Transcript of the Why You Need Glycine: A Panel

Discussion

This is Chris Masterjohn of chrismasterjohnphd.com, and you’re listening to Episode 49 of

Mastering Nutrition, where today we have a special panel discussion with myself, Alex Leaf of
Examine.com, and Vladimir Heiskanen about glycine, a little amino acid with a big impact on
your health. Ready? The show starts now.

0:00:45 Introducing Alex Leaf and Vladimir Heiskanen

Welcome back, everybody. Today’s discussion is all about glycine, and it’s a special episode
where we have a three-person panel discussion. I’m on the panel, and with me I have Alex Leaf
of Examine.com.

Alex is a Certified Sports Nutritionist and personal trainer. He’s got a master’s degree in nutrition
from Bastyr. He’s a full-time researcher at Examine.com involved in updating the supplement
database, writing and editing Examine Research Digest articles, and blogging about nutrition.

But on top of all that, Alex contributed to the glycine page on Examine.com and is currently in
the process of updating it, and that’s a major reason I invited him on for this discussion, because
he’s been really deep into glycine lately. He also teaches about human nutrition and functional
medicine at the University of Western States, and he loves blending the scientific aspects of
nutrition with the pragmatic realities of life to help others achieve their goals, which is what he’s
doing with glycine on this show.

I also have with me Vladimir Heiskanen, who is based in Finland, and during this podcast he
had a cold, and English is not his first language, so bear with him. I invited him on the podcast
because many years ago, about four years ago, he did a very big review on glycine on his blog,
and I’ve talked with him in the background a little bit over email, and so I know that he’s very
familiar with the body of research on glycine. And his blog is Valtsu’s.

He’s been researching and writing about health for several years. He’s currently a dental
student at the University of Helsinki, and he’s been blogging since 2010. He’s interested in
human biology. He’s studied scores of books and cutting-edge scientific reports. And his special
interests are red light therapy, nutrition, mitochondrial function, and obesity.

0:02:44 Cliff Notes

If you are on the run, here are the cliff notes. Glycine is not an essential amino acid, because we
can synthesize it. However, the overwhelming way in which we synthesize glycine depends on
us using folate, and we only have so many needs to use folate, which means that our synthesis
of glycine is restrained by that need. This would have been fine if we were a tiny vertebrate
hundreds of millions of years ago when this pathway emerged, but we are very large animals,
and we have a very high demand for collagen, which is one-third glycine.

We run a deficit of our ability to synthesize glycine relative to our needs of about 10 grams a
day, and that’s a conservative estimate. For people who have high rates of collagen turnover
and poor recovery of glycine, they could run glycine deficits up to 40-60 grams per day.

Traditional human diets utilized collagen-rich tissues, the best sources of glycine, such as skin
and bones. An animal carcass might be half collagen, and you would be economically
restrained in the pre-modern era to use most of that collagen in a way that you really don’t quite
use if all you’re doing with it is boiling the bones to make bone broth.

But, it may be an intrinsic part of our biology that we run a glycine deficit, and the most
compelling thing that Alex brings up in this podcast is that even animals who did not have
traditional diets that were rich in collagen run this glycine deficit, and you can’t justify it based on
eating an unnatural diet. So it seems to be a really intrinsic part of the biology of large
vertebrates that we all run a glycine deficit, and traditional human diets just mitigated that
through the thorough utilization of skin and bones.

Across animal and human studies, glycine has many benefits. In animals, it protects against the
metabolic dysfunction caused by obesogenic diets. In diabetes, it protects many organs. It
protects the liver, the kidneys, the eyes, the brain, et cetera. It has anti-inflammatory effects that
might protect against the harmful effects of endotoxin. So for gut dysbiosis or high-fat diets that
promote the absorption of endotoxin from the gut, glycine may protect against that.

In humans, the most compelling uses of glycine are as follows: 3-5 grams of glycine before a
meal protects against rises in blood sugar after that meal; 15 grams of glycine per day protects
type 2 diabetics from metabolic dysfunction; 3 grams of glycine before sleep improves your
ability to fall asleep and your sleep quality so that you feel more rested when you rise during the
day; 15 grams of gelatin taken before a workout with about 50 milligrams of vitamin C promotes
getting that collagen into your tendons to help your tendon health.

There are rare metabolic disorders that are treated with 20 grams of glycine a day, which
prevents the accumulation of ammonia and the toxic effects of metabolic byproducts that
accumulate in those diseases. And in schizophrenia, 60 grams of glycine a day has shown
beneficial antipsychotic effects.

We also know from the biochemistry that glycine is important to detoxification directly. It’s
important to synthesize glutathione, which is used in detoxification, and is the most powerful
antioxidant we have, and is strongly protective against asthma and other lung conditions.

Best way to take glycine is to use a gelatin or collagen supplement. Hydrolyzed collagen has
better bioavailability than gelatin. Out of the hydrolyzed collagen supplements, Great Lakes is a
great option because it balances cost effectiveness with transparency around testing for
contaminants. But although Vital Proteins costs more, they use an enzymatic process rather
than a heat-mediated process to digest the collagen peptides, and at least some people
digestively tolerate Vital Proteins the best.

About 2 rounded tablespoons of hydrolyzed collagen generally provides 3-4 grams of glycine.
Depending on your priorities, you could take it before your workout, before each meal, or before
bed, or all of those. You can also take glycine as a pure powder. It’s sweet, and you can use it to
replace your sweeteners.

Glycine is overwhelmingly safe. The only potential risk is that collagen, because of its
hydroxyproline content, may raise oxalate levels in the urine. If you’re concerned about that,
listen to the podcast in full detail to get my suggestions around testing and around protective
factors in the diet to make sure that that does not increase your risk of kidney stones.

Alright, that’s it for the cliff notes. Let’s hear a word from my sponsors and then dive deep into
the panel discussion.

0:08:28 Vladimir, Alex, and Chris each share their favorite underappreciated fact about
glycine.

Chris: Okay, let’s introduce the panel. Guys, I’d like you—we’ll start with Vladimir and then Alex.
Could you introduce yourself by name and tell us your favorite underappreciated fact about
glycine.

Vladimir: I am Vladimir Heiskanen. In Finland, we would say Vladimir Heiskanen. And my

blog’s name is Valtsu’s. And the most underappreciated fact about glycine: In mice, it protects
them very strongly against the effects of high-sugar diets, like weight gain and other metabolic
harms.

Chris: Alright, very cool, man. Alex?

Alex: I would say probably the most underappreciated aspect of glycine is that it is a potent
hypoglycemic agent, and there are at least two interventions I’m aware of, one in healthy people
and one in people with type 2 diabetes, that show that it can significantly reduce a blood
glucose spike from eating a carbohydrate-containing meal, and chronic supplementation can
lower HbA1c quite significantly.

Chris: Cool. And that was Alex Leaf. Thanks, Alex. I’m Chris Masterjohn, and my favorite
underappreciated fact about glycine is that glycine is the endogenous buffer of methyl groups
when we get too many, and that means that when we eat a lot of methionine, like we’d get on a
diet high in animal protein, we need a lot more glycine to buffer the extra methyl groups
provided by the methionine. And that means that the more meat we eat, the more glycine-rich
tissues, which is especially the skin and the bones, that we need to eat. And that looks a lot like
eating a whole animal would look like instead of picking the parts that we want to eat, like we
tend to do now. So that’s my favorite part about it.

Alright, what I’m going to do now is I’m going to go into some of the important roles that glycine
plays from a basic mechanistic understanding and how we can make glycine, and then I’m
going to let Alex talk a little bit about whether we need to eat glycine in the diet and why, and I’ll
let Vladimir talk a little bit about some of the health effects, and then we’ll kind of go into a
free-form discussion.

