enzymes so far described is the oxidation of the nicotinic acid co-enzymes.” Is this why I could not tolerate riboflavin before niacin? My blurred vision problems from niacin seem to be more like cataracts caused by riboflavin deficiency then the maculopathy caused by a need for B6 and B6 makes my hypoglycaemia worse. Maybe I will need to add the B6 or B1 after the high dose riboflavin. I will keep looking for any symptoms of deficiency.
With ketones high he was not deficient in fatty acid oxidation, at least he was not as deficient as he was in the respiratory chain as suggested by the high succinate.
So this is vaguely supportive of a riboflavin-responsive respiratory chain problem.
However, riboflavin might still wake up fatty acid oxidation faster then it wakes up the respiratory chain.
Since carnitine will enhance fatty acid oxidation and burden the respiratory chain, and it reversed the riboflavin intolerance, I am going to guess the latter was from respiratory chain activity exceeding fatty acid oxidation, perhaps driven by too high of an NAD/NADH ratio.
Niacin and vitamin A are not as clear and they aren’t on the picture because they don’t fit neatly into the model.
However, I’m going to guess that they were increasing NADH (red zone activity in the diagram) if they were helping the riboflavin intolerance, but this is mainly for parsimony, which doesn’t guarantee accuracy.
So the other marker was extremely high oxalate levels which we did find relief from by eating low oxalate. Riboflavin is necessary for the conversion of tryptophan to niacin and for Pyridoxine as PLP. I’m just wondering how thiamine fits into all of this as a deficiency can also lead to high oxalate levels. I tried to add B6 to the mix yesterday and it was much more tolerable in that it didn’t cause immediate hypoglycaemia now that I’m on high dose riboflavin but it did cause a noticeable burning in my esophagus . B6 seems to lower calcium which is never a good thing for me. But without it the riboflavin at 200 mg made me feel good but tired. B6 gave me my umph back. Gonna see if thiamine is a better choice.
Thank you, wonderful article. Yes, perfecting Energy by seeking answers through genetics and labs!
I’m glad you loved it!
This is awesome! I feel like we are on the cutting edge. I feel privileged and keenly grateful to have access to Chris Masterjohns’s brain.
Thanks!
I have been looking at Sequencing.com and Nebulagenomics also. I have run my 23andMe and Ancestry dot com and FTDNA results through Promethease and seen a few interesting things on Strategene (note these DNA results providers can be inaccurate so not used for diagnosis, just for further research). I think I have a metabolic smoking gun somewhere though, that will turn up on whole exome or whole genome sequencing eventually. I've been using DNA for genealogy for quite a few years and there are quite a few early deaths on my dad's side including suicides. A deep dive into the family tree can be instructive.
I hope you get the results you are after!
https://www.researchgate.net/profile/Gidon-Akler
https://tovanahealth.com/home/about/
They do offer discounts for families and groups.
I meant to say the raw genetics results from Ancestry, 23andMe and FTDNA are not validated and some errors do show up in their reporting (Promethease notes some of these; there are false negatives and false positives from these companies). Dante, Sequencing and Nebula use a different method as far as I can tell with more reads. I am currrently waiting on results for WES from TovanaHealth avg 80x, which will be reviewed by their geneticist Gidon Akler, MD and includes genetic counseling and reporting that is periodically updated. I actually signed up for it a few years ago through FTDNA (no longer offered there) and when I timed out trying to fill out the medical history form, I didn't have the mojo to start over right then. And then I totally forgot about it until recently. I may have other family members test there or elsewhere. Once I have my data I'll be able to run it through Sequencing's or Nebula's reports (they allow uploads) or consult with you on how to manage the bottleneck or bottlenecks.
Nice. I’m also planning on comparing and contrasting genetic reads from different countries later in the year.
Nebula is the kit/lab provider for Sequencing dot com but their reports are different. Nebula was recently acquired by a publicly held company so you can look at the ownership and their plans to further bring down the cost and increase market visibility and accessibility of WGS while addressing orphan disease drug development. For me I’d like to see nutritional interventions first.
Yes but genetics impact nutritional requirements.
Yes, of course! Energy metabolism trumps everything! I believe this is why the carnivore diet fixes nearly everything for nearly everyone! It did for me. Except for a few seasonal allergies here and there... for which I'll try your riboflavin trick asap as it is still May! For some of my carnivore years the allergies have been better than others (sometimes nonexistent), but I haven't been eating eggs this year and it's worse... and I'm homozygous MTHFR C677 on a high fat diet so ... riboflavin is not a bad idea.
