Harnessing the Power of Nutrients: Mastering Nutrition

039: Creatine: Far More Than a Performance Enhancer

Chris Masterjohn, PhD — Thu, 09 Jun 2022 15:03:40 GMT

Originally published December 21, 2017.

Introduction

Creatine, best known for its ability to build muscle and enhance athletic performance, is also critical for fertility, digestion, mental health, protecting your hearing, and keeping your skin vibrant and youthful.

In this episode, Alex Leaf of Examine.Com and I discuss everything you need to know about creatine. I focus on the basic science of what it does in the body, and Alex takes the lead in discussing the practicalities of supplementation.

Show Notes

0:01:47 Cliff Notes
0:06:16 Introduction
0:06:58 Symptoms of rare creatine biosynthesis disorders: global developmental delay, intellectual disabilities, hyperactivity, autistic behavior, and gastrointestinal defects
0:09:11 Creatine’s role in skeletal muscle as a buffer of the ATP supply
0:14:50 Creatine increases muscular contractile power by reducing ionic strength.
0:16:50 Creatine acts as a pH buffer.
0:19:57 Creatine is constantly recycling ATP, even at rest, but during intense exercise, creatine is used up faster than it can be recycled.
0:22:52 The creatine kinase system is especially important in cells and tissues that have 1) fluctuating energy demands, 2) high energy demands, or 3) long, polarized structures.
0:26:17 Creatine’s role in cells with high energy demands: gastric acid secretion in the stomach, nutrient absorption in the intestines, maintenance of intestinal villi
0:29:16 Creatine’s role in cells that are long and polarized: sperm, photoreceptors of the retina, hair cells in the inner ear, and skin (keratinocytes, hair follicles, and sebaceous glands)
0:33:46 Creatine synthesis is dependent on methylation, glycine, and arginine; creatine supplementation can cut the demand for methylation almost in half.
0:37:04 We have about 120 grams of creatine in our body and lose 2-3 grams per day via spontaneous degradation to creatinine.
0:38:36 Creatine supplementation is a strategy to help with methylation problems.
0:40:25 Alex Leaf discusses the practicalities of creatine supplementation; for dosing, 3-5 grams per day on a consistent basis.
0:43:04 Some people (about 20-30% of the population) are non-responders to creatine.
0:44:37 The best form of creatine to take is monohydrate; there is no evidence for the superiority of any other form, and some are inferior.
0:49:54 Timing of creatine supplementation
0:55:25 Why it doesn’t make sense to cycle creatine
0:59:00 Creatine may increase DHT, which might worsen hair loss if you have male-pattern baldness, but there is no direct evidence of this.
1:02:26 Rare anecdotal reports of insomnia from creatine supplementation; this is likely a temporary effect of cutting the methylation demand in half.
1:06:42 Creatine will not damage your kidneys; cystatin C as an alternative marker of kidney function.
1:11:54 Creatine causes weight gain by drawing more water into muscle tissue.
1:13:46 Wrapping up

Creatine Supplement Recommendations

I recommend Optimized Nutrition micronized creatine powder. If you buy a single bottle, it is available for Amazon Prime free one-day shipping, and costs $13.60 per bottle, which is 2.3 cents per gram or 11.5 cents per day when taken at 5 grams per day. You can save 5% if you subscribe to it, 15% if you subscribe to at least four other items, and 20% if you also pay with an Amazon store card.

If you expect to take creatine while traveling, I recommend getting Optimized Nutrition creatine caps. Carrying around capsules is a lot easier than little baggies of powder. This raises the price to about 14 cents per day but the convenience may well be worth it.

Creatine in Foods: The Database

This is the only database of the creatine content of foods on the internet. Check it out here:

Creatine in Foods: The Database

Lab Tests Related to Creatine

If you are supplementing with creatine, you will likely have at least a moderate increase in your serum creatinine. Creatinine is a breakdown product of creatine and its serum level is usually used to estimate the rate at which your kidneys are working. This is called the glomerular filtration rate (GFR). If your creatinine rises in response to creatine supplementation, it could potentially give a false signal that your kidneys are working less efficiently. Quest Diagnostics offers an estimated GFR based on cystatin C, which should be independent of creatine supplementation and avoid this problem.

In theory, you can test your serum creatine (Quest, LabCorp) to see if your endogenous synthesis is adequate. However, these tests are designed to look at diseases that can elevate creatine levels and the reference range would be difficult to interpret. Similarly, Quest offers a creatine biosynthesis disorders panel that is actually designed to look for inadequate synthesis, but the reference range is designed to separate people with severe genetic disorders from everyone else, so will be too broad to be used for moderately decreased creatine synthesis.

A plasma amino acid analysis (my preference: Genova ION Profile + 40 amino acids; also: LabCorp, Quest, Great Plains, and the NutrEval) may reveal low glycine or arginine levels, which could compromise creatine synthesis.

Homocysteine (LabCorp, Quest), when elevated, suggests deficient methylation, which also would compromise creatine synthesis. Homocysteine is included on the Genova ION and Great Plains amino acid profiles listed above but not the others.

For further methylation-related testing, see the lab tests listed in Living With MTHFR (under show notes).

Creatine Links and Research

Walliman, et al. The creatine kinase system and pleiotropic effects of creatine. 2011.

Brosnan, et al. The metabolic burden of creatine synthesis. 2011

Brosnan and Brosnan. The role of dietary creatine. 2016.

Gualano et al. Effect of short-term high-dose creatine supplementation on measured GFR in a young man with a single kidney. 2010.

Gualano et al. In sickness and in health: the widespread application of creatine supplementation. 2012.

Rackayova, et al. Creatine in the central nervous system: From magnetic resonance spectroscopy to creatine deficiencies. 2017.

Jagim, et al. A buffered form of creatine does not promote greater changes in muscle creatine content, body composition, or training adaptations than creatine monohydrate. 2012.

van der Merwe, et al. Three weeks of creatine monohydrate supplementation affects dihydrotestosterone to testosterone ratio in college-aged rugby players. 2009.

Steenge, et al. Stimulatory effect of insulin on creatine accumulation in human skeletal muscle. 1998.

Green et al. Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans. 1996.

Syrotuik and Bell. Acute creatine monohydrate supplementation: a descriptive physiological profile of responders vs. nonresponders. 2004.

Gill et al. Creatine serum is not as effective as creatine powder for improving cycle sprint performance in competitive male team-sport athletes. 2004.

Spillane. The effects of creatine ethyl ester supplementation combined with heavy resistance training on body composition, muscle performance, and serum and muscle creatine levels. 2009.

A patent on creatine nitrate.

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051: Ask Us Anything About Sports Nutrition with Chad Macias, Danny Lennon, and Alex Leaf | May 25, 2019

Chris Masterjohn, PhD — Wed, 23 Oct 2019 09:30:00 GMT

On May 25, members of the CMJ Masterpass joined me, Chad Macias, Danny Lennon, and Alex Leaf in a live Zoom meeting to ask us anything about sports nutrition, and here’s the full recording!

We talk about things like:
Is there a risk of depleting histidine with beta-alanine supplementation?
What’s the best form of fuel to use during a workout?
Candy, or something else?
Nutritional strategies for recovery from soft tissue injuries to muscles, tendons and ligaments from lifting?
Is AMPK the primary regulator of mitochondrial biogenesis in muscle, and does it matter?
Can riboflavin help with exercise performance?
Why the post-workout anabolic window DOES matter, and why you should NOT eat too much protein BEFORE lifting.
Take BCAAs, or just eat protein?
Should athletes cycle caffeine, and does it matter if they are fast or slow oxidizers?
Nitric oxide: does it have important effects by modifying proteins, rather than just affecting blood flow?
Is it delayed-onset muscle soreness if it happens all the time? Or is it a pathology?
Transdermal carnosine (Lactigo) for fibromyalgia, the role of glutamate and neurotoxicity in fibromyalgia and delayed-onset muscle soreness (DOMS), and my own experience with using high blood glutamate to identify how acidity was wrecking me after workouts.
Maximizing muscle growth and optimizing performance on a low-protein diet.
Best time to take Tru Niagen (nicotinamide riboside) and TMG (trimethylglycine), especially the purpose of increasing exercise tolerance.
How important are refeeds for dieters?
Carbohydrate periodization for endurance athletes?
Is there any value to training low during those times where you depend on glucose to either try to train your body to better tap into limited glycogen stores or to try to create a better aerobic response?
Besides leucine, what could help increase protein synthesis to prevent sarcopenia in older adults who strength-train regularly?
For muscle growth, what generally applies to everyone?

All this and much more!

Listen to the Audio

I highly recommend watching the video above so you benefit from seeing the data on the slides, but you can also listen to the audio here:

Show Notes

02:54 Risk of depleting histidine in supplementing with beta-alanine

08:40 Discussions on mix of glucose and fructose and other nutrients during exercise and any

brand recommendations.

19:17 Important nutritional strategies that could help with recovery from soft tissue injuries like

muscles, tendons and ligaments from lifting?

22:55 Is AMPK the primary regulator of mitochondrial biogenesis in muscle or are there are other important pathways that need to be considered and which can be targeted by nutrition in addition to endurance training?

28:43 Discussions on riboflavin

39:30 Protein timing in the window post training for maximizing protein accretion.

44:26 Discussions on the difference of HMB form (calcium salt form or not)

49:07 Pe-workout protein ingestion

54:34 Discussions on BCAAs

59:13 Summary of what helps muscle growth.

1:00:28 How should caffeine be cycled if being used to enhance weightlifting performance and/or weight loss? Is there a difference for fast or slow metabolizers of caffeine?

1:04:25 Discussions more on caffeine

1:09:30 Caffeine on Weightlifters

1:14:30 Nitric Oxide on affecting blood flow.

1:19:35 Discussions on using pH as an analogy in energy metabolism.

1:20:42 Discussions on problems with delayed onset muscle soreness and overall poor soft tissue quality

1:24:34 Discussion on introducing introducing carnosine fibromyalgia patients

1:30:04 Discussions on glutamate

1:31:46 Recommendations for maximizing muscle growth and optimizing performance on a low-protein diet.

1:41:59 Best time to take Tru Niagen, nicotinamide riboside and TMG, trimethylglycine, especially the purpose of increasing exercise tolerance.

1:52:24 Discussions on refeeds

1:54:42 Carbohydrate periodization for those endurance athletes

1:59:12 Is there's any value to training low during those times where you depend on glucose to either try to train your body to better tap into limited glycogen stores or to try to create a better aerobic response?

2:08:27 Besides leucine, what could help increase protein synthesis to prevent sarcopenia in older adults who strength-train regularly?

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050: Ask Us Anything About Hormones with Dr. Carrie Jones | May 10, 2019

Chris Masterjohn, PhD — Sat, 19 Oct 2019 09:30:00 GMT

On May 10, members of the CMJ Masterpass joined me and Dr. Carrie Jones in a live Zoom meeting to ask us anything about hormones, and here’s the full recording! We talk about things like:

What time of day is best to take T4 and/or T3?
How to use pregnenolone to manage perimenopausal insomnia?
Is insomnia different between people who are and aren't on HRT?
Estrogen’s effect on the kynurenine pathway could be keeping you up at night.

What about men with high estrogen?
Over-the-counter supplements to lower SHBG and increased free testosterone? Mycotoxins
Iodine, fatigue, and “detox” reactions.
Loss of libido and sexual sensation with the LEEP procedure: could progesterone and vitamin E help?
What else?
Should I be on testosterone replacement therapy? Supporting hormones with nutrition.
Why is early morning waking a characteristic symptom of depression and what other conditions have early waking as a symptom?
Causes for night sweats in men?
Nutritional advice for breast cancer prevention, and the HRT question.
Water retention near menstruation.
Why would a woman have no cycle? Why would a woman have an anovulatory cycle? What can be done to reverse hypothyroidism other than taking thyroid hormone?

All this and much more!

Listen to the Audio

I highly recommend watching the video above so you benefit from seeing the data on the slides, but you can also listen to the audio here:

Show Notes

04:20 Introduction

07:55 Guidance on what time of day it is best to take T4 and/or T3?

10:37 The use of pregnenolone to manage perimenopausal symptoms, particularly insomnia

12:30 Insomnia is different between people who are and aren't on HRT?

14:15 Estrogen and kynurenine pathway

19:02 Aromatizing in Men

21:40 Over-the-counter supplements to lower SHBG and increased free T, boron, zinc, various herbs

24:20 Discussion about Mycotoxin.

28:48 Discussions in Iodine and mild fatigue and detox.

35:14 Discussion on soft tissue calcification.

40:40 Discussion on LEEP Procedure

45:53 Discussion on testosterone

54:30 Suggestions on supplements to assist with delayed onset muscle soreness.

55:48 How does the body make hormones and what nutrients and foods do they need to do this?

59:29 Know more about hormone production.

1:09:00 Why is early morning waking a characteristic symptom of depression and what other conditions have imbalances of early waking as a symptom?

1:17:00 When should you consider increasing progesterone or estrogen.

1:20:30 Causes for night sweats in men.

1:25:00 Dietary nutritional advice for breast cancer prevention, macronutrient ratios, micronutrient intakes, et cetera. Also any thoughts on risks and benefits of HRT in perimenopause relative to breast cancer risk?

1:28:29 Discussions on Methylation

1:34:35 Struggles with water retention around period.

1:39:23 Why would a woman have no cycle? Why would a woman have an anovulatory cycle?

1:45:02 What can be done to reverse hypothyroidism other than taking thyroid medicine?