0:11:12 Roles of glycine include detoxification, glutathione synthesis, heme synthesis,

creatine synthesis, collagen synthesis, removal of intermediates when metabolic
pathways are backed up, and it acts as a calming neurotransmitter.

So, the roles of glycine. One of the roles of glycine is detoxification as a direct factor to get rid of
stuff that shouldn’t be in our bodies. Glycination is a form of detoxification, and it’s especially
important for getting rid of benzoate, which is used as a food preservative, but it’s also found
naturally in some fruits, especially berries.

And it’s really important for detoxifying salicylate, which can come from aspirin or could be found
in a variety of fruits, vegetables, seeds, nuts, spices, and honey. The salicylates are very
variable in their distribution in those foods, but there are many of those foods that do provide a
lot of salicylates, and if you can’t detoxify the salicylates, you can get negative effects from them
that often mimic allergies and inflammation in a lot of ways.

Glycine is needed to synthesize glutathione. Glutathione is the master antioxidant of the cell.
Glutathionylation is another form of detoxification, so this is a second role in detoxification, but
glutathione does a lot of other things.

Glutathione is needed to maintain the fluidity of mucus. If your mucus in your respiratory tract is
not fluid enough, it could get congested and it won’t work as well. Glutathione combines with
nitric oxide to make our endogenous bronchodilator. This is nitrosoglutathione.

And if you look at asthmatics, asthmatics have lower glutathione status, and they have lower
levels of nitrosoglutathione, the endogenous bronchodilator in their lungs. And during an acute
asthma attack that sends someone to the hospital, during that time while they’re in the hospital,
the nitrosoglutathione levels in their lungs have dropped to zero or near zero. And when asthma
sufferers are inhaling steroids and albuterol as a bronchodilator, they’re basically taking a
pharmaceutical replacement for the nitrosoglutathione that should be their own endogenous
bronchodilator. And glycine is important for that.

Glutathione has many other roles in regulating hundreds of different proteins. It’s important in
regulating metabolism, and so a lot of the metabolic dysfunction that occurs in diabetes, for
example, is a result of poor glutathione status, hyperglycemia being one of those, because
glutathione is necessary to maintain the proper metabolism and uptake of glucose.

Glycine is necessary for the synthesis of heme, so that would be important for hemoglobin,
which carries the oxygen in our blood. But we also use heme in a variety of enzymes. Many of
those enzymes are used in detoxification, and so that’s the third role of glycine in detoxification.
But also, our energy metabolism and our antioxidant defense because of the role of heme in
catalase. And thyroid function. Thyroid peroxidase is also a heme-dependent enzyme.

Creatine is synthesized by combining glycine with the amino acid arginine to make
guanidinoacetate. Guanidinoacetate is then methylated to form creatine, so glycine is important
to creatine synthesis.

Glycine is super important to collagen. In fact, glycine makes up about a third of the collagen
molecule, and collagen is providing structural support to many tissues, including our skin, which
we see on the surface. But 95% of the protein in bone is collagen, and protein makes up about
half of bone. So glycine and collagen are just as important as calcium, phosphorus, and other
minerals to your bone health.

Glycine also plays a role as a neurotransmitter. It antagonizes glutamate in some ways in the
brain. Glutamate is a primary excitatory neurotransmitter, so glycine has a calming effect. It
helps with sleep promotion. And in some cases, it has an antipsychotic effect, as well.

And then finally, I would list the removal of metabolic intermediates when metabolic pathways
are backed up. Now, this happens to a small degree in everyone probably. If you’re burning fat
and you’re releasing fat a rate higher than you’re burning it, you are going to get some
intermediates that can be toxic at high effects, and you’re also going to lock up these
intermediates with coenzyme A, which is one of the major carriers of carbon-based compounds
in energy metabolism. If you don’t have enough CoA because your metabolic pathways are
being backed up, you will save that CoA by trading the CoA that’s holding the metabolic
intermediate for glycine, and you pee out the glycinated metabolic intermediate into your urine,
and that helps keep your energy metabolism going.

Now, this is probably a very small effect in most people, but there are a lot of rare genetic
disorders which—and some are not as rare as you would think because there’s so many of
them—where this becomes a major problem, and those metabolic disorders are treated with 20
grams of glycine a day to help normalize the metabolism and detoxify those intermediates.

0:17:06 Glycine synthesis is almost entirely dependent on folate utilization and generates
about 3 grams per day.

Now, despite all these great things about glycine, glycine is not considered an essential amino
acid, because we can synthesize it. Now, if you consider the biochemical pathways by which we
synthesize glycine, then that provides important understanding for the question of, do we
actually need to consume glycine in the diet? So as we’re going through the synthesis of
glycine, really the ultimate question is, what is the maximal capacity for this synthesis, and what
does that imply for the question of whether we need to eat glycine in the diet?

When we synthesize glycine, the most predominant reason we do this is to support the
methylation process. And I’ve talked about the methylation process in two prior episodes of this
podcast, “Living with MTHFR,” and “Methylate Your Way to Mental Health.” And if you review
those podcasts, it might help with understanding this information here.

But what’s pertinent to glycine is as follows. When we methylate homocysteine to methionine,

which is a process that depends on folate and vitamin B12, we need to provide a methyl group
to folate to make that happen. And that methyl group is a carbon with three hydrogens. The
central part of the methyl group, the carbon, is usually supplied by the amino acid serine, and
when serine provides that carbon, it becomes glycine. That is the predominant mode of
synthesizing glycine. In that way, we provide about 1.1 grams of glycine per day.

There are a variety of other processes where folate is not converted to methylfolate; it’s
converted to other forms of folate that have that carbon atom but they don’t have all the
hydrogens added as the methyl group, such as methylenefolate. And if we look at all these
other pathways where we still need to provide the carbon from serine and we still are able to
synthesize glycine, it makes a significant contribution that goes beyond the methylation of
homocysteine.

When we synthesize purines—these are adenine and guanine, which are used as building
blocks of DNA and RNA—and also energy molecules, such as adenosine triphosphate has
adenine in it. When we do that, we add to this about 400 milligrams of glycine.

When we synthesize DNA, we need to synthesize thymine, which is a component of DNA. And
in that case, we’re also dependent on the carbon atom from folate, and that adds a little over
450 milligrams of glycine.

There’s another way to get that carbon atom on folate, and that’s to take it from the amino acid
histidine. When we do that, we replace folate utilization, and that actually prevents us from
synthesizing glycine, because we’re getting the carbon atom onto folate in a way that does not
require the synthesis of glycine. And so that actually subtracts about 240 milligrams of glycine
from the total that we could synthesize.

If we sum all these together, we’re getting a little over 2 grams of glycine, and they all require
folate utilization to happen.

When we talk about the methylation process, not all of the methylation of homocysteine comes
from vitamin B12 and folate. About half of it, depending on the amount of folate and B12 and
choline in the diet—but about half of it can come from choline.
Choline is oxidized to betaine, also known as trimethylglycine. And trimethylglycine can
methylate homocysteine to methionine, becoming dimethylglycine. That dimethylglycine can
then go into the mitochondrion, where it can donate the two remaining methyl groups to folate
and then become glycine.

It’s been estimated that about 150-250 milligrams of glycine can be generated in that manner,
but when you do that, you are basically replacing serine. Because if you’re using
dimethylglycine to methylate folate twice, that’s two molecules of folate that didn’t take the
carbon from serine, so that’s two molecules of glycine that you’re not making for every one that
you do make.