I’m glad the carnivore diet is working for you!
I think you are generalizing too much from your own experience and those you pay the most attention to. “Nearly everyone” has never gone within ten miles of a carnivore diet, let alone tried it and had it fix everything for them.
Yes, I meant "nearly everyone who has tried it". (Based on my years of hanging around carnivore internet groups, and seeing so many amazing results.) Much more than say, Morley Robbins' Magnesium group. There you sometimes find people saying they've decreased such and such symptoms by 50%, but in the carnivore groups so many people say they have "completely healed" all, or almost all, of their issues, while any remaining ones are 80% better. Except for weight-loss... seems to be the one thing that doesn't happen for some subset of people, though other symptoms get better. I mean I think it's a combination of improved nutrition (so many more B vitamins?), and no plant toxins. Speaking of which, I'm trying to learn more about plant sterols... seems to me they are highly suspect. Why would the body be so interested in eliminating them that it is willing to get rid of perfectly good real cholesterol in order to do so?
I don’t doubt your experience in the forums, though I have several carnivore clients who have lots of residual stuff to work on, and I don’t think it’s always about plant toxins, for some it’s eliminating carbs.
But RCP is a very simple program that is bizarrely focused on one nutrient so it isn’t surprising that you don’t see the dramatic effects you find in people who cut out the entire plant kingdom.
I just don’t think you would see this generalize to a random sample of people they say you see it in those who have self-selected to spend time in these forums.
The body makes its own cholesterol so is not obsessed with holding on to every last drop from food and has no particular need for plant sterols.
This is a great comprehensive overview. I’m interested if you’ve looked at Morley Robbins theories around iron and iron deficiency. Also, your thoughts on mitochondrial function and nutritional support for improving it.
The latter question is exactly what is answered above, though “mitochondrial function” is simply the majority of energy metabolism and otherwise a distraction as a distinction from energy metabolism outside the mitochondria.
I have listened to Robbins’s book and referenced it in the May AMA.
Could psoriasis be caused by a retinyl esters toxicity?
In 1947, the New Enlgland Journal of Medicine published a study in which 11 severe psoriasis patient were put on a diet low in vitamin A and carotene: 7 complete clearing of lesions, 2 marked improvement, 1 slight improvement, 1 no improvement.
Another study shows that psoriasis patients have slightly low retinol-binding protein (RBP) and high dehydroretinol, along with other vitamin A related abnormalities.
https://www.nejm.org/doi/full/10.1056/NEJM194706192362503 (1947 study)
http://www.ncbi.nlm.nih.gov/pubmed/4096526 (vitamin A abnormalities study)
Perhaps. Certainly vitamin A toxicity involves skin lesions that seem related in some way. And it is interesting that sun helps in part through D metabolites.
Thanks for that I have Psoriasis 48 years, may look into lowering those.
I really wish that Chris Masterjohn had taken time out of his busy 24/7 schedule to tell us how to lower retinyl esters without hurting vitamin A status. I haven't had time to research this question but I have been questioning if lowing vitamin A intake would help. Zinc could be part of the puzzle.
Another interesting aspect of psoriasis is that under stress, cortiso. levels in people with psoriasis drop. However, the adrenals function just fine in test, they produce cortisol when stimulated with ATCH. This suggest that understress, there are biological changes that prevent the adrenals from making cortisone, which I suspect is a lack of an unknown substrate.
If nothing else works for you psoriasis, I would suggest trying strontium. I would use high doses for a few weeks, and if it works I would continue with caution. A short-term high dose is safe, and but long term high dosing should be done with intelligence. Read my blog on strontium for more info. Start with this post. https://joeanstett.substack.com/p/benefits-of-strontium
Since you are commenting on the energy article I would point out that I did in fact tell you that, at least in one context: improved NAD+/NADH ratio.
The fact that you take the time to answer our question amazes me. Thanks.
You’re welcome and thank you for your appreciation!
Thanks Joe,I will read that with interest.
I went to see Mazin AlKafaji,considered an expert in treating skin condition via Chinese medicine, this was 2003,in fact for perhaps the first time my P cleared to within 3% and I felt marvellous,unfortunately after about 18 months it slowly returned but it was truly a wonderful 18 months.just recalled I got a lot of sun last year and also took sacromyces boulardi and until winter was almost clear so a much shorter period.