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049: Pantothenic Acid, Part 2 (Foods, Lab Tests, and Supplements)

Chris Masterjohn, PhD — Wed, 09 Oct 2019 17:02:00 GMT

Show Notes

01:14 Recap of Part 1

06:39 Cliff Notes

08:53 The case for why urinary pantothenic acid is the only legitimate marker of nutritional status and why blood concentration is not a useful marker

22:25 How the Adequate Intake for pantothenic acid was established

23:44 The idea of pantothenic acid balance and comparing it to nitrogen balance

35:40 What I think the recommended pantothenic acid intake should be

39:08 The effect of different forms of food processing on loss of B5 from foods

44:23 Dietary sources of B5, divided into five tiers

48:13 The contribution of the gastrointestinal microbiome to B5 status

01:00:14 Causes of suboptimal status or deficiency of pantothenic acid

01:06:01 Prevalence of suboptimal pantothenic acid status

01:06:34 When I think supplementation with high doses is warranted

01:07:12 What are some of the benefits, besides fixing deficiency, that we might get from supplementing with pantothenic acid or its derivatives?

01:07:28 The use of pantethine as a therapeutic for dyslipidemia

01:17:03 Comparison of pantethine supplementation to high-dose niacin for lowering blood lipids

01:19:35 Topical dexpanthenol for skin health and wound healing

01:23:15 The effect of pantothenic acid supplementation on acne

01:26:44 The effect of pantothenic acid supplementation on sports performance

01:35:00 The effect of pantothenic acid supplementation on hair health

01:36:36 The effect of pantothenic acid supplementation on arthritis

01:42:33 Summary of pantothenic acid supplementation

01:46:30 Is there any reason to use pantothenic acid specifically versus other forms such as pantethine?

01:48:51 Does it matter if you take pantothenic acid in divided doses or all at once?

01:51:10 Does it matter if you take pantothenic acid with food?

01:52:53 Two insightful quotes from papers on pantothenic acid

01:58:10 Pantothenate should be known as the B vitamin that we know the least about, not the B vitamin that we are least likely to become deficient in.

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048: Pantothenic Acid, Part 1 (What It Is and Why We Need It)

Chris Masterjohn, PhD — Wed, 19 Jun 2019 16:55:00 GMT

Time Stamps

00:37 Cliff Notes

08:01 Symptoms of experimentally induced pantothenic acid deficiency

09:56 It is thought that pantothenic acid deficiency doesn’t occur naturally.

12:58 Experiments inducing pantothenic acid deficiency

20:05 Signs and symptoms of suboptimal pantothenic acid status

20:53 Is there pantothenic acid toxicity?

24:52 Hypothetical problems of taking high doses of pantothenic acid

25:53 What pantothenic acid is

29:27 Comparisons to niacin and riboflavin

31:13 Roles of coenzyme A

40:02 Roles of 4’-phosphopantetheine

42:11 Burning fat requires 20% more vitamin B5 than burning carbohydrate; and why in the context of severe deficiency of B5 or impairment in the metabolism of B5 a high-fat diet could have devastating consequences.

47:09 The importance of the ratio of acetyl-CoA to free CoA in regulating many metabolic pathways

55:02 There are metabolic disorders, such as fatty acid oxidation disorders, that compromise the pool of coenzyme A.

57:02 Synthesis of coenzyme A

01:00:47 How coenzyme A synthesis is regulated

01:05:38 Degradation of coenzyme A

01:09:44 The physiology of pantothenic acid absorption

01:19:29 A 2015 paper showed that 4’-phosphopantetheine can cross cell membranes via passive diffusion.

01:22:59 The physiology of pantothenic acid transport in the blood

01:26:11 Cellular uptake of pantothenic acid from the blood

01:27:20 Tissue distribution of pantothenic acid

01:30:00 There may be a particularly high need for pantothenic acid in adolescence.

01:31:01 Mothers actively transfer pantothenic acid to their fetuses and into their milk at their own expense.

01:33:29 Pharmacokinetics of supplementation

01:42:20 A case for why food is superior to supplements for vitamin B5

01:46:41 Inborn errors of coenzyme A metabolism include pantothenate kinase-associated neurodegeneration (PKAN).

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047: Niacin, Part 2: Blood Tests, Foods, and Supplements

Chris Masterjohn, PhD — Sat, 16 Mar 2019 16:48:00 GMT

Introduction

In part 1 we covered what niacin is and why you need it. Here’s part 2, where Alex Leaf and I cover blood tests, foods, and supplements!

How much do we need? The RDA has some flaws, including claiming women need less than men, when all the evidence shows women need *more* than men.
Why eating enough protein is so essential, yet so unreliable as a way of boosting niacin status.
How the niacin in your coffee, seeds, and grains is all locked up and unavailable, and how to release it through proper preparation. Do you drink light roast or dark roast? You may either hate or love this episode… or you might just switch coffees.
Should we take high-dose niacin to lower cholesterol? Alex has a theory on how we can do that without getting diabetes. 😬
High-dose niacin can cause liver failure and can kill lab mice. But Alex and I know how to steer clear of that problem!
NAD-boosting supplements are the new darling of the anti-aging industry. But should we take nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), or should we endure all the whole-body burning 🔥 that the folks injecting NAD+ are so hyped up about? We discuss the promises and problems of these approaches.
Why you should match glycine to one form of niacin and trimethylglycine (TMG) to all of them.

Show Notes

00:38 Cliff Notes

01:35 Recap of Part 1

09:33 Markers of niacin status

11:34 Methylated metabolites of niacin in the urine as a marker of niacin status

13:07 Caveat to using methylated metabolites of niacin in the urine as a marker of niacin status

14:17 Erythrocyte NAD(H)/NADP(H) ratio, the “niacin number,” as a marker of niacin status

16:57 Caveat to the niacin number as a marker of niacin status

22:35 Critique on how the RDA for niacin was established

34:14 How protein intake affects the dietary requirement for preformed niacin

36:50 Estrogen regulates the synthesis of niacin from tryptophan.

37:37 In men in particular, niacin synthesis from tryptophan might just be a way to clear excess tryptophan.

39:33 General discussion about protein requirements

43:47 How different forms of food processing, such as nixtamalization, fermentation, and sprouting, increase the bioavailability of niacin

46:53 Niacin in coffee

47:54 Niacin in nutritional yeast

48:18 Dietary sources of niacin, divided into five tiers

53:59 Niacin in herbs and spices, including spirulina

57:48 The contribution of the microbiome to niacin status is not well studied.

58:58 Where we would expect to see niacin deficiency

59:40 Risk factors for niacin deficiency include Hartnup’s disease, megaduodenum, intestinal malabsorption, carcinoid tumors, certain drugs, alcoholism, HIV/AIDS, and deficiencies of iron, riboflavin, and B6.

01:03:54 Risk factors for suboptimal niacin status include a diet based on unprocessed whole grains, a diet based on sugar and fat, a diet low in non-collagen protein, any form of cellular damage, and low ATP levels.

01:08:44 How metformin and berberine could affect niacin status

01:11:30 The effect of leucine and muscle growth on niacin status

01:13:55 The prevalence of inadequate niacin intake and niacin deficiency

01:18:02 Contributors to niacin toxicity

01:19:09 The use of nicotinic acid to benefit blood lipids and reduce heart disease risk

01:25:16 Potential side effects of taking nicotinic acid to manage blood lipids include the flushing reaction, liver harm, and increased diabetes risk.

01:28:23 The mechanism behind high-dose nicotinic acid-induced insulin resistance and how you could mitigate it

01:42:02 Rodent studies of nicotinamide riboside supplementation

01:44:58 Human studies of nicotinamide riboside supplementation

01:50:34 Why the rodent studies of nicotinamide riboside supplementation look more promising than the human studies

01:58:17 What is the probability that someone would get longevity benefits from supplementing with nicotinamide riboside?

01:59:16 Whether or not Alex and Chris will start supplementing with niacin after doing the research for this podcast

02:00:16 Should someone with hypercholesterolemia consider taking nicotinic acid? How should they manage the side effects, and which form is best?

02:04:54 Does it matter if niacin is taken with food?

Niacin Links and Research

Yvan-Charvet L, Kling J, Pagler T, Li H, Hubbard B, Fisher T, Sparrow CP, Taggart AK, Tall AR. Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib. Arterioscler Thromb Vasc Biol [Internet]. 2010 Jul;30(7):1430–1438. Available from: http://dx.doi.org/10.1161/ATVBAHA.110.207142 PMCID: PMC2917780

Khera AV, Patel PJ, Reilly MP, Rader DJ. The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality. J Am Coll Cardiol [Internet]. 2013 Nov 12;62(20):1909–1910. Available from: http://dx.doi.org/10.1016/j.jacc.2013.07.025 PMID: 23933538

Kamanna VS, Ganji SH, Kashyap ML. Recent advances in niacin and lipid metabolism. Curr Opin Lipidol [Internet]. 2013 Jun;24(3):239–245. Available from: http://dx.doi.org/10.1097/MOL.0b013e3283613a68 PMID: 23619367

Garg A, Sharma A, Krishnamoorthy P, Garg J, Virmani D, Sharma T, Stefanini G, Kostis JB, Mukherjee D, Sikorskaya E. Role of Niacin in Current Clinical Practice: A Systematic Review. Am J Med [Internet]. 2017 Feb;130(2):173–187. Available from: http://dx.doi.org/10.1016/j.amjmed.2016.07.038 PMID: 27793642

Wang W, Basinger A, Neese RA, Christiansen M, Hellerstein MK. Effects of nicotinic acid on fatty acid kinetics, fuel selection, and pathways of glucose production in women. Am J Physiol Endocrinol Metab [Internet]. 2000 Jul;279(1):E50–9. Available from: http://dx.doi.org/10.1152/ajpendo.2000.279.1.E50 PMID: 10893322

Goldie C, Taylor AJ, Nguyen P, McCoy C, Zhao X-Q, Preiss D. Niacin therapy and the risk of new-onset diabetes: a meta-analysis of randomised controlled trials. Heart [Internet]. 2016 Feb;102(3):198–203. Available from: http://dx.doi.org/10.1136/heartjnl-2015-308055 PMCID: PMC4752613

Maciejewski-Lenoir D, Richman JG, Hakak Y, Gaidarov I, Behan DP, Connolly DT. Langerhans cells release prostaglandin D2 in response to nicotinic acid. J Invest Dermatol [Internet]. 2006 Dec;126(12):2637–2646. Available from: http://dx.doi.org/10.1038/sj.jid.5700586 PMID: 17008871

Hanson J, Gille A, Zwykiel S, Lukasova M, Clausen BE, Ahmed K, Tunaru S, Wirth A, Offermanns S. Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice. J Clin Invest [Internet]. 2010 Aug;120(8):2910–2919. Available from: http://dx.doi.org/10.1172/JCI42273 PMCID: PMC2912194

Dunbar RL, Gelfand JM. Seeing red: flushing out instigators of niacin-associated skin toxicity. J Clin Invest [Internet]. 2010 Aug;120(8):2651–2655. Available from: http://dx.doi.org/10.1172/JCI44098 PMCID: PMC2912206

Stern RH, Spence JD, Freeman DJ, Parbtani A. Tolerance to nicotinic acid flushing. Clin Pharmacol Ther [Internet]. 1991 Jul;50(1):66–70. Available from: https://www.ncbi.nlm.nih.gov/pubmed/1855354 PMID: 1855354

Stern RH, Freeman D, Spence JD. Differences in metabolism of time-release and unmodified nicotinic acid: explanation of the differences in hypolipidemic action? Metabolism [Internet]. 1992 Aug;41(8):879–881. Available from: https://www.ncbi.nlm.nih.gov/pubmed/1640866 PMID: 1640866

Kourtzidis IA, Dolopikou CF, Tsiftsis AN, Margaritelis NV, Theodorou AA, Zervos IA, Tsantarliotou MP, Veskoukis AS, Vrabas IS, Paschalis V, Kyparos A, Nikolaidis MG. Nicotinamide riboside supplementation dysregulates redox and energy metabolism in rats: Implications for exercise performance. Exp Physiol [Internet]. 2018 Oct;103(10):1357–1366. Available from: http://dx.doi.org/10.1113/EP086964 PMID: 30007015

Piepho RW. The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol. Am J Cardiol [Internet]. 2000 Dec 21;86(12A):35L–40L. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11374854 PMID: 11374854

Poddar SK, Sifat AE, Haque S, Nahid NA, Chowdhury S, Mehedi I. Nicotinamide Mononucleotide: Exploration of Diverse Therapeutic Applications of a Potential Molecule. Biomolecules [Internet]. 2019 Jan 21;9(1). Available from: http://dx.doi.org/10.3390/biom9010034 PMCID: PMC6359187

Fricker RA, Green EL, Jenkins SI, Griffin SM. The Influence of Nicotinamide on Health and Disease in the Central Nervous System. Int J Tryptophan Res [Internet]. 2018 May 21;11:1178646918776658. Available from: http://dx.doi.org/10.1177/1178646918776658 PMCID: PMC5966847

Chi Y, Sauve AA. Nicotinamide riboside, a trace nutrient in foods, is a vitamin B3 with effects on energy metabolism and neuroprotection. Curr Opin Clin Nutr Metab Care [Internet]. 2013 Nov;16(6):657–661. Available from: http://dx.doi.org/10.1097/MCO.0b013e32836510c0 PMID: 24071780

Dollerup OL, Christensen B, Svart M, Schmidt MS, Sulek K, Ringgaard S, Stødkilde-Jørgensen H, Møller N, Brenner C, Treebak JT, Jessen N. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. Am J Clin Nutr [Internet]. 2018 Aug 1;108(2):343–353. Available from: http://dx.doi.org/10.1093/ajcn/nqy132 PMID: 29992272

Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun [Internet]. 2018 Mar 29;9(1):1286. Available from: http://dx.doi.org/10.1038/s41467-018-03421-7 PMCID: PMC5876407

Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, Tian R, Shen DD, O’Brien KD. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One [Internet]. 2017 Dec 6;12(12):e0186459. Available from: http://dx.doi.org/10.1371/journal.pone.0186459 PMCID: PMC5718430

Morgan JM, Capuzzi DM, Guyton JR. A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients. Am J Cardiol [Internet]. 1998 Dec 17;82(12A):29U–34U; discussion 39U–41U. Available from: https://www.ncbi.nlm.nih.gov/pubmed/9915660 PMID: 9915660

Keenan JM. Wax-matrix extended-release niacin vs inositol hexanicotinate: a comparison of wax-matrix, extended-release niacin to inositol hexanicotinate “no-flush” niacin in persons with mild to moderate dyslipidemia. J Clin Lipidol [Internet]. 2013 Jan;7(1):14–23. Available from: http://dx.doi.org/10.1016/j.jacl.2012.10.004 PMID: 23351578

Soudijn W, van Wijngaarden I, Ijzerman AP. Nicotinic acid receptor subtypes and their ligands. Med Res Rev [Internet]. 2007 May;27(3):417–433. Available from: http://dx.doi.org/10.1002/med.20102 PMID: 17238156

Ellinger P, Kader MM. Nicotinamide metabolism in mammals. Biochem J [Internet]. 1949;44(1):77–87. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16748483 PMCID: PMC1274811

Stratford MR, Dennis MF, Hoskin P, Phillips H, Hodgkiss RJ, Rojas A. Nicotinamide pharmacokinetics in humans: effect of gastric acid inhibition, comparison of rectal vs oral administration and the use of saliva for drug monitoring. Br J Cancer [Internet]. 1996 Jul;74(1):16–21. Available from: https://www.ncbi.nlm.nih.gov/pubmed/8679452 PMCID: PMC2074616

Dragovic J, Kim SH, Brown SL, Kim JH. Nicotinamide pharmacokinetics in patients. Radiother Oncol [Internet]. 1995 Sep;36(3):225–228. Available from: https://www.ncbi.nlm.nih.gov/pubmed/8532910 PMID: 8532910

McKenney JM, Proctor JD, Harris S, Chinchili VM. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA [Internet]. 1994 Mar 2;271(9):672–677. Available from: https://www.ncbi.nlm.nih.gov/pubmed/8309029 PMID: 8309029

Pieper JA. Understanding niacin formulations. Am J Manag Care [Internet]. 2002 Sep;8(12 Suppl):S308–14. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12240702 PMID: 12240702

Wallace TC, McBurney M, Fulgoni VL 3rd. Multivitamin/mineral supplement contribution to micronutrient intakes in the United States, 2007-2010. J Am Coll Nutr [Internet]. 2014;33(2):94–102. Available from: http://dx.doi.org/10.1080/07315724.2013.846806 PMID: 24724766

Moreschi I, Bruzzone S, Nicholas RA, Fruscione F, Sturla L, Benvenuto F, Usai C, Meis S, Kassack MU, Zocchi E, De Flora A. Extracellular NAD+ is an agonist of the human P2Y11 purinergic receptor in human granulocytes. J Biol Chem [Internet]. 2006 Oct 20;281(42):31419–31429. Available from: http://dx.doi.org/10.1074/jbc.M606625200 PMID: 16926152

Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, Tian R, Shen DD, O’Brien KD. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One [Internet]. journals.plos.org; 2017 Dec 6;12(12):e0186459. Available from: http://dx.doi.org/10.1371/journal.pone.0186459 PMCID: PMC5718430

Jacobson EL, Jacobson MK. [19] Tissue NAD as a biochemical measure of niacin status in humans. Methods in Enzymology [Internet]. Academic Press; 1997. p. 221–230. Available from: http://www.sciencedirect.com/science/article/pii/S0076687997801139

Jacobson EL, Jacobson MK. Biochemical method to measure niacin status in a biological sample [Internet]. US Patent. 6287796, 2001 [cited 2019 Feb 16]. Available from: https://patentimages.storage.googleapis.com/19/41/2d/a1de97bc17d927/US6287796.pdf

Fu CS, Swendseid ME, Jacob RA, McKee RW. Biochemical markers for assessment of niacin status in young men: levels of erythrocyte niacin coenzymes and plasma tryptophan. J Nutr [Internet]. academic.oup.com; 1989 Dec;119(12):1949–1955. Available from: http://dx.doi.org/10.1093/jn/119.12.1949 PMID: 2621487

Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids : Health and Medicine Division [Internet]. [cited 2019 Feb 16]. Available from: http://www.nationalacademies.org/hmd/Reports/2002/Dietary-Reference-Intakes-for-Energy-Carbohydrate-Fiber-Fat-Fatty-Acids-Cholesterol-Protein-and-Amino-Acids.aspx

Dölle C, Skoge RH, Vanlinden MR, Ziegler M. NAD biosynthesis in humans--enzymes, metabolites and therapeutic aspects. Curr Top Med Chem [Internet]. ingentaconnect.com; 2013;13(23):2907–2917. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24171775 PMID: 24171775

Clegg KM. BOUND NICOTINIC ACID IN DIETARY WHEATEN PRODUCTS. Br J Nutr [Internet]. cambridge.org; 1963;17:325–329. Available from: https://www.ncbi.nlm.nih.gov/pubmed/14045335 PMID: 14045335

Adrian J, Frangne R. Synthesis and availability of niacin in roasted coffee. Adv Exp Med Biol [Internet]. Springer; 1991;289:49–59. Available from: https://www.ncbi.nlm.nih.gov/pubmed/1897406 PMID: 1897406

Frederick DW, Loro E, Liu L, Davila A Jr, Chellappa K, Silverman IM, Quinn WJ 3rd, Gosai SJ, Tichy ED, Davis JG, Mourkioti F, Gregory BD, Dellinger RW, Redpath P, Migaud ME, Nakamaru-Ogiso E, Rabinowitz JD, Khurana TS, Baur JA. Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle. Cell Metab [Internet]. 2016 Aug 9;24(2):269–282. Available from: http://dx.doi.org/10.1016/j.cmet.2016.07.005 PMCID: PMC4985182

Liu L, Su X, Quinn WJ 3rd, Hui S, Krukenberg K, Frederick DW, Redpath P, Zhan L, Chellappa K, White E, Migaud M, Mitchison TJ, Baur JA, Rabinowitz JD. Quantitative Analysis of NAD Synthesis-Breakdown Fluxes. Cell Metab [Internet]. 2018 May 1;27(5):1067–1080.e5. Available from: http://dx.doi.org/10.1016/j.cmet.2018.03.018 PMCID: PMC5932087

Creeke PI, Dibari F, Cheung E, van den Briel T, Kyroussis E, Seal AJ. Whole blood NAD and NADP concentrations are not depressed in subjects with clinical pellagra. J Nutr [Internet]. academic.oup.com; 2007 Sep;137(9):2013–2017. Available from: http://dx.doi.org/10.1093/jn/137.9.2013 PMID: 17709435

Strohm D, Bechthold A, Isik N, Leschik-Bonnet E, Heseker H. Revised reference values for the intake of thiamin (vitamin B1), riboflavin (vitamin B2), and niacin. NFS Journal [Internet]. Elsevier; 2016 Aug 1;3:20–24. Available from: http://www.sciencedirect.com/science/article/pii/S2352364615300432

Pissios P. Nicotinamide N-Methyltransferase: More Than a Vitamin B3 Clearance Enzyme. Trends Endocrinol Metab [Internet]. 2017 May;28(5):340–353. Available from: http://dx.doi.org/10.1016/j.tem.2017.02.004 PMCID: PMC5446048

Ongol MP, Niyonzima E, Gisanura I, Vasanthakaalam H, Others. Effect of germination and fermentation on nutrients in maize flour. Pakistan Journal of Food Sciences [Internet]. Pakistan Society of Food Scientists and Technologists; 2013;23(4):183–188. Available from: https://www.researchgate.net/profile/Niyonzima_Eugene2/publication/281554021_Effect_of_germination_and_fermentation_on_nutrients_in_maize_flour/links/55ed7ecd08ae21d099c759db.pdf

Carpenter KJ. The relationship of pellagra to corn and the low availability of niacin in cereals. Experientia Suppl [Internet]. Springer; 1983;44:197–222. Available from: https://www.ncbi.nlm.nih.gov/pubmed/6357846 PMID: 6357846

Ghosh HP, Sarkar PK, Guha BC. Distribution of the Bound Form of Nicotinic Acid in Natural Materials. J Nutr [Internet]. Oxford University Press; 1963 Apr 1 [cited 2019 Feb 14];79(4):451–453. Available from: https://academic.oup.com/jn/article-abstract/79/4/451/4779288

Lerner F, Niere M, Ludwig A, Ziegler M. Structural and functional characterization of human NAD kinase. Biochem Biophys Res Commun [Internet]. 2001 Oct 19;288(1):69–74. Available from: http://dx.doi.org/10.1006/bbrc.2001.5735 PMID: 11594753

Sorci L, Cimadamore F, Scotti S, Petrelli R, Cappellacci L, Franchetti P, Orsomando G, Magni G. Initial-rate kinetics of human NMN-adenylyltransferases: substrate and metal ion specificity, inhibition by products and multisubstrate analogues, and isozyme contributions to NAD+ biosynthesis. Biochemistry [Internet]. 2007 Apr 24;46(16):4912–4922. Available from: http://dx.doi.org/10.1021/bi6023379 PMID: 17402747

Heimburger DC. Clinical Manifestations of Nutrient Deficiencies and Toxicities. In: Ross AC, editor. Modern Nutrition in Health and Disease [Internet]. Available from: https://chrismasterjohnphd.com/textbook

Kirkland JB. Niacin. In: Ross AC, editor. Modern Nutrition in Health and Disease [Internet]. Available from: https://chrismasterjohnphd.com/textbook

Niacin [Internet]. Linus Pauling Institute. 2014 [cited 2019 Feb 14]. Available from: https://lpi.oregonstate.edu/mic/vitamins/niacin

Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, its Panel on Folate, Vitamins OB, Choline. Niacin [Internet]. National Academies Press (US); 1998 [cited 2019 Feb 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK114304/

Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, its Panel on Folate, Vitamins OB, Choline. Riboflavin [Internet]. National Academies Press (US); 1998 [cited 2019 Feb 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK114322/

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046: Niacin, Part 1: What It Is and Why You Need It

Chris Masterjohn, PhD — Fri, 01 Mar 2019 17:40:00 GMT

Introduction

Niacin is vitamin B3. You use it to make NAD, the ultimate anti-aging molecule that repairs your DNA and lengthens your telomeres, and the most foundational molecule in our entire system of energy metabolism.

It is especially important to protecting your mind, your skin, and your gut.

You use it to release all your neurotransmitters. This is why depression sets in as the earliest sign of deficiency and why, when it gets bad enough, it leads to suicidality or schizophrenia-like psychosis.

You use constantly it to repair the microscopic damage done to your skin every time you step out into the sunlight. This is why red, inflamed skin appears on the backs of your hands or on your face when you’re deficient, but only if you get outdoors a lot.

You use it to fuel the rapid turnover of cells in your intestines (the cells that absorb the nutrients in our food are replaced every 2-3 days!), and to repair those cells from the constant barrage of insults they face (think of everything those cells *don’t* let in our body 💩and the fact that *they* need to stare all that stuff down!) This is why deficiency will give you diarrhea and make you deficient in lots of other nutrients.

You use it for lots of other things too, like participating with riboflavin to make the methyl group of methylfolate and recycle glutathione, the master antioxidant of the cell. You use it to recycle vitamin K, to support detoxification in the liver, and to synthesize cholesterol, fatty acids, neurotransmitters and nucleotides.

Who needs more? We all do!

Why? Because just aging alone depletes niacin and getting sick or developing diseases as we age depletes it all the more. Niacin repairs damage, so the more damage we face the more we consume.

In fact, this is why many people are taking supplements like nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), to slow the onset of aging, or to age more gracefully. Some people are even injected NAD!

But should we be?

And what about the dark side of niacin? We all know the flush -- the redness and itching that accompanies high-dose niacin that people take to lower cholesterol. At high doses, niacin can even damage the liver. How? By sapping methyl groups. Sapping methyl groups can give you liver failure when it’s *really* bad, but sapping them just a little can leave you feeling weak, emotionally stuck, or tied up in a mental funk.

In this two-part podcast series, Alex Leaf and I tackle all of these questions. This is part 1, where we teach you what niacin is and why you need it.

In part 2, we’ll cover how to get niacin in foods, blood tests, and supplements.

Show Notes

00:37 Cliff Notes

5:31 The stories of Julie, John, and Jane

11:32 Symptoms of pellagra: the three Ds of dermatitis, dementia, and diarrhea, and the fourth D, death

18:02 Speculative signs and symptoms of suboptimal niacin status

19:10 Symptoms of excess niacin

20:45 Excess niacin will reduce the supply of methyl groups, which can lower creatine synthesis and affect neurotransmitters, and is probably what underlies niacin-induced liver damage.

24:30 Explaining the stories of Julie, John, and Jane in the context of niacin deficiency or toxicity

28:18 Chemical properties of niacin

31:08 How niacin and nicotinic acid derived their names

33:00 Chemical structures of nicotinic acid, nicotinamide, nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and nicotinamide adenine dinucleotide (NAD)

37:05 The biochemistry of niacin

37:57 The differences between NAD(H) and NADP(H) in metabolism

41:07 NAD is often broken down to form ADP-ribose.