So although choline can be a source of glycine, actually getting more choline—which I think is
overall a good thing—actually getting more choline probably subtracts from the amount of
glycine you can synthesize rather than adding to it.

There are a few other pathways that have nothing to do with folate where we can synthesize
glycine, but they sum up to hardly more than 100 milligrams a day. So in net, when we look at
this, we’re looking at about 3 grams, a little under 3 grams of glycine that we can synthesize,
almost entirely from processes that are dependent on folate utilization.

0:23:37 Glycine is consumed in the diet, but methionine, found abundantly in animal
protein, increases the need for glycine.

But we can also consume glycine in the diet. On a low-protein diet, we might be getting 1.5
grams of glycine, but on a high-protein diet, we might get as much as 9 grams of glycine. For
example, if you got 150 grams of protein per day all from sirloin steak, you’d probably get about
9 grams of glycine.

But here’s the thing. That steak is very rich in methionine. Every time you get more methionine
than you need to support the methylation process, you dump the extra methyl groups by
methylating glycine.

If you methylate the glycine, you can basically have two fates to it. The glycine can go into the
mitochondrion, can donate the methyl groups back to folate, and then become glycine again
and serve its purpose. And if you do that, you’re still basically getting nowhere and even actually
taxing the total amount of glycine that you have.

The reason is, say methionine comes in. Methionine provides a methyl group that you didn’t
need folate utilization for. Because you didn’t need folate utilization, you never turned serine into
glycine. So that’s one glycine molecule that you didn’t make. Then you methylate glycine. The
best possible fate of that glycine is to go into the mitochondrion and deliver its methyl group to
folate. That’s one methyl group on folate that did not need to be taken from serine and so never
got turned into glycine. So you salvaged the glycine, but you’ve lost two glycine molecules that
you didn’t make, so you’re reducing the synthesis.

But let’s say that glycine tries to deliver the methyl group to folate and there’s not enough
unmethylated folate to take it. Then you’re going to pee out the methylated metabolites of
glycine. So not only are you synthesizing less, but you’re literally losing it in the urine.

Unfortunately, no one’s really done out, like if you eat 50 grams of protein with this much
methionine, how much more glycine do you need? We don’t have randomized controlled trials
showing this amount of steak means you need this much more glycine. But given the fact that
the methionine depletes the glycine, the extra glycine that’s in that steak might not actually be
making any net contribution. Maybe it compensates for what you’re losing, but it might not
actually be doing your glycine any favors to eat that steak.

0:26:33 MTHFR mutations worsen glycine status.

I’ll mention one last thing before I pass this on to Alex. One of the issues that I’ve been talking a
lot about in the “Living with MTHFR” podcast, in the “Methylate Your Way to Mental Health”
podcast, and in some of the recent Chris Masterjohn Lite videos is what happens when you
have a genetic polymorphism in the MTHFR enzyme, which is what produces the methyl group
on folate.

When you have an MTHFR mutation, let’s say it’s the worst-case scenario, where you’re
homozygous for C677T and your MTHFR is reduced 75%. If using methylfolate is the biggest
source of glycine synthesis, totaling 1.1 grams a day, you’re losing 75% of that pathway,
because you’re reducing the use of that pathway 75%.

In addition to that, methylfolate is actually what prevents you from methylating glycine. It’s the
off switch for that glycine buffer system. If you don’t have enough methylfolate, you will
methylate glycine even when you don’t have enough methyl groups. So you don’t even need to
eat a steak to provide too much methionine. You’ll be methylating glycine anyway.

So you’re not synthesizing as much glycine, you’re peeing out glycine as methylated
metabolites into the urine, and then if you eat a steak, you provide the excess of methionine that
worsens all of that. So my suspicion is that glycine status is going to be worse in the case of
MTHFR mutations, and eating a diet high in animal protein if you don’t make up for that glycine
somehow is probably going to put you in the worst-case scenario.

Let’s take this back to the high level here and think about someone who has a perfectly working
methylation system. They don’t have any of these mutations. They’re able to synthesize several
grams of glycine a day. Alex, I want to pass this on to you now and pose the question, is 3
grams of glycine a day enough, and what do we know about that, and what does it mean for
whether someone actually needs to eat glycine in their diet?
0:29:10 Over the course of evolution, our collagen requirements increased substantially,
but our ability to synthesize glycine stayed the same.

Alex: The short answer is that 3 grams per day of glycine would be enough if we were small
vertebrates crawling out from the ocean 500 million years ago, which is when the glycine
methylation pathway was believed to have emerged in evolutionary history. And it makes sense
when you look at all of the pathways in which glycine can be synthesized in the body and you
compare the synthesis amounts to the theoretical pathways of glycine consumption, all of the
metabolic requirements of glycine require the amount of glycine that the body is capable of
synthesizing, itself.

Where we run into issues is when you add in the glycine needed to promote collagen turnover.
Obviously, us and other land animals have a lot more collagen than our early ancestors,
because we’re just bigger. So that’s kind of the evolutionary argument for why we have this
constraint to begin with, is that this pathway developed in early vertebrates when collagen
requirements were incredibly low, but it stuck with us through evolutionary time, and as we
evolved and developed more and more collagen, this pathway just stayed the same.

And so we gradually ran up a larger and larger glycine deficit, because our collagen
requirements increased. And as you recall, collagen is one-third glycine by necessity, and when
you have 80% of the protein in your body being collagen, that’s a lot of glycine.

So then you have to question, okay, from this evolutionary perspective, the glycine constraint
would not only apply to humans, because if this evolutionary explanation makes sense, it should
appear in all large, terrestrial animals, not just us, because we all came from the same common
ancestor.

And while this is going to be reaching quite a bit, keep in mind how Chris said that glycine is a
tremendous component of bone health, not just joint health. And when you look at other large
land animals, both in the wild and in captivity, which means that it’s going to be across a range
of diets, we have it noted in elephants, rhinoceroses, most other great apes, such as gorillas
and bonobos, and we even have some evidence in Neanderthal skeletons, of degeneration.

And the question is, why would a disease such as osteoarthritis and osteoporosis, why would
these appear in wild animals and Neanderthals? And a potential explanation is because they
don’t make enough glycine. And over time, this deficit accumulates and eventually causes
structural breakdown.

Now, it’s not life-threatening by any means. It’s actually a perfect example of Bruce Ames’ triage
theory, which posits that short-term survival is always prioritized over long-term health. So if
you’re not consuming enough glycine in your diet to promote healthy levels of collagen turnover
and optimal bone health, it’s probably not going to get you killed when you’re running away from
a predator, so it may not necessarily be something that natural selection wants to get rid of,
because as long as you make it to reproductive age, you’re good to go.

0:33:25 We run a deficit of our ability to synthesize glycine relative to our needs of about
10 grams per day, according to the most conservative estimate.

Now, that being said, I think it’s important to note that the 3 grams of glycine we make, when
pitted up against our own personal collagen requirements, runs a deficit of about 10 grams of
glycine per day. And on that level, we can just pretty much say that most humans would be well
off supplementing their diet with 10 grams of glycine per day, preferably in the form of some type
of collagen.

And that’s for reasons unrelated to glycine, such as that when you consume collagen, some of
the peptides are absorbed intact and are incorporated directly into joint tissue and promote
collagen synthesis. So you might as well get multiple benefits instead of just taking pure glycine.

But where I wanted to go with this is that that 10 grams of glycine is a very heavily conservative
estimate. If we look at where this estimation came from, it is based on a reference middle-aged
man, age 30-50 years old, who weighs 70 kilograms, or about 154 pounds, and who is
sedentary. So automatically, if you’re bigger than that, if you weigh more than 154 pounds,
you’re probably going to need more glycine. Why? Because you have more mass, and that
means you have more collagen, and that means you need more glycine to support collagen
turnover.