Thanks again I’ll definitely look into your post .
Then, why not recommend to supplement flush niacin, as a general rule for the population, to increase NAD+ through the Preiss-Handler pathway?
Because not everyone needs a pharmacological boost to NAD, and even though NAD declines in aging and disease states you can easily fix that with moderate dietary improvements.
At the population level you will cause glycine and methyl group depletion in many people.
I’m someone who benefits so much from niacin and glycine and methyl groups send me to a bad place. The other day I was reading an article on how cats have low conversion of tryptophan to niacin, lower delta 6 desaturase levels and need to stay away from oxalate. It seems I am a cat, lol. I think I saw an image once of St. Christopher with a dog’s head ;) I wonder if dogs benefit from more glycine, lol. This is why cats should not be fed dog food ;) Anyways, my point in all this silly nonsense is that I agree that we can’t be suggesting everyone take niacin or glycine as a general rule.
Hahaha yes this is why population-level megadosing recommendations would be a disaster.
Amazing!! This article is well thought out. Chris is many leagues above most of the nutrition gurus in the space at the moment, thank you for your work. W/ regards to energy metabolism, the most recent change I have made in my health has been vitamin B1 megadosing for my IBS. It has massively reduced bloating, gas, indigestion and as a side effect has improved my energy levels! I'm not sure of the effects on my blood sugar though which would be interesting. Thanks to Eliot Overton for making me aware of this as well.
Thanks! This likely shows that your IBS is caused by energy metabolism impairment and isn’t a “gut issue” at root cause.
which type of B1 and how did you dose it?
What is the fee for the results from the Sergey Andryukhin’s app Gene Inspector from already done Dante WGS?
That is under negotiation, but currently it is only accessible in a consultation context and until the negotiations are finished clients are not being charged directly.
Hey- so much great information! There’s so much testing here. When people work with you, can you narrow down which tests are most relevant? Or, do you still suggest doing everything listed above?
I’m a big fan of narrowing down everything, though if money isn’t an issue, people will get faster results going comprehensive.
You can use the Cheat Sheet cost-saving approach to DIY the narrowing, or I can help in a consult.
Definitely food for thought (pun unintended)... Interesting to see a kind of grand unified theory for wellness, based on energy metabolism. However, your earlier remarks in the article suggested another important dimension, that of entropy. The article does not appear to address directly the question of entropy reduction.
This might be the point where a novice like me might ask questions about inflammation, for example, or even psychoneuroendocrinoimmunology. There may be a grand unified theory, but it appears to this layperson to lie in the interaction among several critical systems. I'd appreciate your thoughts. Thanks!
It does address that. The role of energy is to reduce entropy. I linked to my first two lessons in energy metabolism where this is discussed in more detail, and this is also basic science in, for example, Chem 101.
Yes, I am proposing the grand underlying foundation on top of which all systems operate. Its sort of like operating system vs program or app.
See for example the two bullet points in the first section after "The simplest way to view this is as follows."
The first bullet point is the operating system. The second refers to all the apps.
Thanks, Chris, for a prompt reply. I am going to compare your essay with a fascinating introduction to PNEI on MDPI here: https://www.mdpi.com/2673-396X/2/3/22
Cool, let me know what you come up with in the comparison.
if you have an allergy to sulfa oral medications, would there be a possible link to these sulfur issues and histamines?
It may or may not, it would be more likely if the reaction conforms to the health issues described in the Sulfur Protocol.
Great article. Just signed up on the 101 course, I actually got the cliff notes last year. Just wondering if you've looked into how caffeine can affect micronutrients absorption, specifically vitamin D? I drink a few cups of black and green tea throughout the day, sometimes with meals. Really appreciate your research, and can't wait to get my lessons from the 101 course!
Interesting question. I think if you take it separate from the D it should be fine, and it's probably not caffeine that has the biggest impact of coffee but rather other components.
Awesome, you're right that there's a lot of compounds in tea that can interact with other nutrients. Btw LOVE the vitamin a lesson and can't wait for B1 tomorrow!! 😍😍
Oh I missed that point and focused on caffeine and went to coffee. Yes tea is full of stuff that negatively impacts nutrient absorption.
😨 didn't know about this! most conventional advice says tea is good for you with antioxidant and all that, and just watch for caffeine past certain time of day. Would love to know more about what could be negatively impacting nutrient absorption. Btw fascinating lesson on riboflavin, time to liver it up!
Awesome!