42:10 How PARPs (including PARP1 and tankyrase) and sirtuins use NAD to protect us from DNA damage, repair DNA damage, lengthen telomeres, and regulate gene expression

48:31 ADP-ribosyltransferases (ARTs)

50:47 The NAD metabolites cyclic ADP-ribose, linear ADP-ribose, O-acetyl-ADP-ribose, and NAADP are involved in regulating calcium transport, which is especially important for neurotransmitter release.

52:28 How the biochemistry of niacin explains the deficiency symptoms

57:37 The biochemistry of how we get niacin from foods and how we dispose of excess niacin

01:01:14 How the degradation pathways of niacin explain the liver toxicity and flushing reaction from different forms of niacin

01:16:12 Extended-release niacin

01:18:57 Rationale for nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) supplementation

01:27:39 Physiology of niacin absorption and circulation

01:35:04 Endogenous synthesis of niacin

01:35:37 Tracer studies of oral and intravenous nicotinamide riboside supplementation in mice

01:40:00 Estrogen is a strong regulator of the conversion of tryptophan to niacin.

01:42:07 Pharmacokinetic study of Niagen (nicotinamide riboside) supplementation in humans

Niacin Links and Research

Ellinger P, Kader MM. Nicotinamide metabolism in mammals. Biochem J [Internet]. 1949;44(1):77–87. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16748483 PMCID: PMC1274811

Pieper JA. Understanding niacin formulations. Am J Manag Care [Internet]. 2002 Sep;8(12 Suppl):S308–14. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12240702 PMID: 12240702

Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, Tian R, Shen DD, O’Brien KD. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One [Internet]. journals.plos.org; 2017 Dec 6;12(12):e0186459. Available from: http://dx.doi.org/10.1371/journal.pone.0186459 PMCID: PMC5718430

Clegg KM. BOUND NICOTINIC ACID IN DIETARY WHEATEN PRODUCTS. Br J Nutr [Internet]. cambridge.org; 1963;17:325–329. Available from: https://www.ncbi.nlm.nih.gov/pubmed/14045335 PMID: 14045335

Kirkland JB. Niacin. In: Ross AC, editor. Modern Nutrition in Health and Disease [Internet]. Available from: https://chrismasterjohnphd.com/textbook

Niacin [Internet]. Linus Pauling Institute. 2014 [cited 2019 Feb 14]. Available from: https://lpi.oregonstate.edu/mic/vitamins/niacin

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045: Why You Should Manage Your Riboflavin Status and How to Do It

Chris Masterjohn, PhD — Sat, 16 Feb 2019 17:28:00 GMT

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Introduction

Riboflavin is the ultimate fat-burning nutrient. It makes even a bad MTHFR work right, and it keeps you looking young and beautiful forever.

Here’s everything you need to know about why you should manage your riboflavin status and how to do it.

In this podcast I join with Alex Leaf of Examine.Com. I focus on what riboflavin is and what it does, while Alex focuses on riboflavin supplements.

Going into this podcast I changed my mind about three important things:

While I had always discussed riboflavin as relevant to methylation and MTHFR, I had kept it in the back seat in my methylation protocol. Half way through recording this podcast I realized that it really deserves a front seat in my MTHFR protocol. In fact, it may be the case that there’s nothing wrong with the common MTHFR polymorphisms at all and that they only appear to hurt MTHFR activity because most of us aren’t getting enough riboflavin. And why aren’t we? Liver. Liver. We just have to eat liver.
In Testing Nutritional Status: The Ultimate Cheat Sheet, I had included HDRI’s erythrocyte glutathione reductase activity test as test for assessing riboflavin status. After doing the research for this podcast, I am now convinced that this test is only reliable as a marker of riboflavin status when the lab tests the enzyme activity with and without the addition of riboflavin, which HDRI doesn’t do. I will be revising the cheat sheet soon to rely solely on LabCorp’s whole blood riboflavin test for assessing riboflavin status.
I have, for years, believed that riboflavin 5’-phosphate (aka, flavin mononucleotide or FMN) supplements are better than plain old riboflavin, especially for people who are hypothyroid or have low adrenal status, since these conditions impair the activation of riboflavin to it’s 5’-phosphate form. After doing the research for this podcast I now believe that for healthy people it makes no difference and that for people with small intestinal pathologies, the cheaper, less fancy, plain old “riboflavin” is likely to be more effective.

In this podcast we being by considering the fictional stories of people who seem to have little in common. We then explain their stories by looking at the signs and symptoms of riboflavin deficiency. We consider the science of what riboflavin is, how it is used by the body, what it does for us, how to have great riboflavin status, and how to become deficient. We round this out with an extensive discussion of riboflavin supplementation.

Show Notes

Riboflavin is the ultimate fat-burning nutrient. It makes even a bad MTHFR work right, and it keeps you looking young and beautiful forever.

Here’s everything you need to know about why you should manage your riboflavin status and how to do it.

In this podcast I join with Alex Leaf of Examine.Com. I focus on what riboflavin is and what it does, while Alex focuses on riboflavin supplements.

Going into this podcast I changed my mind about three important things:

While I had always discussed riboflavin as relevant to methylation and MTHFR, I had kept it in the back seat in my methylation protocol. Half way through recording this podcast I realized that it really deserves a front seat in my MTHFR protocol. In fact, it may be the case that there’s nothing wrong with the common MTHFR polymorphisms at all and that they only appear to hurt MTHFR activity because most of us aren’t getting enough riboflavin. And why aren’t we? Liver. Liver. We just have to eat liver.
In Testing Nutritional Status: The Ultimate Cheat Sheet, I had included HDRI’s erythrocyte glutathione reductase activity test as test for assessing riboflavin status. After doing the research for this podcast, I am now convinced that this test is only reliable as a marker of riboflavin status when the lab tests the enzyme activity with and without the addition of riboflavin, which HDRI doesn’t do. I will be revising the cheat sheet soon to rely solely on LabCorp’s whole blood riboflavin test for assessing riboflavin status.
I have, for years, believed that riboflavin 5’-phosphate (aka, flavin mononucleotide or FMN) supplements are better than plain old riboflavin, especially for people who are hypothyroid or have low adrenal status, since these conditions impair the activation of riboflavin to it’s 5’-phosphate form. After doing the research for this podcast I now believe that for healthy people it makes no difference and that for people with small intestinal pathologies, the cheaper, less fancy, plain old “riboflavin” is likely to be more effective.

00:37 Introduction

01:46 Three things that I’ve changed my mind about while doing the research for this podcast

04:24 Cliff notes

08:17 Three stories of riboflavin deficiency

12:09 Signs and symptoms of riboflavin deficiency

15:35 Speculative symptoms of suboptimal riboflavin status

17:52 Chemical properties of riboflavin

21:26 Medical applications: infants with jaundice, eye surgery for keratoconus, and treatment of fungal keratitis

24:42 Chemical structure of riboflavin, flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD)

27:06 Riboflavin’s roles in the body: energy metabolism, the antioxidant system, methylation, detoxification, and other nutrient interactions

28:07 Riboflavin’s roles in energy metabolism

33:37 How the different macronutrients (carbohydrate, fat, and protein) affect the riboflavin requirement differently

40:09 Riboflavin’s role in the antioxidant system

44:17 Riboflavin’s roles in the methylation system

46:34 Riboflavin’s interactions with other nutrients: vitamin B6, niacin, and iron

49:51 Riboflavin’s roles in detoxification

51:47 Other riboflavin-dependent enzymes include NADPH oxidase, monoamine oxidase, and protein disulfide isomerase.

53:35 The physiology of riboflavin absorption

56:35 The physiology of riboflavin utilization and the importance of magnesium, ATP, thyroid hormone, adrenal hormones, and protein

01:00:48 The gold standard marker of riboflavin status is the erythrocyte glutathione reductase activity coefficient (EGRAC).

01:06:15 LabCorp’s whole blood riboflavin test, normalized to the concentration of blood hemoglobin, is the closest commercially available equivalent to the EGRAC.

01:08:07 Why urinary glutaric acid is not a specific marker of riboflavin status

01:08:58 Measuring riboflavin status should be done after an overnight fast, and biotin does not interfere with the test.

01:09:59 How the RDA for riboflavin was established

01:16:06 How much riboflavin is needed to optimize riboflavin status and maximally suppress the EGRAC?

01:21:29 Why high doses of riboflavin might be beneficial in cases of suboptimal magnesium, energy, thyroid, or adrenal status

01:25:07 Dietary sources of riboflavin

01:30:43 Free riboflavin is found in milk, fortified flours, and many riboflavin supplements.

01:33:00 Riboflavin is destroyed by light.

01:35:20 Riboflavin is produced in the colon, but it is unknown how much this contributes to systemic riboflavin status.

01:37:39 Factors that interfere with riboflavin status and utilization

01:45:06 Genetic defects in riboflavin metabolism and transport

01:47:54 How common is riboflavin deficiency and suboptimal riboflavin status?

01:52:40 Riboflavin supplementation for iron deficiency anemia

01:54:33 The relationship between riboflavin and the MTHFR C677T polymorphism and effects on homocysteine and blood pressure

02:03:36 Riboflavin supplementation and exercise performance

02:08:34 Whether or not riboflavin supplementation could impair adaptations to exercise

02:12:29 Riboflavin supplementation for migraines

02:19:10 Rapid fire questions

02:19:25 Does it matter whether we take free riboflavin or riboflavin 5’-phosphate?

02:20:24 Should riboflavin be taken with food?

02:24:32 How often should you take riboflavin?

02:26:24 Does it matter if you take riboflavin in one dose or divided doses?

02:27:17 Are there any adverse effects of riboflavin supplements?

Riboflavin Calculator

Click here to use the calculator.

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044: Nutrition in Neuroscience Part 4

Chris Masterjohn, PhD — Fri, 01 Feb 2019 17:13:00 GMT

Show Notes

00:00:39 Cliff Notes
00:06:12 Anatomy of the brain
00:10:45 The role of the basal ganglia in suppressing the investment of energy in any type of program until there is a worthwhile reason not to suppress it, and how dopamine acts as a signal of value in the basal ganglia via disinhibition
00:19:00 Why we can view Parkinson’s as fundamentally not a problem with movement but as a problem with a perception of the value of investing energy in controlling movement
00:22:26 Tonic and phasic dopamine and the importance of COMT-mediated methylation for regulating the tonic level of dopamine
00:30:36 The importance of GABA in suppressing the programs that dopamine doesn't signal has value in order to make the dopamine signal of value meaningful
00:31:33 Overview of the autonomic nervous system; the sympathetic nervous system mediates the fight-or-flight response, and the parasympathetic nervous system mediates the rest-and-digest response.
00:35:16 The roles of acetylcholine and norepinephrine in the autonomic nervous system, and the importance of nitric oxide to the sexual functions of the autonomic nervous system
00:38:33 Sleep and circadian rhythms, the importance of vitamin A, morning sun exposure, and avoiding blue light at night
00:42:17 Melatonin synthesis, the importance of vitamin B6, BH4, oxidative stress, vitamin B5, methylation, and tryptophan uptake into the brain
00:45:16 Why you can't mimic your natural melatonin rhythm with melatonin supplements
00:47:00 Antidiuretic hormone, the importance of light hygiene for preventing you from getting up to pee in the middle of the night, and why salt might also help
00:50:51 Whether the timing of carbohydrate, protein, and choline supplements makes a difference for your daytime wakefulness, your nighttime sleepiness, your deep sleep, and your REM sleep
00:54:49 The possibility that glycine and magnesium could help get rid of conditioned fear responses
00:55:35 Thoughts on consciousness; are we a ghost in the machine, or are we just a machine?
01:00:29 The default mode network is fundamentally about our inward, introverted-directed processes, contrasted with the executive control network, which is fundamentally about our relationship to the outside world and our extraverted functions.
01:04:54 How activities that had nothing to do with people skills but allowed me to flex my extroverted muscles, like exploring the outside world on my own, helped me with my people skills
01:10:53 Nutrition cannot replace the cognitive work necessary to have a healthy mindset and life, but nutrition does make it easier to do the right thing for your mental health.

Nutrition in Neuroscience Related Content

Mastering Nutrition: Methylate Your Way to Mental Health With Dopamine

Meat, Organs, Bones, and Skin: Nutrition for Mental Health

The Pursuit of Happiness: How Nutrient-dense Animal Fats Promote Mental and Emotional Health

Start Here for Methylation

Chris Masterjohn Lite: Your Nitric Oxide Genes, Blood Pressure, and Asthma covers nutrition for nitric oxide, which plays a role in the sexual functions of the autonomic nervous system.

Mastering Nutrition: Why You Should Manage Your Zinc Status and How to Do It covers the role of zinc in nitric oxide production

An assortment of other posts on zinc.

My recommendations for better sleep.

Vitamin A Plays an Essential Role in Setting the Circadian Rhythm and Allowing Good Sleep, on the role of vitamin A in melanopsin function.

Mastering Nutrition Episode 10: How to Know if Your Genetics Contribute to Your Sensitivity to Blue Light and Poor Sleep, and What to Do About it on genetic variation in the melanopsin protein.

Mastering Nutrition: Why You Should Manage Your Zinc Status and How to Do It, since the opsin proteins are zinc-dependent.

Getting Better Sleep — Cool, Dark, And Lots of B6, Carbs, Calories, and Fat

Chris Masterjohn Lite: How to Manage Your Vitamin B6 Status

Masterclass With Masterjohn: The Antioxidant System

Mastering Nutrition: Why You Need Glycine -- A Panel Discussion

Balancing Methionine and Glycine in Foods: The Database

Chris Masterjohn Lite: Get Better Sleep With Glycine

Chris Masterjohn Lite: How to Manage Your Magnesium Status

Nutrition in Neuroscience Research

The textbook, Neuroscience.