Moreover, I’m going to assume that most people listening to this podcast are active in one way
or another. They’re not sedentary. And guess what happens when you’re physically active.
Collagen turnover increases. And so if you have increased rates of collagen turnover, you’re
going to need more glycine to support that.

And the final one, and this is probably the largest contributor is that the paper that suggested
the glycine deficit of 10 grams per day used the most conservative estimates that they could find
so as to not overstate their position. In particular, they found that studies evaluating collagen
turnover had a range of 80-98% for the amount of glycine that’s recycled.

And what this means is that they used the 98% end to make their estimate, which means that
whenever collagen in your body is broken down, 98% of the glycine that gets released from that
collagen is going to be recycled and reused, which means that we only need to worry about the
2%, the problem being that the data they base that on documented glycine recycling being as
low as 80%, which means that if you swap out those percentages in the calculations they use,
then 10 grams of glycine per day suddenly jumps up to 35-40 grams per day.

And it’s probably likely that people have different levels of glycine recycling capacity in their
body depending on various genetic factors and other crap that we haven’t identified. Point being
that 10 grams of glycine per day from some type of glycine-rich protein food, like collagen, or
from just pure supplemental glycine is an absolute minimum that everyone should be thinking
about. And that requirement, especially if you’re larger and you’re physically active, could be
substantially higher.

Chris: Very interesting. Another situation that I think of is people at risk for osteoporosis have
high rates of bone turnover and particularly have high bone turnover versus bone growth. And
it’s kind of fascinating to think about the fact that if you have high bone turnover, you’re
presumably losing more of that glycine, but if you need that glycine for bone growth, then maybe
that’s a big part of why that deficit is there.

0:38:09 Running a glycine deficit is an intrinsic part of the biology of large vertebrates,
but our ancestors mitigated this deficit by eating collagen-rich diets.

I want to ask you one question here, Alex, which is, I thought before I had this conversation with
you, I always thought of this evolutionary perspective on the glycine deficit as being a product of
having always consumed a lot of glycine through utilizing the whole animal nose to tail. And the
big problem with that now seems to be that if animals that you would not expect that to be part
of their diet, for example mostly plant-eating animals, had that same nature of glycine deficit,
you can’t really say they have the glycine deficit because they always ate lots of bones, if they
mostly ate leaves and berries.

So how do you now think about this idea that traditional diets tended to use a lot of collagen? Is
that something that humans developed as a strategy? Is it just total coincidence because of the
economics? How do you think about that now?

Alex: That’s a really good question. I would say it might be a little of both. If we consider it from
a completely pragmatic aspect, our ancestors were not going to waste food. And so there is
potential that it could have just been entirely by chance that they ate collagen-rich diets,
because collagen is the main protein in all animals, and they didn’t want to waste any animals
that they had to go through the trouble of catching and cooking.

It could also be that they—a lot of traditional cultures kind of have traditions that we try to
explain with modern science about why they continue to do them, right? Maybe they do them
because they get some benefit from them, but they aren’t able to explain scientifically what that
benefit is. And so it wouldn’t be far-fetched either to believe that when they went on pure muscle
meat diets, maybe they felt worse, and so then they realized, hey, if I eat all the skins and
tendons and everything, I feel better, and that just kind of got baked into their tradition.

It could also be that somehow we had different tribes that prioritized different parts of animals,
and the ones that succeeded were the ones who ate all the collagen, because it promoted
better bone health, joint health, they were able to be better hunters because of that, they didn’t
get as sore, they could catch more food. There’s a lot of possibilities, and it’s really all
speculation.
But the biggest takeaway from this is that our ancestors were in a glycine deficit, and I don’t
think there’s any way to get around that. I think that eating collagen-rich foods is very important,
but from an evolutionary perspective, our diets did not supply adequate glycine ever. This has
been an issue that has stuck with us for a while, simply because running a glycine deficit does
not threaten short-term survival. If you can reproduce, then you’re going to pass on these
shortcomings, and we don’t need to reach super old age to reproduce.

0:41:54 Glycine competes with other amino acids for intestinal absorption, and free
glycine is absorbed less efficiently than glycine in the form of di- or tripeptides, as found
in collagen.

And on that note, I want to mention another interesting tidbit about glycine absorption when it
comes to looking at, for example, eating your sirloin steak, is that studies conducted in the early
’90s and in the ’80s tried to tease out the pharmacokinetics of glycine ingestion.

And using isolated amino acids, they identified two primary receptors in the small intestine that
glycine is absorbed through. One of them is shared by all large, neutral amino acids, such as
the branched-chain amino acids and methionine, while the other is specific exclusively to
glycine and proline.

Now, the unfortunate truth here is that glycine gets the short end of the stick. With methionine,
for example, and leucine, for that matter, both rich in animal proteins, each of those by
themselves inhibits the absorption of glycine by over 50% when present in equal or greater
amounts, which they usually are in animal foods. This effect is compounded when the two are
combined, up to 86%.

So, yeah, methionine might increase glycine requirements within the body, but guess what. It
also reduces the amount you absorb from the food source, which is just going to compound the
issue even further.

Similarly, with proline, proline reduces the absorption of glycine by about 50%. This isn’t so
much an issue, because a lot of glycine can still get through that exclusive transporter, but it
does become a problem when you start combining it with all of the other amino acids. And this
one is a lot harder to explain from an evolutionary perspective, because we never had the ability
to take glycine as an isolated amino acid.

Chris: I want to ask a quick question about that. Can you clarify, were those studies dietary
studies in humans where they were looking at the total absorption?

Alex: Yes, so they were studies conducted in humans using free-form amino acids to have
complete control over the composition of the formulas. And what they used to evaluate the
absorption was serum levels of glycine. So I’m not sure, Chris, if you know there could be other
ways glycine shows up in the body after absorption, but these were just using blood levels of
glycine within the couple hours following ingestion.

Chris: Yeah, I think that’s a really interesting question, and I think there are. Right? So when
you’re digesting amino acids, they’re water-soluble. They’re going to travel through the portal
vein into the liver. The liver is where the whole centerpiece of methylation is, and so that’s where
the glycination is taking place, that’s where most glutathione synthesis takes place, that’s where
the glycine buffering system is going to be largest.

So the basic science of the transporters suggests to me that you are going to have lower
absorption. Probably the quantitative estimate of how much lower is not a good marker,
because if you imagine the food going through your intestines, you got a lot of intestinal space.
If something competes for absorption, it’s going to compete for absorption until it’s absorbed,
and then all of the sudden, it’s not competing anymore.

And so if that happens fast enough, you have a lot of room left in the intestinal tract to finish
absorbing the things that are less effective at getting into the transporters, but yeah, that’s an
interesting possibility. Maybe that’s an additional constraint on our ability to get much glycine
benefit from eating diets rich in those other amino acids, as we’d get in steak. And it seems like
a really compelling argument to either supplement with glycine or include collagen-rich foods.

Alex: And the last thing I want to add to that is another reason to preferentially get glycine from
collagen is that these same studies also compared the absorption of free glycine amino acid to
glycine peptides. And what they found is that the absorption of glycine when it’s in the form of
either a dipeptide of tripeptide, so when it’s bound to one other amino acid or two other amino
acids, is that it can increase the absorption 9- to 12-fold above just the glycine amino acid alone.

Chris: Wow, that’s really interesting. That potentially explains why some of my consulting clients
report GI distress when they take free glycine and not collagen, but I’ve also seen the opposite.

0:46:56 In animal studies, glycine protects against the metabolic consequences of

obesogenic diets, diabetes complications, cancer, liver injury, and kidney injury; and it
has anti-inflammatory effects that might protect against endotoxins.

Vladimir, you produced a blog post that was what seemed like a really comprehensive review of
animal studies and human studies looking at glycine supplementation. Can you tell us a bit
about what the range of benefits that we’ve seen through those studies?

Vladimir: Yeah. When I took a look at PubMed, I kind of quickly found like 300 scientific articles
on the health benefits of this glycine amino acid. The first thing I noticed was that there were
these rat trials where they fed extremely high amounts of sugar or alcohol to them, and they
started to get health problems, such as fat gain or high blood pressure or insulin resistance. And
even after eating this sugar or alcohol for a few months, if you started glycine after that, it could
prevent most of the health harms caused by these substances.

Then there were like dozens of different indications that glycine seemed to be also helpful for.
For example, different complications of diabetes, for example, in kidneys, eyes, immune system.
The one I was very surprised by was glycine’s effect on cancer. They have some rodent studies
where they injected the mouse or rat with a tumor, and it decreased its growth. Glycine has
some anti-inflammatory effects. That’s probably one of the theories of why it protects them from
lipopolysaccharides, that are also called endotoxins. Glycine also protects animals from sepsis.

Chris: That’s pretty interesting, because there’s a lot of research going on now looking at
whether high-fat diets promote endotoxin absorption, and that’s one of the arguments against
high-fat diets. What are your thoughts on whether glycine supplementation might mitigate some
of those effects, or even dysbiosis in the gut, I suppose, would also be another source. What do
you think about that?

Vladimir: Not very much is known about endotoxemia in humans, because most of the
experimental research is coming from rodents, but many researchers basically think that if you
eat junk food, a lot of calories, and fat, that can lead to so-called metabolic endotoxemia that is
inflammation caused by excess lipopolysaccharides in your blood. That could be a contributor to
low-level inflammation that many of us are suffering nowadays. And I think eating glycine could
give some kind of protection against that.

One topic that has been quite hugely studied in animals has been liver injury. In animals,
especially rats, I think glycine has protected against maybe 10 different ways to cause liver
injury. And that could be significant in humans, because we have so many people nowadays
who have fatty liver and liver cirrhosis.

Glycine has also protected kidney against injuries, and it has been also protective against
intestinal diseases, such as colitis or gastric lesions. Glycine has also protected rats against
joint inflammation or acute tendon inflammation. There is at least one study also where glycine
protected animals against osteoporosis, bone loss. It also protected rats against dental cavities.

0:51:19 In human studies, glycine supplementation promotes healthy sleep and blood
glucose regulation.

Chris: A few studies that I’ve recently learned about that I think are really interesting are one
study showing that 3 grams of glycine before bed would help you not only fall asleep but get
better sleep.

So in individuals who either have insomnia or who have poor quality sleep, where they might
sleep enough but they don’t feel rested during the day, getting 3 grams of glycine before bed
helps them fall asleep, but it also lowers their core body temperature, which is one of the things
that you need for good sleep. And it helps them get into slow-wave sleep faster and helps
stabilize slow-wave sleep.

And the end result is that even if their problem is not falling asleep but is just getting good sleep,
all of those things are benefited so that even though glycine has a calming effect in the brain,
they feel higher energy during the day, because the sleep is better. So that’s one of the most
interesting studies to me.

And while I was researching that, I also found a study where they used 60 grams of glycine for
an antipsychotic effect in schizophrenics. And that seemed like an extraordinary dose, until Alex
was just talking about some of the estimates of what the deficit might be if your collagen
turnover is high. Maybe the glycine deficit is actually that high.

Alex, do you have anything you want to add to some of the benefits of supplementation that
have been studied?

Alex: Yeah, so the sleep aspect is definitely one of the more interesting ones. And that has
been replicated in several studies. I think that’s important to emphasize, because a lot of the
stuff with glycine is preliminary, done in animal models, and just has a low base of research to
draw conclusions from.

But the sleep stuff has been replicated in several studies in humans, and they all are consistent.
So while it’s not a lot of studies, they’re well-done and they produce a consistent result, so the
chances of low-dose 3 grams of glycine before bed benefiting your sleep quality is probably
pretty good.

Something I mentioned at the beginning of this podcast was the underappreciated effect of
glycine on blood glucose regulation. And I want to talk a little bit about this, because I think that
it’s just a really easy, for lack of a better term, hack that a lot of people can do to optimize their
glycemic management, whether they be a healthy person just wanting to maintain optimal
health or if they’re someone who is fighting with type 2 diabetes or another condition that could
impact blood sugars.

Chris: Alright, cool.

0:54:24 Glycine is overwhelmingly safe.

I want to change directions a little bit here and talk about safety. We’re talking about
potentially—on a low level, we can say, just eat the skin and bones of the animals you’re eating,
and I think that’s a really simple way to get more glycine from food. But then we also start talking
about supplementing with collagen.
You might be supplementing with 2 rounded tablespoons of collagen to try to get 3 grams of
glycine. If you’re going to try to get 10 grams, you’re going to be using a lot of collagen. If you’re
trying to get 20 or 30 grams of glycine, you’re either taking the amino acid itself, or you’re using
tablespoons and tablespoons of collagen.

So I’d like to turn the floor to either of you guys. What do you guys think about any of the
potential side effects or risks of supplementing with these high doses?

Alex: Frankly, unless you’re somebody who has a genetic mutation or something messing with
your neurotransmitters and you have actual reactions to glycine, keeping in mind, as Chris
mentioned, that it has been used to treat psychosis, and that’s due to its effects as a
neurotransmitter. So there are chances you could react negatively to it in that regard.

Outside of those people, I don’t think that supplementing glycine has any pragmatic concerns,
because the people, when they were using treatment methods with psychosis, they were
ingesting up to 80 grams per day split with each meal. So that would be like 20 grams per meal
that they were taking, and there weren’t any negative effects obviously, in fact, it benefited them
because of their psychosis.

Also, when you look at toxicology studies in rodents, the upper limit at which glycine begins to
have harmful effects is a human-equivalent dose of about 8 grams per kilogram body weight, so
that would be about 600 grams per day for the standard human. I don’t think anyone’s running a
glycine deficit of 600 grams per day, and you’re probably going to need to be well below that to
optimize your health. So don’t eat a half kilogram of glycine, and I think you’re good.

Chris: Yeah, that’s definitely a lot of glycine.

0:57:00 Collagen supplementation may increase urinary oxalate excretion.

One of the things that I see thrown around a bit, and actually, I just put out a “take 3 grams of
glycine before bed for sleep” video, and on Facebook, I have people saying that’s really not
good for people with kidney stones because the glycine can be turned into oxalate. My reaction
to that is, there is a pathway where glycine can be turned into oxalate, and oxalates do promote
kidney stones, but that’s definitely not a major fate of glycine. The major fates of glycine are all
the things that I had talked about at the beginning of this podcast.

But I think there’s a related question of, when you consume collagen, you’re consuming
hydroxyproline in that collagen, and I think that’s a lot more likely to generate oxalate.
Interestingly enough, the pathway where hydroxyproline generates oxalate, the oxalate is
basically a byproduct of generating glyoxylate, and that glyoxylate can be converted into
glycine. So it would seem to me that unless there’s something wrong with those pathways, given
the fact that we run a glycine deficit, you would probably be turning most of that into glycine
rather than oxalate.
So it seems to me that someone with kidney stones or a high risk of kidney stones should
probably monitor their oxalate levels to see if supplementing with glycine is affecting oxalate. I
don’t know if that’s really a risk, but I think if you can measure your oxalate levels and know
they’re fine or measure your urinary oxalate excretion and know it’s fine based on the collagen
that you’re using, then I think that should provide comfort in that case. But I don’t really think
that someone who doesn’t have a high risk of kidney stones is actually at risk from consuming
collagen.