Impaired Locomotion and Dopamine Signaling in Retinoid Receptor Mutant Mice

What does dopamine mean?

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043: Nutrition in Neuroscience Part 3

Chris Masterjohn, PhD — Fri, 25 Jan 2019 17:00:00 GMT

Introduction

Part 3 of how NUTRITION has a HUGE impact on your BRAIN!

Everything in your brain is something you ate, something you made from something you ate, or, in a few cases, something your mother ate. Nutrition impacts your mental and emotional health, the function of your five senses, and your conscious and unconscious control over your body movements.

Join me as I lead you in a safari through the textbook, “Neuroscience,” pointing out along the way all the interesting connections to nutrition. Listen in for part 2 on the THE FIVE SENSES!

Show Notes

00:00:35 Cliff Notes
00:02:50 Exteroception and proprioception are mediated by mechanoreceptors.
00:05:34 Pain is mediated by nociceptors, which are unspecialized, low-sensitivity neurons.
00:07:12 Capsaicin activates the TRPV1 receptor, which is also activated by hot temperatures.
00:09:12 The use of topical capsaicin to relieve chronic pain
00:12:25 Interoception is our sense of the physiological state within the body.
00:14:22 Why anorexics crave spicy foods
00:16:20 Managing pain in the peripheral nervous system; acidity sensitizes pain receptors.
00:18:16 Managing the fatty acids that help resolve inflammation, particularly arachidonic acid and DHA, to help with peripheral sensitization to pain
00:20:01 Combining aspirin with fish oil, glycine, and bicarbonate to help with peripheral sensitization to pain
00:24:50 Central sensitization to pain occurs through an LTP-like process, which is mediated by NMDA receptors.
00:26:47 Overview of vision and the importance of vitamin A
00:32:22 The role of vitamin A in preventing night blindness and its very closely related role in setting your circadian rhythm
00:35:56 Overview of hearing
00:38:22 Nutrients important for hearing
00:39:46 Overview of smell
00:41:42 Overview of taste

Nutrition in Neuroscience Related Content

Chris Masterjohn Lite: Do you really need to be taking fish oil?

Chris Masterjohn Lite: The Omega-6 / Omega-3 Fatty Acid Ratio: Should You Care?

Chris Masterjohn Lite: Why Aspirin Goes Best With Bicarbonate and Glycine

Chris Masterjohn Lite: 3 Ways to Clear Stubborn Inflammation

Vitamin A Plays an Essential Role in Setting the Circadian Rhythm and Allowing Good Sleep, on the role of vitamin A in melanopsin function.

Mastering Nutrition Episode 10: How to Know if Your Genetics Contribute to Your Sensitivity to Blue Light and Poor Sleep, and What to Do About it on genetic variation in the melanopsin protein.

Mastering Nutrition: Why You Should Manage Your Zinc Status and How to Do It, since the opsin proteins are zinc-dependent.

Assorted other posts on zinc.

Testing Nutritional Status: The Ultimate Cheat Sheet is a comprehensive guide for testing nutritional status for all the nutrients discussed in this episode, and more. Use the code MASTERINGNUTRITION for $5 OFF.

Nutrition in Neuroscience Research

The textbook, Neuroscience.

Depletion of Plasma Glycine and Effect of Glycine by Mouth on Salicylate Metabolism During Aspirin Overdose

Diuresis or Urinary Alkalinizing for Salicylate Poisoning

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042: Nutrition in Neuroscience Part 2

Chris Masterjohn, PhD — Fri, 18 Jan 2019 16:57:00 GMT

Introduction

Part 2 of how NUTRITION has a HUGE impact on your BRAIN!

Join me as I lead you in a safari through the textbook, “Neuroscience,” pointing out along the way all the interesting connections to nutrition. Listen in for part 2 on the NEUROTRANSMITTERS!

Show Notes

0:00:37 Cliff Notes
0:04:15 Overview of neurotransmitters
0:06:55 Glutamate is the primary excitatory neurotransmitter.
0:14:08 De novo glutamate in the central nervous system is overwhelmingly made from glucose.
0:16:55 Ketogenic diet for epilepsy
0:20:12 Glutamate metabolism
0:23:42 There are two classes of glutamate receptors: ionotropic and metabotropic.
0:24:45 There are three classes of metabotropic glutamate receptors, their actions are complex and variable, and they can be excitatory or inhibitory.
0:25:05 The ionotropic glutamate receptors include AMPA receptors, NMDA receptors, and kainite receptors, all of which have a depolarizing effect by allowing sodium and potassium to flow freely through them.
0:27:47 Four unique things about the NMDA receptor: magnesium is required to block its ion channel, it’s important for coincidence detection, it allows calcium to come into the cell, and it has a glycine-binding site.
0:33:16 Long-term potentiation (LTP) and long-term depression (LTD) are important for forming memories, and glutamate receptors play an important role.
0:40:48 GABA and glycine are the two primary inhibitory neurotransmitters of the central nervous system.
0:44:04 GABA and presumably glycine can be stimulatory if there is more chloride on the inside of the neuron than the outside.
0:48:53 Evidence that GABA might cross the blood-brain barrier
0:51:44 GABA in foods
0:54:14 GABA metabolism in the nervous system
0:56:08 Glycine
1:02:02 Acetylcholine
1:07:50 The biogenic amines include histamine, serotonin, and the catecholamines (dopamine, norepinephrine, and epinephrine).
1:08:30 Synthesis of the catecholamines
1:10:46 Dopamine
1:14:08 Norepinephrine
1:16:32 Histamine
1:20:15 Serotonin
1:23:10 ATP and adenosine
1:26:38 Peptide neurotransmitters
1:27:00 Hypothalamic releasing hormones include thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), and gonadotropin-releasing hormone (GnRH).
1:29:15 Melanocyte-stimulating hormone (MSH)
1:29:32 Oxytocin
1:30:18 Vasopressin
1:30:57 Synthesis of the neuropeptides Substance P, MSH, oxytocin, and vasopressin requires glycine, zinc, copper, and vitamin C.
1:34:24 Endocannabinoids and the importance of arachidonic acid, EPA, and DHA

Nutrition in Neuroscience Related Content

Chris Masterjohn Lite: Could Oxaloacetate Supplements Help With Glutamate Sensitivity?

Chris Masterjohn Lite: 5 Ways to Help With Glutamate Sensitivity and Glutamate Dominance

Chris Masterjohn Lite: Does Glycine or GABA Wake You Up?

Chris Masterjohn Lite: Carbs or Keto for Sleep?

Chris Masterjohn Lite: How to Manage Your Magnesium Status

Mastering Nutrition: Why You Need Glycine -- A Panel Discussion

Balancing Methionine and Glycine in Foods: The Database

Chris Masterjohn Lite: Get Better Sleep With Glycine

Start Here for Methylation has glycine and choline resources, and covers the methylation process used in the synthesis and degradation of biogenic amines.

Mastering Nutrition: Methylate Your Way to Mental Health With Dopamine

The Pursuit of Happiness: How Nutrient-Dense Animal Fats Promote Mental and Emotional Health, covers the endocannibinoids.

Nutrition in Neuroscience Research

The textbook, Neuroscience.

Relaxation and immunity enhancement effects of gamma-aminobutyric acid (GABA) administration in humans. on the use of GABA for fear of heights and to alter anxiety- and focus-related brain waves.

γ-Aminobutyric acid (GABA) administration improves action selection processes: a randomised controlled trial on use of GABA to improve decision-making under pressure.

Desarrollo de un pan de masa madre rico en GABA y péptidos IECA contains a table on the GABA content of foods on page 84 of the PDF.

Acetylcholinesterase inhibitor from plants on the different plants containing natural acetylcholinesterase inhibitors.

A Mass Spectrometry-Based Method to Screen for α-Amidated Peptides on the neuropeptides that require glycine, vitamin C, copper, and zinc for their biological activity.

Effects of copper occupancy on the conformational landscape of peptidylglycine α-hydroxylating monooxygenase also on the neuropeptides that require glycine, vitamin C, copper, and zinc for their biological activity.

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041: Nutrition in Neuroscience Part 1

Chris Masterjohn, PhD — Fri, 11 Jan 2019 16:47:00 GMT

Introduction

Nutrition has a HUGE impact on your brain!

Join me as I lead you in a safari through the textbook, “Neuroscience,” pointing out along the way all the interesting connections to nutrition. Listen in for part 1 on the basic cellular functions of neurons!

Show Notes

0:00:38 Cliff Notes
0:09:33 The primary type of cell in the nervous system is the neuron.
0:11:05 Glial cells are the assistants of the nervous system.
0:11:56 Cells in the nervous system are polarized.
0:13:28 Mitochondria are typically only located at the synapse of neurons and in the middle of photoreceptors; creatine is important for transporting energy in a cell where ATP production is highly polarized.
0:21:18 Sources of creatine
0:22:47 Brief overview of how to support methylation
0:25:41 The polarization of astrocytes and the obligate need for glucose in the brain
0:32:08 Electrical signaling, resting membrane potential, depolarization, threshold potential, hyperpolarization, and the importance of sodium, potassium, and chloride
0:39:47 How to get enough sodium, chloride, and potassium in the diet
0:48:26 The sodium-potassium ATPase uses ATP to pump three sodium ions out of the cell and two potassium ions into the cell, so magnesium and all of the nutrients involved in energy metabolism are important.
0:53:18 How action potentials propagate
0:58:14 Myelin and the importance of cholesterol
1:01:27 Smith-Lemli-Opitz Syndrome is a rare genetic disorder of cholesterol synthesis that results in neurological problems that are corrected by dietary cholesterol.
1:04:07 Calcium acts as a second messenger in the nervous system, and the cytosolic calcium concentration has to be kept very low for this to work, which requires ATP energy.
1:08:57 Other roles of calcium in the nervous system
1:10:09 Sufficient dietary calcium and ATP energy are needed to support the second messenger roles of calcium.

Nutrition in Neuroscience Links

The textbook, Neuroscience.

Mastering Nutrition Episode 48: Creatine: Far More Than a Performance Enhancer

Consuming Creatine in Foods and Supplements, with the internet’s first searchable database of creatine in foods.

Masterclass With Masterjohn 2.34: This is Why We Make Ketones, on why the polarization of astrocytes means the glucose requirement of the brain can never be brought down to zero.

Start Here for Methylation has all my methylation resources collected into one place.

Chris Masterjohn Lite: Why Salt Raises Blood Pressure in Some People

Chris Masterjohn Lite: 3 Ways to Get Enough Potassium

Chris Masterjohn Lite: The Best Way to Supplement With Potassium

When the Brain Is Hungry for Cholesterol describes how dietary cholesterol can become meaningful to the brain when it’s demand for cholesterol is increased above normal.

Research paper: Dietary cholesterol promotes repair of demyelinated lesions in the adult brain.

Several episodes on calcium.

Several episodes on thiamin (vitamin B1).

Chris Masterjohn Lite: How to Manage Your Vitamin B6 Status.

The ongoing masterclass on energy metabolism.

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040: Why You Should Manage Your Thiamin Status and How to Do It

Chris Masterjohn, PhD — Sun, 14 Jan 2018 16:18:00 GMT

Introduction

Thiamin, or vitamin B1, is central to both energy metabolism and antioxidant defense. While its deficiency causes many problems, out of all the B vitamins its deficiency is most neurological in nature, because energy metabolism of the brain becomes severely compromised, and because neurotransmitters derived from protein cannot be produced. In its most severe form, beriberi, it can cause loss of muscle control, twitching, muscles freezing into awkward positions, and seizures.

Carbohydrates require twice as much thiamin as fat. This means, on the one hand, that high-carbohydrate diets increase the need for thiamin, and on the other hand, that people who are deficient in thiamin may have neurological symptoms that resolve when they go on a low-carbohydrate, high-fat diet.

Thiamin is widely distributed in foods. Historically, diets high in refined grain produced beriberi, but now refined grains are enriched in thiamin, so its deficiency is rarely caused by diet. However, certain foods such as raw fish and moths that are eaten in some cultures contain thiamin antagonists, gastrointestinal microbes can degrade thiamin, and there are various environmental causes of thiamin deficiency, such the algae that grow in dead zones. As such, environmental exposure to thiamin antagonists may be a more common cause of thiamin deficiency than poor dietary intake.

Still, some foods are much higher in thiamin than most others, with whole grains, legumes, yeast, and red meat being among the best sources.

Show Notes

0:01:00 Cliff Notes
0:06:27 Thiamin is centrally involved in energy metabolism and is required to metabolize fat, protein, and especially carbohydrate.
0:07:26 Thiamin is critical to the pentose phosphate pathway, which supports antioxidant status, detoxification, the recycling of vitamin K and folate, and the synthesis of fatty acids, cholesterol, neurotransmitters, and nucleotides.
0:08:34 Clinical thiamin deficiency syndromes: beriberi, Wernicke’s encephalopathy, and Korsakoff’s psychosis.
0:11:24 Signs and symptoms of moderate thiamin deficiency: poor glucose tolerance, poor antioxidant status, poor vitamin K or folate status, feeling better on a low-carb diet.
0:12:04 Dietary causes of thiamin deficiency; food sources of thiamin are meat, legumes, whole grains, and enriched, fortified grains.
0:15:18 Other causes of thiamin deficiency: persistent vomiting, alcoholism, GI diseases that cause malabsorption, liver diseases, HIV/AIDS, and diabetes.
0:18:01 Thiamin antagonists can occur in raw fish and shellfish, seasonally in ferns, and in the larvae of the African silkworm Anaphe venata.
0:20:43 Sulfite destroys thiamin in vitro; the metabolism of sulfur amino acids, found primarily in animal protein, generates sulfite; molybdenum is required to detoxify sulfite.
0:22:53 Thiamin-destroying bacteria and fungi have been found in the human gut; infections and indoor toxic molds may cause thiamin antagonism.
0:23:59 Markers of thiamin status: whole blood thiamin pyrophosphate, erythrocyte transketolase activity.
0:28:02 Thiamin’s role in energy metabolism: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched-chain alpha-keto acid dehydrogenase.
0:30:56 Other functional markers of thiamin deficiency: elevated alpha-ketoglutarate, alanine, lactate, and possibly pyruvate on the Genova ION Profile with 40 amino acids or some other combination of plasma amino acids and urine organic acids.
0:34:24 Keep in mind that all of the thiamin-dependent enzymes in energy metabolism also require lipoic acid.
0:35:25 How to address thiamin deficiency: fix the dietary pattern, consider supplementation (thiamin hydrochloride, benfotiamine, or thiamin pyrophosphate), and address any relevant medical conditions.

Lab Tests Related to Thiamin Status

Whole blood thiamin pyrophosphate (LabCorp) and erythrocyte transketolase activity (available from HDRI as “ETKA” on their requisition form) are low in thiamin deficiency.

On the Genova ION Profile + 40 amino acids or an equivalent combination of plasma amino acids and urine organic acids, alanine, alpha-ketoglutarate, lactate, and possibly pyruvate are elevated in thiamin deficiency.

Links and Research Related to Thiamin

Institute of Medicine (US) Panel on Micronutrients. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. 2001.

The “Thiamin” chapter of Ross, Modern Nutrition in Health and Disease. 2012.

McCarrison. Studies in Deficiency Disease. 1921.

Higdon, Linus Pauling Micronutrient Information Center. Thiamin. 2013.

Alaei Shahmiri. High-dose thiamine supplementation improves glucose tolerance in hyperglycemic individuals: a randomized, double-blind cross-over trial. 2013.

Hoyt. Optic neuropathy in ketogenic diet. 1979.

Balk. Wild birds of declining European species are dying from a thiamine deficiency syndrome. 2009.

Evans. Thiaminases and their effects on animals. 1975.

Kreinbring. Structure of a eukaryotic thiaminase I. 2014.

Ayoade. Seasonal ataxia: A case report of a disappearing disease. 2014.

Riley. Increasing thiamine concentrations in lake trout eggs from Lakes Huron and Michigan coincide with low alewife abundance. 2011.

Lepak. Clupeid response to stressors: the influence of environmental factors on thiaminase expression. 2013.

Zhu. Pharmacokinetics of the transdermal delivery of benfotiamine. 2016.

Park. Comparative Pharmacokinetic Analysis of Thiamine and Its Phosphorylated Metabolites Administered as Multivitamin Preparations. 2016.

Jayaprakash. Wernicke’s Encephalopathy – ‘Pushing the Envelope’ of Patient’s Profile: A Case Report. 2016.

Thomson. The evolution and treatment of Korsakoff’s syndrome: out of sight, out of mind? 2012.

Nishimoto. High-dose Parenteral Thiamine in Treatment of Wernicke’s Encephalopathy: Case Series and Review of the Literature. 2017.

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038: Are We All Evolved to Eat High Protein?

Chris Masterjohn, PhD — Wed, 04 Oct 2017 14:45:00 GMT

Introduction

In August of this year, 25-year-old bodybuilding mom Meegan Hefford was found unconscious in her apartment, brought to the hospital where she was declared brain-dead, and died soon after. The cause? “Too much protein before competition,” according to the New York Post. She had recently doubled her gym routine, started dieting, and begun slamming protein shakes in preparation for an upcoming bodybuilding competition. No one knew she had a rare genetic disorder that would make the breakdown of protein acutely toxic for her until after her death.

Does this tragic case carry lessons for the rest of us without rare genetic disorders? In this episode, I make the answer a definitive YES.

Show Notes

Does this tragic case carry lessons for the rest of us without rare genetic disorders? In this episode, I make the answer a definitive YES.

0:00:45 Cliff Notes
0:03:34 The tragic case of Meegan Hefford
0:05:12 Proteins and amino acids, which serve many functions in the body, contain nitrogen; nitrogen is liberated as ammonia, which is toxic to the central nervous system
0:07:27 The urea cycle in the liver disposes of nitrogen as urea
0:08:55 Jose Antonio has shown in athletic populations that consuming 4-5 times the RDA for protein has no observable harmful effects
0:13:36 Urea cycle disorders are multifactorial and don’t usually manifest unless there are multiple stresses on the urea cycle (high protein intake, fasting, dieting, illness, exercise, carbohydrate restriction)
0:20:08 The details of the urea cycle
0:26:28 N-acetylglutamate is an activator of the urea cycle and is stimulated by the amino acid arginine; supplementing arginine is a potential strategy to increase the activity of the urea cycle
0:30:33 Other genetic defects in energy metabolism or problems of a nutritional or metabolic nature can negatively impact the urea cycle; importance of acetyl CoA, ATP, the raw inputs bicarbonate and aspartate, and arginine
0:36:37 Understanding inborn errors of metabolism in their most severe states can provide enormous insight that applies generally
0:39:09 Uses of arginine outside the urea cycle
0:41:31 Common polymorphism in ornithine transcarbamylase, OTC, is associated with increased risk of hypertension and Alzheimer’s disease, plausibly as a result of decreased arginine supply
0:46:43 Conclusions for researchers, clinicians, consultants, and people just trying to be healthy

How to Know If You Have a Common OTC (Urea Cycle Enzyme) Polymorphism

If you have 23andMe, search your raw data for this SNP:

rs5963409

G (or C) is the normal allele and A (or T) is the risk allele.

Currently, this polymorphism is known to increase the risk of hypertension and Alzheimer’s. There is no evidence that this can be treated with diet or supplements, or that it affects protein tolerance. However, it is reasonable, as argued in this podcast, to believe this may increase the risk of lethargy, weakness, or brain fog in response to otherwise healthy amounts of protein or in response to catabolic stress (fasting, dieting, exercise, illness, carbohydrate restriction). If this is true it may show up in plasma amino acids and urinary organic acids as one or more of the following: low arginine, high ornithine, low citrulline, or high orotate. Strategies for improving these situations theoretically include a lower protein diet, avoiding catabolic stress, or arginine supplementation.

Links and Research Related to “Are We All Evolved to Eat High Protein?”

New York Post: Bodybuilder mom dies from too much protein before competition

Meegan Hefford’s Instagram page

Case report: Fatal hyperammonaemia due to late-onset ornithine transcarbamylase deficiency.

Jose Antonio’s research on the safety of high protein diets.

For understanding the urea cycle, this section of Berg, Biochemistry, is free. To purchase a biochemistry textbook for understanding this and other pathways, get Ferrier, Biochemistry if you are a beginner or Berg, Biochemistry if you are intermediate or advanced. The 2002 version of the Berg book, linked to above, is free, but the new edition is more up to date and is much more usable since the free version can be searched but not browsed or read straight through. See my all my textbook recommendations here.

Research study: Inhibition of N-acetylglutamate synthase by various monocarboxylic and dicarboxylic short-chain coenzyme A esters and the production of alternative glutamate esters.

Research study: Association of ornithine transcarbamylase gene polymorphisms with hypertension and coronary artery vasomotion.

Research study: Is the ornithine transcarbamylase gene a genetic determinant of Alzheimer’s disease?

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037: Living With MTHFR

Chris Masterjohn, PhD — Sat, 12 Aug 2017 14:39:00 GMT

Introduction

MTHFR is an enzyme that allows folate (vitamin B9) to support the cellular process of methylation, which is important for the synthesis of creatine and phosphatidylcholine, the regulation of gene expression, neurotransmitter metabolism, and dozens of other processes. There are two common polymorphisms that decrease its activity, A1298C and C677T, with C677T having the stronger effect. Genetic decreases in MTHFR activity are associated with cardiovascular disease, neurologic and psychiatric disorders, pregnancy complications and birth defects, and cancer.

While discussions of these polymorphism tend to focus on supplementing with methyl-folate, this should only be a small piece of the puzzle, and may be unnecessary in the context of a diet rich in natural food folate. The bigger pieces of the puzzle are restoring choline, creatine, and glycine.

In this episode, I describe how the methylation system works, how it’s regulated, and how it’s altered with MTHFR variations. I then use this to develop a detailed dietary strategy and an evaluative strategy to make sure the dietary strategy is working.

Show Notes

0:00:34 Cliff Notes
0:05:19 Introduction of Living with MTHFR
0:06:09 Bird’s eye view of methylation & MTHFR
0:07:28 How to know if you have MTHFR
0:10:01 Prevalence (these are really common)
0:13:34 This is not a genetic disease: this is a variation in metabolism
0:14:12 Health Associations
0:15:59 Mechanisms of what MTHFR does
0:24:35 Methylation system as a whole (methyltransferases)
0:29:53 How the system is regulated
0:49:08 Two Addenda: COMT and Agouti Mouse Study
0:53:15 Mechanistic impact of polymorphisms (% down in enzyme activity)
0:57:44 It’s not all about 5-methyl folate
0:58:39 You can restore normal flux
1:01:48 Compensate with choline
1:06:29 Creatine
1:08:37 Glycine Buffer
1:09:46 Why upping Methionine and SAMe is bad idea
1:12:03 Dietary Strategy – Basic Objectives
1:15:18 Folate
1:19:38 Protein
1:20:51 Creatine
1:26:09 Glycine
1:28:45 Reiterate problem with methionine/and SAMe in context of meat for creatine 900-1200 mg choline
1:33:46 The evaluative strategy
1:35:00 StrateGene Report
1:36:56 Homocysteine, methionine and glycine
1:39:41 HDRI methylation panel
1:40:37 Folate in plasma and FIGLU
1:42:44 Other tests of interest

How to Know If You Have an MTHFR Mutation

I recommend getting 23andMe Health and Ancestry and then running your raw data through StrateGene.

A Dietary Strategy for MTHFR Polymorphisms

1) Get the RDA for folate from non-fortified whole foods.

For adults and children 14 years and older, the RDA is 400 micrograms, except that it is 600 for pregnant and lactating women, regardless of age.
For children, the RDA increases from 65 micrograms in the first six months, to 80 in the second six months, 150 for 1-3-year-olds, 200 for 4-8-year-olds, and 300 for 9-13-year-olds.
Feel free to use (as an adult, not for children), 400 or 600 micrograms per day of a methyl-folate supplement, providing you are adding it to a folate-rich diet rather than using it to replace food folate. I recommend Jarrow Methyl Folatebased on cost, dose, and the fact that it is otherwise the same high-quality product as sold by other manufacturers in more expensive, higher-dose supplements.

2) Consume at least the RDA for protein.

The RDA for protein is 0.36 grams per pound bodyweight.
Most people need more than this for other reasons, such as optimizing body composition, preventing loss of lean mass during weight loss, reaching satiety to manage energy intake, or reaching athletic goals. You may need one gram per pound body weight or more, depending on your goals, but the RDA is adequate to support the methylation pathway.

3) Get 3 grams of creatine per day.

1-2 pounds of muscle meat or fish (but not organ meats, eggs, dairy, or plant proteins) will supply on average 3 grams of creatine.
Large volumes of muscle protein may be undesirable for someone with an MTHFR mutation because it could exacerbate the loss of glycine.
Alternatively, you can supplement with 3 grams of creatine (or 5, if you wish, the standard maintenance dose for athletes). I’m currently using Optimum Nutrition Micronized Creatine Powder.

4) Consume 900-1200 mg/d choline.

This can be obtained by eating 4-5 egg yolks per day.
You can substitute 100 grams of liver for two egg yolks.
You can meet this choline amount by eating a very large volume of low-carbohydrate plant foods. See Meeting the Choline Requirement for more details.
You can supplement with phosphatidylcholine, but be careful of the labeling. Usually the supplement lists the phosphatidylcholine, and not the choline yield. A 420 mg capsule of phosphatidylcholine only provides 55 mg of choline, which means you’d have to take 22 capsules per day to get 1200 mg. On the basis of quality, soy-free status, and good feedback from others about the taste, I recommend Micro Ingredients Sunflower Lecithin. Although the choline content is not guaranteed, on the basis of this paper I recommend consuming four to five tablespoons per day to reach the recommended choline yield.
If you find that memory loss, poor cognitive function, or weakness are your primary symptoms of concern, consider using alpha-GPC for your choline at the same dose. This form is more effective at converting to acetylcholine, a neurotransmitter involved in neuromuscular function.

5) Boost your glycine intake.

At a minimum, use the skin and bones of the animals you eat. For example, eat chicken with the skin instead of without. Use the bones to make bone broth. If you eat canned fish, get the fish with edible bones.
Consider supplementing with glycine. I recommend using between 1/2 serving and 3 servings of Vital Proteins Marine Collagen, on the basis that it has a much higher glycine content than beef hide products made by the same company or others with a similar devotion to quality and cleanness of source.

6) Be careful with SAMe. SAMe supplements support methylation, but MTHFR mutations increase the use of glycine to buffer SAMe levels, even when you don’t have enough. While I do not make a blanket recommendation against supplementing with SAMe, I caution against its use in this context because it could aggravate the loss of glycine. If you use it, be careful, and consider monitoring your glycine levels (see recommended lab tests below).

Lab Tests Recommended for MTHFR Polymorphisms

1) Homocysteine. Available from LabCorp, Quest, and the Genova ION panel, aim to keep your numbers between 6 and 9, rather than the larger range on the report.

2) Plasma or serum folate. Available from Quest or LabCorp, aim to be in the normal range as listed. Avoid RBC folate unless you also corroborate it with plasma or serum.