0:59:06 Strategies to minimize risk of kidney stones: ensure optimal B6 status; measure
urinary oxalate excretion; monitor urine pH; get 800-1200 mg calcium; other protective
factors are vitamin A, magnesium, and citrate.

Alright, this is Chris coming in post-production to add a few things based on research that I’ve
done since this podcast was recorded. First of all, to convert hydroxyproline to glycine, you need
vitamin B6. And it’s entirely plausible that in the general population, B6 status is poor enough
that if you did a study where you fed people gelatin, you’d see increased oxalate excretion
because the B6 status wasn’t high enough in order to prevent that hydroxyproline from being
converted into oxalate and allow it to be converted back into glycine.

Generally, animal foods are richer in B6 than plant foods and have much higher B6
bioavailability than those plant foods. However, cooking, even at normal cooking levels, not only
degrades vitamin B6 but converts it into a B6 antagonist so that if you just take meat and you
cook it, the total decrease in bioavailability when you sum up the effects of destroying B6 and
creating the B6 antagonist, is to decrease the bioavailable B6 by 40%. That’s almost cutting it in
half. It’s between a third and a half.

And in plant foods, the B6 that you get from them depends on your riboflavin status and your
liver health. So the basic risk factors for not getting enough B6 in the diet are to not eat many
animal foods and to cook all your food or to overcook your food and to not include many raw
foods.

Bananas stick out as a good source of B6, because even though they’re plants and the B6 still
depends on liver health and riboflavin status, the absorbability of that B6 is much higher than
most other plant foods, because it’s not bound up to sugars that make it not absorbable to
anywhere near the extent of most other plant foods. And bananas are also super easy to eat
raw, and so the more raw foods you eat, the better your B6 status is.

So I would say, eat animal foods, don’t overcook your animal foods, eat a lot of raw foods, and
include a good dose of raw bananas in there. And that’s pretty good defense against B6
deficiency. Oral contraceptives, high estrogen levels, and nonsteroidal anti-inflammatory drugs,
drugs for tuberculosis and Parkinson’s disease, all increase the need for B6.

Sulfite accumulation, which might be driven by molybdenum deficiency—and dietarily that

basically means eating a lot of animal products and not many legumes, and so it’s sort of like
you really need a balanced diet if you want this stuff, right? Because you need the animal foods
for the B6. Legumes are a great source of molybdenum. If you’re not getting enough, the animal
protein’s probably going to cause sulfite to accumulate and basically rob you of vitamin B6.

But then there’s also a spectrum of genetic issues that decrease your B6 status. There are
genetic issues that require 100 milligrams of vitamin B6 just to get rid of deficiency signs. And
anecdotally, there seem to be a lot of people who have symptoms that resolve on 30-100
milligrams of pyridoxal 5′-phosphate a day when really, they should only need 5 milligrams if
they’re trying to approximate a good diet. So there’s definitely some genetic and other issues
that mess with B6 status that seem to be more common than you would expect.

So one way to just approach this is to look at your B6 status. You can measure your plasma
levels of pyridoxal 5′-phosphate, and you can look in an organic acids test. The best for this is
the Genova ION Panel, and you’ll see xanthurenate, kynurenate, and quinolinate in there. If all
three of those are elevated, that’s really robust evidence of a B6 deficiency. But the most
sensitive one in there is xanthurenate. So if you’re just running a mild deficit of B6, you should
see elevated xanthurenate in your urine. And you’d have to have a pretty bad deficiency to see
the quinolinate rise. That’s the least sensitive one. The kynurenate is kind of in the middle.

So if you test these things and you see your B6 status is poor, you got to improve it. And you
can normalize those markers, and that probably will render the collagen not a problem.

But the other thing you can do is just measure your oxalate excretion. So if you get a 24-hour
urinary oxalate test, then you can get that while you’re eating your regular diet that includes all
of the collagen you would like to supplement with to see if that raises your urinary oxalate levels
too high. And you can get a spot urine test, a random urine test, for oxalate levels providing that
you get it in the couple hours after a collagen-rich meal with the type of collagen, the level of
collagen that you want to be using—or gelatin or whatever.

Now, the principle risk of oxalates is kidney stones. Yes, blood levels of oxalate elevated could
potentially cause many other problems, but you need a 30-gram dose of gelatin to even start
raising blood oxalate levels. So we’re mainly talking about a risk of oxalate in the urine.

The risk of oxalate in the urine is kidney stones, but you don’t get kidney stones just because
you excreted oxalate in the urine. Usually calcium-oxalate crystals in kidney stones are
nucleated around uric acid crystals or around calcium-phosphate crystals.

The principle risk factor for developing uric acid stones is having a low urine pH. So you can
monitor your urine pH, and if you get it into the 6.4-6.8 range by eating a diet rich in fruits and
vegetables, plenty of potassium—and to the extent you need it, a little bit of baking soda on an
empty stomach, such as a quarter teaspoon; test it against what you need, the dose and
frequency of bicarbonate on an empty stomach that you need to bring your urine into the 6.4-6.8
range—you’re not going to get uric acid crystals. And without uric acid crystallizing, you’ve
eliminated one of the two main risk factors for making the oxalate in your urine crystalize.

Calcium-phosphate crystals are the other part of that. And the main way you prevent those is to
get 800-1200 milligrams of calcium in your diet. Calcium itself is protective against kidney
stones—is particularly protective against calcium-phosphate kidney stones, because when you
consume calcium in the intestines, you prevent the absorption of excess phosphate. And then
when the calcium gets into your blood, it prevents the rise in parathyroid hormone that initiates
bone resorption, and phosphorus does the opposite of that.

So basically, the calcium is funneling phosphate into your bones, whereas if you had less
calcium and you had more phosphate, you’d have more parathyroid hormone, more PTH, and
that would basically funnel calcium-phosphate from your bone into your blood and from your
blood into your kidneys.

Another risk factor for the parathyroid hormone-mediated bone resorption, is acid load. So if you
follow the recommendations that I made just before for the alkalinizing effects that will prevent
uric acid, you will probably also help minimize PTH-mediated bone resorption and thereby help
minimize calcium-phosphate crystals in your urine. And I think those are the main factors that
are going to mean that even a little bit extra oxalate in your urine probably is no big deal at all.

Another thing that is not well-established but is at least established in animal experiments, if you
get enough vitamin A—in humans, probably about 15,000 IU a day, adjusted for body weight off
of the animal experiments—you can feed the animals tons of oxalate and they won’t get oxalate
kidney stones in the way that they do without the extra vitamin A. That’s another protective
factor.

A couple other protective factors: magnesium and citrate are both helpful. So magnesium citrate
or other sources of citrate, such as potassium citrate or even just citric acid from, for example,
lemon juice, like 4 ounces of lemon juice spread in your water throughout the day. Magnesium
citrate would be particularly helpful if you don’t eat a lot of plant products and your magnesium
status is low. Maybe use it at 100 or 200, maybe 400 milligrams a day, but at some dose that
doesn’t loosen your stool.

These things together are probably more important than minimizing your urinary oxalate load.
And as long as your oxalate excretion from collagen or gelatin is not ridiculously high, but just a
little bump in oxalate, providing your practicing these protective factors, I wouldn’t worry about it.

Anyway, this stuff is covered in my Testing Nutritional Status: The Ultimate Cheat Sheet. So get
it all encapsulated in concise and clickable format at chrismasterjohnphd.com/cheatsheet.
Alright, now back to our glycine discussion.

Vladimir, do you have any thoughts to add?

Vladimir: Yeah, so when I went through the like 300 papers about glycine a few years ago, I
picked up some papers that showed some toxic effects from glycine. But as far as I remember,
none of them used glycine orally, like as food. But instead, one paper said that glycine is the
worst irrigating fluid that you can use, probably in surgery.

And also, in some studies, collagen had some harmful effects when it was given directly to the
brain, but if you forget these papers, it’s very difficult to find data on the harmful effects, and in
some papers, they gave even like 5% of the calories as glycine and showed mostly benefits to
the animals.

Chris: Yeah, well, it seems like if those studies are not dietary studies and if the dietary studies
suggest that the maximum safe dose is somewhere around—what was it, Alex? 600…what was
it?

Alex: 600 grams per day for an average human, 8 grams per kilo body weight.

Chris: Yeah, then it seems like the overwhelming balance suggests this is safe.

1:10:55 Practicalities of glycine supplementation; how Vladimir, Alex, and Chris get their
glycine; and how collagen and glycine fit into the overall protein requirement.

Let’s turn this a little bit more practical. Let’s say you’re talking to a friend, and they’re asking
you your thoughts on what you would do if you were them. They don’t have any particular
conditions, but they just want—they’re listening to this, and they’re like, I need more glycine.
Vladimir, what would you tell them is the best thing to do, and how do you get your glycine?

Vladimir: I’ve been eating glycine powder in small amounts.

Chris: That’s just pure glycine?

Vladimir: Yes.

Chris: And how much?

Vladimir: Like 2 grams per day is my goal, but I’m very bad at using supplements. I also like—

Chris: Are you good at using food?

Vladimir: Yes. Yes. And if you eat…

Chris: Do you eat… go ahead.

Vladimir: If you eat more plant proteins, like for example, nuts, they have high amounts of
glycine and low amounts of methionine, and that’s very common in many plant proteins.

Chris: Well, that’s a good point. I mean, from what I’ve looked at, the glycine isn’t a whole lot
different, but the methionine is so much lower that you’re probably definitely getting more
glycine benefit from those proteins. So do you intentionally avoid eating meat then for that
reason?

Vladimir: I try to eat semi-vegetarian. For me, it’s difficult to avoid meat, because I’ve learned to
like it so much, but in my country, eating plants is becoming much more popular, and we have
many new products that have, for example, pea—how do you pronounce—pea protein.

Chris: Ah, yeah. Pea protein.

Vladimir: Yeah. And I buy them sometimes, but I’m planning to learn to eat them even more.
But now that Alex mentioned this study about absorption of pure glycine, I hadn’t seen it before.
That was very interesting. So maybe…

Chris: Yeah, time to step up the collagen.

Vladimir: Yeah.

Chris: Alex, what would be your advice? Someone who just, they don’t have any particular
concerns. They just want to think, I just want a good diet. What do you think someone should be
doing with glycine just promoting general health and from a prevention perspective?

Alex: I would actually tell them to eat collagen as the first line. And this could be as simple as
literally going out and buying Jell-O, which is collagen. And in fact, that’s basically what was
used in a human study that showed that consuming collagen before a workout increases
collagen synthesis in active adults, which I should note is an effect that cannot be achieved by
eating essential amino acids.

It’s been demonstrated that feeding someone leucine and the branched-chain amino acids
along with all the other essential amino acids does a really good job at stimulating muscle
protein synthesis, but it has zero effect on collagen protein synthesis turnover. But eating
collagen increases collagen protein synthesis and has no effect on muscle protein synthesis. I
think that’s very telling about what our diet should include.

And so collagen is one-third glycine. Collagen protein is one-third glycine by weight, by

necessity. And my preference for someone would be to, since glycine’s primary role in the body
is to support collagen turnover, would be to obtain the glycine in something else that promotes
collagen turnover, which is collagen. So it just makes sense to try to get your glycine from
collagen when you can.

Now, collagen is also really expensive, especially compared to just bulk glycine powder. And so
if we want to stay pragmatic, not everyone’s going to have the money to drop bombs on
hydrolyzed collagen. And in those situations, I think that obtaining 10, 20, ideally 30 grams of
hydrolyzed collagen per day and then adding additional glycine to that is a very reasonable
middle ground.

And this kind of gets at some of the other benefits of glycine, like its effect on blood glucose. 4
grams of glycine before a meal containing carbohydrates has been shown to cut the blood
glucose and insulin response by 50%. That sounds pretty good. So this effect has been
observed with hydrolyzed collagen as well, so collagen and glycine before you eat
carbohydrates might benefit your blood sugar.

But yeah, I think that just pragmatically, get your collagen in, and if you feel up to it, add in some
glycine. Possibly replace the sugar in your pantry with glycine, because they’re the same
sweetness. And I’ve actually often wondered what would happen if the food industry replaced all
the sugar they put in foods with glycine as their sweetener of choice. I’m pretty sure people
would start downing the sodas.

Chris: And so, Alex, what do you do now for your collagen? And one related question that I
thought of while you’re talking is, how do you think about how it fits into the protein requirement?
Because if you decide to replace the protein—and this kind of intersects with what we were
saying before about methionine and Vladimir trying to eat less animal protein to conserve the
glycine and get more of the benefit—but if you’re talking about it from an athletic perspective,
collagen just doesn’t have the essential amino acids that you need to build your muscle protein.
So what are you doing? And I’m looking at you right now, you look pretty muscular. How do you
approach the intersection with total protein and meat?

Alex: Okay, so I’ll start with what I do. I personally use a Great Lakes hydrolyzed collagen
supplement. I like the brand Great Lakes, because they’re actually one of the cheapest that is
on the market, and they’re from grass-fed, pastured, humanely treated cows that are raised
exclusively in the U.S., and they’re very transparent about testing, and they do batch testing to
ensure that they’re free of pesticides, heavy metals, all that stuff. So they’re a really safe bet for
just getting pure collagen. The fact, again, that they’re probably one of the cheapest ones I’ve
found on the market, as well, is an added bonus for the quality that you’re getting.

What I personally do is I eat three meals a day. And I will have 10 grams of hydrolyzed collagen
with each meal in addition to a teaspoon, or about 4-5 grams, of glycine. Doing this, I’m getting
total daily glycine of about 25 grams per day, because 30 grams of collagen, one-third of that is
glycine, 10 grams, plus another 5 at each meal, that’s 15, 20, 25 grams. And the collagen
peptides from those 10-gram servings I’m eating at each meal is giving my body a continual
small dose of collagen synthesis, just like eating other forms of protein and essential amino
acids at each of those meals is giving me muscle protein synthesis.

As far as balancing it out, I’ve come to the conclusion that when we think about total dietary
protein intake, it’s not just a single value. Protein is just a term used to refer to all of the amino
acids in our diet when they’re connected together. And what our body is interested in is each of
the amino acids, not the protein itself.

So the way I look at collagen is, I wouldn’t add it to whatever protein goal you’re trying to reach,
because if you think about it like pouring—let’s say you have a container and you put in a bunch
of big rocks, and these big rocks serve as your main sources of protein in the diet. Then adding
in collagen and glycine is like pouring sand around those rocks. It doesn’t increase the size of
the container or the space that’s being taken up. Rather, it fills in the deficits that are left by the
rocks, themselves.