3) Plasma methionine, glycine, and sarcosine. Available on a LapCorp amino acids profile, a Quest amino acids profile, a Genova ION panel, or a NutrEval, methionine and glycine should be toward the middle of the range rather than the bottom and sarcosine is best being as low as you can get it.

4) The HDRI methylation panel. Aim to keep 5-CH3-THF in the normal range. If it is specifically low while other folate forms are normal, this suggests your MTHFR mutation is impacting your methylation pathway negatively. The “extended” panel has methionine and homocysteine, but not glycine or sarcosine.

5) Other tests of interest. Serum creatine from Quest or LabCorp might be a good way of testing whether your MTHFR mutation is affecting your creatine synthesis if you are not supplementing. Aim to be in the normal range. The combination of creatine, creatinine, and guanidinoacetate (the direct precursor to creatine) from the same urine sample can be used to test problems with creatine synthesis. Unfortunately, these are only offered from labs looking for a genetic disorder, such as Mayo Clinic, Greenwood Genetics Center, and Baylor Genetics, and I’m not sure if they are easy to order for someone with no suspicion of a metabolic disorder or whether the reference ranges would be relevant for looking at the impact of an MTHFR mutation.

Update: Quest now offers this combination as “Creatine Biosynthesis Disorders Panel, Urine.”

Posts and Episodes Related to “Living With MTHFR”

You Asked Me Anything About Methylation, Facebook Live, 06/25/16 | Mastering Nutrition Episode 17

Methylate Your Way to Mental Health With Dopamine | Mastering Nutrition Episode 34

Meeting the Choline Requirement — Eggs, Organs, and the Wheat Paradox | December, 2010 blog post

How to Get Enough Folate | Chris Masterjohn Lite

Folate: You Can Freeze Your Liver But Not Your Veggies | Chris Masterjohn Lite

Supercharge Your Folate With Pastured Egg Yolks and Sprouted Legumes | Chris Masterjohn Lite

Carbs and Sports Performance | Masterclass With Masterjohn Energy Metabolism Lesson 17

This discusses the role of creatine in energy metabolism.

Should We Avoid Animal Protein to Optimize Methylation? | May, 2015 blog post

Beyond Good and Evil: Synergy and Context With Dietary Nutrients | The first section of this December 2012 article on methionine, B vitamins, and glycine is very relevant.

Research Related to “Living With MTHFR”

Liew and Gupta. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. 2015.

Chao et al. Correlation between methyltetrahydrofolate reductase (MTHFR) polymorphisms and isolated patent ductus arteriosus in Taiwan. 2014.

van der Put, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? 1998.

Reed et al. Mathematical analysis of the regulation of competing methyltransferases. 2015.

Reed et al. A mathematical model gives insights into nutritional and genetic aspects of folate-mediated one-carbon metabolism. 2006.

Mudd et al. Methyl balance and transmethylation fluxes in humans. 2007.

Gregory and Quinlivan. In vivo kinetics of folate metabolism. 2002.

Bertolo and McBreairty. The nutritional burden of methylation reactions. 2013.

Wolff et al. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. 1998.

Brosnan and Brosnan. The role of dietary creatine. 2016.

Brosnan, et al. The metabolic burden of creatine synthesis. 2011.

Kalhan. Whole body creatine and protein kinetics in healthy men and women: effects of creatine and amino acid supplementation. 2016.

Ipsiroglu et al. Changes of tissue creatine concentrations upon oral supplementation of creatine-monohydrate in various animal species. 2001.

Population reference values for plasma total homocysteine concentrations in US adults after the fortification of cereals with folic acid

Petr et al. Effect of the MTHFR 677C/T polymorphism on homocysteinemia in response to creatine supplementation: a case study. 2013.

Shin et al. Choline intake exceeding current dietary recommendations preserves markers of cellular methylation in a genetic subgroup of folate-compromised men. 2010.

Yan et al. MTHFR C677T genotype influences the isotopic enrichment of one-carbon metabolites in folate-compromised men consuming d9-choline. 2011.

Ganz. Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis. 2016.

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036: Is Insulin Really a Response to Blood Glucose?

Chris Masterjohn, PhD — Sun, 30 Jul 2017 14:30:00 GMT

Introduction

Insulin is almost universally considered a hormone whose primary purpose is to regulate blood glucose levels. Indeed, it does this. But is that the whole picture? When we look at what governs pancreatic insulin secretion inside the beta-cell, it’s about total energy and the versatility of the short-term energy supply, not about glucose. When we look at what insulin does to energy metabolism, it does far more than regulate blood glucose: it governs how we use energy and what we do with it.

What is insulin really doing? Find out in this episode. I can’t promise the episode is practical, but I promise it’s incredibly thought-provoking.

Show Notes

Here’s what you’ll find in this episode, and more:

0:00:57 Cliff Notes
0:05:40 Insulin is widely perceived as a response to blood glucose, yet there are a variety of reasons to see it as a response to short-term energy status and the versatility of that short-term energy.
0:07:42 Defining “insulin signaling.”
0:10:56 Dietary effects on insulin and glucagon: fat, protein, and carbohydrate.
0:14:40 Effects of insulin outside of energy metabolism: for example, glutathione synthesis, production and activation of thyroid hormone, protection against glycation.
0:21:04 Insulin signaling is directly triggered by the level of ATP in the pancreatic beta-cell.
0:28:06 Amplification signals in beta-cell: anaplerosis, cataplerosis, lipogenesis, and the pentose phosphate pathway.
0:38:26 The anatomy and physiology of macronutrient transport mean that fat and carbohydrate are delivered to the pancreatic beta-cell in very different ways, resulting from circulatory routes and the relative expression of glucose transporters and lipoprotein lipase.
01:00:10 Unique roles of glucose in specialized energetic pathways.
01:00:48 Cytosolic ATP generation depends on glucose and is important to red blood cells, astrocytes, the lens and cornea of the eye, the kidney medulla, the testes, and under conditions of high-intensity exercise, stress, hypoxia, or suffocation.
01:04:05 Only glucose can allow a tissue to borrow energy from the liver in the Cori cycle.
01:07:27 Glucose is the primary anaplerotic substrate; protein is secondary; fat has little anaplerotic pathway.
01:08:48 Only glucose can support the pentose phosphate pathway, which provides NADPH and 5-carbon sugars for DNA; RNA, all of the energy carriers in energy metabolism (NADPH, NADH, FADH2, Coenzyme A, ATP); synthesis of nucleotides, neurotransmitters, fatty acids, and cholesterol; recycling of vitamin K and folate.
01:14:36 Insulin as a response to total energy and energetic versatility.

Masterclass Lessons Related to “Is Insulin Really a Response to Blood Glucose?”

Lactate: Rescuing NAD+ and Generating ATP From Glycolysis | MWM 2.15

Anaplerosis: Why Carbs Spare Protein in Ways That Fat Can’t | MWM 2.16

Is Insulin Really a Response to Carbohydrate or Just a Gauge of Energy Status? | MWM 2.23

The Pentose Phosphate Pathway: How Glucose Supports Antioxidant Defense, Detoxification, Nutrient Recycling, and Far More | MWM 2.27

Insulin as a Gauge of Short-Term Energy Supply and Energetic Versatility | MWM 2.28

Research and Educational Resources Related to “Is Insulin Really a Response to Blood Glucose?”

Kawai et al. Postprandial glucose, insulin and glucagon responses to meals with different nutrient compositions in non-insulin-dependent diabetes mellitus.1987

Komatsu. Glucose‐stimulated insulin secretion: A newer perspective. 2013.

Keane and Newsholme. Metabolic Regulation of Insulin Secretion. 2014

Tortora, Principles of Anatomy and Physiology: 14th Edition , 2013, pp. 906-9, 642-6. 752-4, 787-8, 801-2, 912, and 920-2.

Byers et al. Avian and Mammalian Facilitative Glucose Transporters. 2017.

Kersten. Physiological regulation of lipoprotein lipase. 2014.

Cruz et al. Glucose and Insulin Stimulate Heparin-releasable Lipoprotein Lipase Activity in Mouse Islets and INS-1 Cells A POTENTIAL LINK BETWEEN INSULIN RESISTANCE AND β-CELL DYSFUNCTION. 2001.

Nyrén et al. Localization of lipoprotein lipase and GPIHBP1 in mouse pancreas: effects of diet and leptin deficiency. 2012.

Kalwat and Cobb. Mechanisms of the amplifying pathway of insulin secretion in the β cell. 2017.

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035: The Biochemistry of Why Insulin Doesn’t Make You Fat

Chris Masterjohn, PhD — Sat, 22 Jul 2017 14:06:00 GMT

Introduction

Do carbs and insulin make you fat? The argument centers on the ability of insulin to promote the conversion of carbohydrate to fat and lock fat in adipose tissue, as well as the necessity of glucose to provide the backbone to fat molecules within adipose tissue. But the argument ignores that all of these pathways are fundamentally regulated at a biochemical level by how much energy you need and how much you have. In episode 44 of Mastering Nutrition, we take a deep dive into the details of the biochemistry and physiology and see how insulin serves as a gauge of whole-body energy and glucose availability but simply can’t be the thing that makes you fat.

Show Notes

In this episode, you’ll find all of the following and more:

0:00:45 Cliff Notes
0:03:19 The biochemistry and physiology of the carbohydrate/insulin hypothesis of obesity: insulin stimulates de novo lipogenesis (fatty acid synthesis), promoting the conversion of carbohydrate to fat; insulin stimulates lipoprotein lipase (LPL) and inhibits hormone-sensitive lipase (HSL) at adipose tissue, locking fat into fat cells; since adipose tissue lacks glycerol kinase, it cannot reuse the glycerol backbone of fats digested by lipoprotein lipase, and dietary carbohydrate is needed to provide the glycerol 3-phosphate that forms the backbone of newly resynthesized triglycerides.
0:09:37 All biochemical pathways are regulated by cellular energy status. Key players are ATP, ADP, AMP, AMP kinase (AMPK), NADH/NAD+, FADH2/FAD, Ca2+, CoA and acyl CoAs, and citrate.
0:23:46 Although insulin promotes storage of fat in fat tissue, this can be overridden by low energy status.
0:33:13 Although insulin promotes fat storage, it causes a proportionate increase glucose oxidation, so no net change in caloric balance.
0:39:11 Glucose oxidation in muscle is driven by energy status and that determines the availability of glucose to adipose tissue.
0:53:51 Glucose can act as the source of glycerol 3-P for adipose tissue triglyceride synthesis, but it isn’t necessary because of gluconeogenesis and glyceroneogenesis. Furthermore, while it can serve this role, the degree to which it does so is driven by energy status.
0:58:53 Glucose can act as a source of glycerol 3-P for adipose, but it needs a source of fatty acids, which come mainly from fat as long as energy status is high enough.
0:59:54 Insulin can drive de novo lipogenesis, but only when energy status is high enough.
1:13:07 What happens when we eat carbs alone, fat alone, or both in the context of low and high energy status.
1:25:20 The path to weight loss is the path to a sustainable caloric deficit.

Masterclass Lessons Related to “The Biochemistry of Why Insulin Doesn’t Make You Fat”

What Shuts Down Glycolysis and Glucose Uptake? Too Much Energy. | MWM 2.21

What Shuts Down Fat Burning? Too Much Energy. | MWM 2.22

Research and Educational Resources Related to “The Biochemistry of Why Insulin Doesn’t Make You Fat”

For biochemistry textbooks, I recommend Ferrier, Biochemistry for beginners and Berg, Biochemistry and for intermediate or advanced readers. The Berg book is in its eighth edition (2015), but the fifth edition (2002) is freely available. Huge swaths are the same between them, but many portions are updated and a handful of sections are added new or fundamentally changed. The free version is hard to read straight through because it is searchable but not browsable. The Kindle or hardcover versions are much easier to read.

Tortora, Principles of Anatomy and Physiology: 14th Edition, 2013 is a good resource for understanding the transport routes of fat and carbohydrate from an anatomy and physiology perspective.

Byers et al. Avian and Mammalian Facilitative Glucose Transporters. 2017.

Kersten. Physiological regulation of lipoprotein lipase. 2014.

Winder. Cellular energy sensing and signaling by AMP-activated protein kinase. 2007.

Mitrou et al. Rates of Glucose Uptake in Adipose Tissue and Muscle in Vivo after a Mixed Meal in Women with Morbid Obesity. 2009.

Reshef. Glyceroneogenesis and the triglyceride/fatty acid cycle. 2003.

Hanson. Glyceroneogenesis revisited. 2003.

Hellerstein. De novo lipogenesis in humans: metabolic and regulatory aspects. 1999.

Acheson. Glycogen storage capacity and de novo lipogenesis during massive carbohydrate overfeeding in man. 1988.

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034: Methylate Your Way to Mental Health With Dopamine

Chris Masterjohn, PhD — Mon, 17 Jul 2017 13:59:00 GMT

Introduction

Our consciousness is like a net. We want the net to be fluid enough to let thoughts that bother us pass through without grabbing our attention, but strong enough to grab on to the ideas and motivations that will drive us to achieve what we value in life. Nutrition has a big impact on this net. In this episode, learn how foods like liver, egg yolks, meat, leafy greens, legumes, collagen, bone broth, spinach, wheat, and beets can help you achieve a fluid yet stable mental disposition resistant to anxiety, depression, and distraction.

Show Notes

In this episode, you’ll find all the following and more:

0:00:36 Cliff notes
0:05:19 Three stories illustrating how foods impact mental stability and fluidity.
0:06:07 How veganism profoundly worsened my OCD and panic attacks and going Weston A. Price made them disappear.
0:12:01 Jeffrey is an entrepreneur who uses intermittent fasting and low-protein lunches to remain hyper-focused through the workday, but at the risk of an occasional panic attack.
0:15:05 Jordan uses methylation supplements to optimize his energy and mental focus, but can experience a spectrum of methylation states that range from bodily tiredness on one end to intense focus suitable for creative and analytic work in the middle, to flighty productivity suitable for errands on the high end, to a severe crash characterized by apathy.
0:21:19 The methylation system and the roles of sulfur amino acids (methionine and cysteine), magnesium, ATP, B6, serine and glycine, folate, B12, niacin, riboflavin, thiamin, choline, betaine, and creatine.
0:27:20 The two principle fates of homocysteine.
0:33:15 Glycine as the endogenous buffer of extra methyl groups.
0:35:42 Obtaining betaine and choline from foods.
0:38:45 Creatine as a methyl group sparer.
0:41:27 Niacin and nicotinamide riboside as a tax on the methylation system.
0:43:29 Tonic and phasic dopamine, and how methylation mediated by catechol O-methyltransferase (COMT) regulates the balance.
0:50:24 How the balance of tonic and phasic dopamine determines the ease of switching mental states.
0:56:58 Worrier vs. warrior phenotype.
1:02:14 Histamine in the brain as an alertness signal and a potential contributor to panic attacks.
1:05:00 Explaining the three stories.
1:15:24 Practical conclusions.

Research Related to “Methylate Your Way to Mental Health With Dopamine”

Taylor S. Association between COMT Val158Met and psychiatric disorders: A comprehensive meta-analysis. 2017.

Bilder et al. The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes. 2004.

Turnbridge EM. The catechol-O-methyltransferase gene: its regulation and polymorphisms. 2010.

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033: Can Fat Fuel the Athlete?

Chris Masterjohn, PhD — Sat, 08 Jul 2017 13:53:00 GMT

Introduction

In this episode, we look at whether fat can fuel the athlete. We begin with the physiological principles involved, then take a look at the evidence from studies swapping fat for carbs to see how it impacts athletic performance.

Show Notes

0:00:42 Cliff Notes
0:08:33 The three systems of energy metabolism in skeletal muscle: phosphagen (creatine phosphate and ATP), anaerobic glycolysis (conversion of glucose to lactate), and oxidative phosphorylation (use of carbohydrate, protein, or fat to produce energy using oxygen).
0:10:11 The different sources of fuel have different proximities to the site of muscular contraction (in declining order: phosphagens, glycolysis using muscular glycogen, aerobic metabolism of glycogen, use of fatty acids from adipose tissue or glucose produced by the liver).
0:12:41 As a result of the different proximities to the site of muscular contraction, the different fuels are used at different rates.
0:16:03 Fat provides an enormous amount of energy, but slowly; glucose supplies are limited, but provide energy rapidly.
0:18:56 After a short period of time at high intensity creatine must be recycled through anaerobic glycolysis or oxidative phosphorylation.
0:20:41 It can take minutes to become aerobic, so after a few seconds of running on creatine you’re dependent on glucose for intensity at least until the aerobic lag is over.
0:28:57 Even when you’re maximally aerobic, pushing your intensity further requires glucose.
0:30:40 The evidence.
0:30:53 Romijn 1993: when eating 3-400 g carb/d, light intensity burns almost 100% fat, high intensity burns mostly carbohydrate, and moderate intensity burns about half fat half carbohydrate.
0:36:34 Phinney 1983: <20 g/d carb does not hurt endurance when the goal is to cycle at least 60 rpm without giving up, but it decimates muscular glycogen and forces adaptations to use less glycogen during moderate intensity exercise.
0:39:27 Volek 2016: Endurance athletes who chose themselves to eat low-carbohydrate diets providing ~82 g/d carbs for at least six months burned less carbohydrate and more fat during a 3-hour moderate intensity treadmill run, but had zero changes to their stores of muscular glycogen or their utilization of glycogen during exercise.
0:46:44 Paoli 2012: A high-protein, possibly “ketogenic” diet (perhaps) with lots of herbal performance enhancers, might not hurt performance if you ignore the effect of weight loss on the difficulty of body weight exercises.
0:54:45 Wilson 2017: Keto does not hurt 1RMs on the bench press or squat or impair gains of muscular circumference, but it wipes out gains on all-out cycling unless you carb load before the test.
0:58:12 Burke 2017: High-carb all the time is the best diet for competitive race walking, even better than periodized training and certainly better than low-carb.
01:04:21 The Lakers went low-carb in 2013 and their performance tanked to an unprecedented level. It’s an historical anecdote and you can’t prove cause and effect. Nevertheless, known physiology strongly favors the view that you can’t win basketball games relying on fat for your peak intensity.
01:11:41 Bottom line: fat can help you go long; if you want to go hard or go fast, get glucose.

Research and Educational Resources Related to “Can Fat Fuel the Athlete?”

For background, Poortmans, Principles of Exercise Biochemistry.

Gastin PB. Energy System Interaction and Relative Contribution During Maximal Exercise. 2001.

Jones and Vanhatalo. The ‘Critical Power’ Concept: Applications to Sports Performance with a Focus on Intermittent High-Intensity Exercise. 2017.

Chidnok,et al. Muscle metabolic responses during high-intensity intermittent exercise measured by 31P-MRS: relationship to the critical power concept. 2013.

Barclay CJ. Energy demand and supply in human skeletal muscle. 2017.

van Hall G. The Physiological Regulation of Skeletal Muscle Fatty Acid Supply and Oxidation During Moderate-Intensity Exercise. 2015.

Romijn et al. Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. 1993.

Phinney et al. The human metabolic response to chronic ketosis without caloric restriction: physical and biochemical adaptation. 1983

Phinney et al. The human metabolic response to chronic ketosis without caloric restriction: preservation of submaximal exercise capability with reduced carbohydrate oxidation. 1983.

Volek et al. Metabolic characteristics of keto-adapted ultra-endurance runners. 2016.

Paoli et al. Ketogenic diet does not affect strength performance in elite artistic gymnasts. 2012.

Wilson et al. The Effects of Ketogenic Dieting on Body Composition, Strength, Power, and Hormonal Profiles in Resistance Training Males. 2017.

Burke et al. Low carbohydrate, high fat diet impairs exercise economy and negates the performance benefit from intensified training in elite race walkers. 2017.

Ken Berger, Nutrition in the NBA Part 1.

NBA Teams: Los Angeles Lakers Records Year by Year.

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032: Is Coconut Oil Killing Us?

Chris Masterjohn, PhD — Sat, 24 Jun 2017 13:47:00 GMT

Introduction

In this episode, I weigh in on the American Heart Association’s new Presidential Advisory and Dietary Fats and Cardiovascular Disease, and all the headlines that have been spinning on the supposed risks of coconut oil.

Show Notes

In this episode, you will find all of the following and more.

0:00:53 The recent headlines on coconut oil.
0:01:50 The American Heart Association’s new Presidential Advisory, “Dietary Fats and Cardiovascular Disease” is not centrally about coconut oil, but it laments the popularity of coconut oil.
0:04:06 This is a position paper reinforcing the conventional view about saturated fat as the stance against it within the scientific community has begun to soften around the edges. The 2015 dietary guidelines and the 2016 Ramsden paper reflect that softening.
0:11:37 The inclusion and exclusion criteria of the “4 core trials” of the AHA meta-analysis.
0:13:36 The 4 core trials.
0:13:58 The Finnish Mental Hospitals Study makes the largest contribution to the AHA conclusion but was not a randomized controlled trial and doesn’t belong in this list.
0:20:42 The Oslo Diet-Heart Study was included and made a contribution, yet other trials were excluded on the basis of confounding that were far less confounded than Oslo.
0:24:37 The LA Veterans Administration Hospital Study showed that a vitamin E-deficient diet makes you vulnerable to the heart disease-promoting effects of smoking, and that vegetable oils cause more cancer than cigarettes.
0:33:38 The Medical Research Council study showed a trend toward a benefit of soybean oil that was not statistically significant. Lack of heat damage to the fats in the diet, coenzyme Q10, and omega-6/omega-3 balance could have played a role in the trend.
0:38:08 Exclusion of Rose 1965 and Minnesota Coronary Survey from the “4 core trials” was fair.
0:39:32 Controversy over the possible contribution of trans fats to the results of the Sydney Diet Heart Study. But this as a basis for exclusion could have excluded the LA Veterans Administration Hospital Study as well.
0:44:57 The impact of including or excluding MRC and Sydney shows how the conclusions are driven not by the cumulative data but on the qualitative decisions about which studies to include.
0:49:01 The observational studies are hopelessly confounded by popular campaigns about the heart-healthiness of replacing saturated fat with polyunsaturated fat.
0:53:00 The experiments in monkeys using lard, palm oil, and dietary cholesterol to bring their plasma cholesterol to 300-400 mg/dL.
0:55:30 The oxidation of lipoproteins drives atherosclerosis and polyunsaturated fats drive the oxidation. This is embraced by the leading conventional thinkers.
1:02:59 The AHA position on coconut oil is based on its effect on LDL-C, explicitly arguing in favor of ignoring its effects on HDL-C, and explicitly acknowledging the complete absence of clinical evidence.
1:10:10 Coconut oil has benefits unrelated to heart disease, such as the antimicrobial (antifungal and antibacterial) effects of lauric, capric, and caprylic acids, and the increased energy expenditure and decreased appetite caused by capric and caprylic acids.
1:13:58 Coconut oil could protect against heart disease due to its low polyunsaturated fat content.
1:16:29 Traditional Pacific island diets were far higher in saturated fat than the standard American diet, yet heart disease was absent.
1:19:07 The Tokelau Migrant Study showed that the freedom from heart disease on Tokelau, where coconut consumption pushed saturated fat over 50% of calories, was not due to genetics or age.

Links and Research Related to “Is Coconut Oil Killing Us?”

The American Heart Association Presidential Advisory, “Dietary Fats and Cardiovascular Disease”

As the Cholesterol Consensus Crumbles, the Stance on Saturated Fat Softens (blog post, podcast)

The Scientific Report of the 2015 Dietary Guidelines Committee

The eighth edition of the actual Dietary Guidelines

The 2010 Mozaffarian meta-analysis

The 2016 Ramsden paper

The reason for randomization

Ramsden’s criticism of the Finnish Mental Hospitals Study

My discussion of the Finnish Mental Hospitals Study in How to Read a Science Paper

Controversy over trans fat contribution to Sydney Diet-Heart results

Coenzyme Q10 protects against PUFA-induced aging in rodents.

Coenzyme Q10 in foods.

Daniel Steinberg’s Cholesterol Wars

Good Fats, Bad Fats: Separating Fact From Fiction

AJCN Publishes a New PUFA Study That Should Make us Long For the Old Dayscovers many of the trials discussed herein.

The effect of dietary fat on the total-to-HDL-cholesterol ratio

Absence of heart disease on Kitava, where coconut is the main source of fat.

Absence of heart disease in Pukapuka and Tokelau, where coconut consumption was even higher.

Stephan Guyenet’s series on the Tokelau Migrant Study

MCT oil decreases hunger.

MCT oil increases energy expenditure.

Masterclass With Masterjohn: Oxidative Stress and Heart Disease

Masterclass With Masterjohn: Vegetable Oils and Heart Disease, Examining the Controversy

Episode 30: What to Do About High Cholesterol

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Harnessing the Power of Nutrients: Mastering Nutrition

039: Creatine: Far More Than a Performance Enhancer

Introduction

Show Notes

Creatine Supplement Recommendations

Creatine in Foods: The Database

Lab Tests Related to Creatine

Creatine Links and Research

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051: Ask Us Anything About Sports Nutrition with Chad Macias, Danny Lennon, and Alex Leaf | May 25, 2019

Listen to the Audio

Show Notes

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050: Ask Us Anything About Hormones with Dr. Carrie Jones | May 10, 2019

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Show Notes

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049: Pantothenic Acid, Part 2 (Foods, Lab Tests, and Supplements)

Show Notes

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048: Pantothenic Acid, Part 1 (What It Is and Why We Need It)

Time Stamps

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047: Niacin, Part 2: Blood Tests, Foods, and Supplements

Introduction

Show Notes

Niacin Links and Research

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046: Niacin, Part 1: What It Is and Why You Need It

Introduction

Show Notes

Niacin Links and Research

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045: Why You Should Manage Your Riboflavin Status and How to Do It

Introduction

Show Notes

Riboflavin Calculator

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044: Nutrition in Neuroscience Part 4

Show Notes

Nutrition in Neuroscience Related Content

Nutrition in Neuroscience Research

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043: Nutrition in Neuroscience Part 3

Introduction

Show Notes

Nutrition in Neuroscience Related Content

Nutrition in Neuroscience Research

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042: Nutrition in Neuroscience Part 2

Introduction

Show Notes

Nutrition in Neuroscience Related Content

Nutrition in Neuroscience Research

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041: Nutrition in Neuroscience Part 1

Introduction

Show Notes

Nutrition in Neuroscience Links

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040: Why You Should Manage Your Thiamin Status and How to Do It

Introduction

Show Notes

Lab Tests Related to Thiamin Status

Links and Research Related to Thiamin

Other Posts About Thiamin

Other Posts About Measuring and Managing Nutritional Status

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038: Are We All Evolved to Eat High Protein?

Introduction

Show Notes

How to Know If You Have a Common OTC (Urea Cycle Enzyme) Polymorphism

Links and Research Related to “Are We All Evolved to Eat High Protein?”

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037: Living With MTHFR

Introduction

Show Notes

How to Know If You Have an MTHFR Mutation

A Dietary Strategy for MTHFR Polymorphisms

Lab Tests Recommended for MTHFR Polymorphisms