So it’s not, in my opinion and from my perspective, when you eat collagen and glycine, you’re
not increasing your protein intake from 150 to 180 grams. You’re just making the 150 you do
have a more balanced profile of amino acids. And I think that’s important because, again, the
collagen protein doesn’t affect the synthesis of anything but collagen in your body. That’s what
all the other essential amino acids are for. So it’s just complementing your main food.

Chris: Yeah, that’s generally how I’ve thought of it as well. If you’re shooting as a goal to get
150 grams of protein a day as a body composition goal, I’ve always chosen to not count the
collagen towards that and add it—Right. Alex just said you have to consider the calories. Yeah,
so collagen does carry calories. So it’s got to replace something. It’s just that if it’s—I think it
really depends on your goals, too.

So if you’re thinking about this from a disease prevention perspective that is more influenced by
methylation than protein supply—if you’re thinking about preventing sarcopenia, you want to
bias towards higher protein. If you’re thinking about maximizing your body composition or losing
weight and not losing your muscle mass, you want to be thinking about higher protein.

But it might be a lot different if you start thinking about getting optimal methylation for mental
health or getting optimal methylation for long-term cancer prevention and things like that. But to
me, that really comes down to altering the protein intake in the sense that, if I were afraid that I
had high risk of cancer, that I’d been diagnosed, I’d probably be eating less protein. But I would
be eating—if my goal as an athlete to maximize body composition was 150, I’d be taking it out
of that pool, and I’d be thinking of that pool separately from the collagen, like Alex was just
saying.

I would add, though, that the synthesis of any nonessential amino acid is highly dependent on
your total protein intake, because there aren’t any amino acids that you can synthesize without
nitrogen. So if you’re not meeting your total protein intake in terms of total—you do have a total
nitrogen requirement, because you have a requirement for nitrogen to synthesize the
nonessential amino acids, such as glycine, if we use those terms. And we have nitrogen
requirements to make urea and other things.

So your glycine synthesis will suffer if you bring protein down to zero, and one of the interesting
studies that came out of 1980s was looking at vegetarians and glutathione synthesis. And the
vegetarians were consuming—you could eat a vegetarian diet that’s pretty high in protein if you
use a lot of eggs and dairy, but vegetarians tend to eat less protein, and these vegetarians were
eating less protein, and so they didn’t have the building blocks to make glutathione.

But one of the reasons that we know that glycine was limiting is because they were excreting
oxoproline, also known as pyroglutamate. If you were to measure things in an organic acids test
today, they’d probably call it pyroglutamate. They were excreting high amounts of that, and that
is a specific compound that you excrete when you do not have enough glycine to make
glutathione. And they raised the protein intake in these vegetarians, and the oxoproline
excretion went down, which means that now they had enough glycine to make glutathione.

So it wasn’t the essential amino acids that are part of the glutathione molecule that were
limiting. It was the glycine, and they had to eat enough total protein. Maybe it was from
providing glycine, but obviously, they weren’t able to synthesize enough glycine. And so you just
need to meet your total protein requirement to be able to make glycine. Alex, you wanted to add
something?

Alex: Yeah, what you just said reminded me, too, if we think back for a sec to the evolutionary
stuff we were talking about earlier and how it makes sense now that this is a legitimate
shortcoming in our genetic code, the fact that we can’t make enough glycine that we need, this
is supported, too, by the fact that when you look at some studies from the ’80s conducted in
infants who were breastfed, they found increased levels of 5-oxoproline levels in breastfed,
perfectly healthy infants.

So these infants did not have enough glycine to meet the requirements that they needed to
synthesize glutathione, let alone collagen turnover. But these are infants being breastfed, and
they’re completely healthy, right? And isn’t breastmilk supposed to supply everything it needs?
Well, maybe if the issue wasn’t the fact that—again, it’s a genetic shortcoming in humans. So
the fact that this exists for something so natural as breastfeeding strongly indicates that it is a
legitimate—like, there was no point in evolutionary history where this was never an issue.

Chris: So Alex, what do we do about that?

Alex: Find a collagen supplement. Start taking it. Possibly buy bulk glycine on Amazon. The
stuff’s dirt cheap. It’s as sweet as sugar, so use it in your tea and coffee instead. Just make an
effort to get more glycine, because it has some pretty theoretically significant effects on your
long-term health, that unfortunately research just isn’t there yet, especially because a lot of the
conditions it plays a role in, like osteoarthritis and osteoporosis, take really long times to
develop, and you don’t know how running a chronic glycine shortage, how much damage you’re
doing.

Chris: Thanks, Alex. I’m also using Great Lakes collagen. I think Great Lakes is great. I think
Vital Proteins is great. Some people have asked me about Zint and Bulletproof. I haven’t check
them out, but I think any of these are good options, and it makes sense to look at what works
best for you pricewise, as long as the ingredients are quality. So I’m personally using Great
Lakes at the moment just because I’m satisfied with the price and quality characteristics.

I do have a consulting client who reports digestive distress with Great Lakes and not Vital
Proteins, and that could relate to the fact that Vital Proteins uses an enzymatic process instead
of a heat process to predigest the collagen, so there are reasonable differences that you might
respond to.

I use collagen before bed in 2 tablespoons to promote sleep, and I’ll also do the same thing
before a workout. And in that case, I’m doing it for the health of my joints and tendons. I know
Alex talked about using glycine before a workout to increase collagen synthesis.

One additional point is there was a study done that showed that if you want to get the glycine
into your tendons to support tendon health, you really need to do it before exercise, because
whereas your muscles can take up things from the blood in an active manner because they’re
very metabolically active, the tendons are largely passively taking up what the blood is
supplying them, and when you’re exercising, you’re increasing your blood flow into the joints
and tendons, and so that provides a very short window of increased blood flow where you can
actually deliver that glycine in. So I think before a workout makes a lot of sense from a joint and
tendon health perspective.

And one thing that I’m now thinking of that I hadn’t before this conversation is to use a little bit at
each meal for the glucose moderating effect. So particularly if you’re vulnerable to blood sugar
spikes or if you’re eating a large carbohydrate load, it seems to make a lot of sense to include a
little bit of glycine at each meal.

I think one thing that is really underappreciated apart from these basal levels is that when
people have deficient levels of methylfolate, as in an MTHFR mutation situation, people think a
lot about supplementing with high doses of methylfolate. They don’t think about the glycine, but
those are conditions of significantly greater glycine wasting. And the same thing with the meat.

1:29:45 Lab tests to assess glycine status

And I think it’s worth talking a little bit about, if you’re able to run some tests, how might you
know whether you’re actually getting enough glycine. I think one thing that can be really useful
is to, if your insurance covers it or you have the money to burn through, to get a Genova ION
Panel with 40 amino acids. You can more or less approximate this with any combination of an
amino acids panel and a urinary organic acids panel, but one thing you want to see is that your
glycine levels in your blood are at least midrange, if not on the high end of the range.

And you can also look at the question of, are you wasting glycine as methylated metabolites, as
you would expect to be the case if your methionine intake is too high or your methylfolate levels
are deficient. And what happens then is you will see elevated sarcosine levels in your blood. So
I think when you do see that, that’s—if your glycine levels are low and your sarcosine levels are
high, you know your problem is, you’re methylating the glycine and wasting it, and you need to
either reduce your methionine intake so you need to better use strategies to boost and conserve
your methylfolate. If you listen to the podcast “Living with MTHFR” that I did a few episodes ago,
there’s a lot of strategies to work around that particular case.

Anyway, thank you so much, guys. This was a great discussion. And yeah, here’s to collagen.

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