This Changes How I Think About Creatine

Can a simple 5g scoop of creatine do more than just build muscle? In today’s video, I’m reacting to Thomas DeLauer’s insights on how creatine might “spare” your body’s methylation cycle—and then diving deep into the actual clinical data to see if it really lowers homocysteine.

As a vascular surgeon, I’m always looking for ways to reduce cardiovascular risk. We know that high homocysteine is a major red flag for heart attack and stroke, but the evidence for using creatine to fix it is surprisingly nuanced.

In this video, we cover:

The "Metabolic Cost" of making your own creatine.
How methylation impacts your DNA repair and neurotransmitters.
My breakdown of the 2015 Journal of Nutrition study on creatine and homocysteine.
Why the "MTHFR mutation" changes the whole conversation.
My current stance on methylated B vitamins vs. creatine.

Chapters: 
0:00 - Reaction to Thomas DeLauer’s Creatine Theory 
1:15 - How Creatine Synthesis Drains Your Body 
3:02 - The Glycine Connection: Joints, Skin, and Detox 
5:42 - Implications for MTHFR and High Homocysteine 
8:18 - Does Creatine Lower Homocysteine? (Open Evidence Search) 
12:28 - Deep Dive: Bangladesh Randomized Controlled Trial 
18:10 - The Verdict: Folic Acid vs. Creatine 
21:30 - My Recommendations for Patients

Let me know your thoughts on creatine in the comments! Are you taking it for more than just the gym?

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Dr. Johnston is a double board-certified vascular and general surgeon in San Diego, specializing in metabolic and cardiovascular prevention. She’s the founder of CorSight Health and a passionate advocate for reimagining how medicine approaches chronic disease.
  
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Transcript

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SPEAKER_01 0:00

In Saturday's Ask Me Anything You Guys Wanted to Know About Creatine. Here's what I had to say. Um, I took 10 grams today. Then this video popped up on my feed and I wanted to watch it with you and explore what I might have missed about creatine with Tom DeLauer, who is a well-known coach and fitness personality. If you're new here, I am Dr. Lily Johnston. I'm a board-certified vascular surgeon, but I specialize in cardiometabolic prevention. So hopefully you will never need me as a surgeon.

SPEAKER_00 0:35

When you give yourself a scoop of creatine, something very interesting happens, and it has nothing to do with building muscle, dropping fat, or lowering inflammation. Your body no longer has to make creatine when you take a scoop of it, because creatine is one of the most metabolically expensive compounds to make. This is one of the most important videos you could probably ever watch on creatine. Taking the scoop of creatine is literally relieving your body of major, major workloads. Okay, everybody talks about taking creatine for muscle. They talk about it for strength, for brain health. All of that is real, super valid. But the most interesting thing that creatine does is actually nothing to do with any of that. Okay, it has to do with what your body stops doing once it doesn't have to make any more creatine because you're providing it externally. Making creatine inside your body burns through almost half of your body's methyl groups. The same methyl groups that you need for DNA repair and for neurotransmitter production. So things like dopamine and serotonin. I mean, this is crazy. Like, why is no one talking about this?

SPEAKER_01 1:28

Make I find it curious because I don't know at baseline, like how much creatine will your body synthesize, and how much are we overwhelming that system when we are exogenously taking or giving creatine? Because right, most people are taking on the order of five grams a day, maybe 10, even 15 grams a day, if we are using some of the higher dosing protocols that maybe we're gonna get into. I I don't think the body actually makes that much naturally. Can we use that much? Maybe. And maybe we don't make that much because it is metabolically expensive to make it. I don't know that it's more metabolically taxing than muscle protein synthesis or some of the other physiologic things that the body does do. In general, your body will do what it needs to do. So even if it's metabolically expensive to generate molecules of creatine for its purposes, the body will do that. The body doesn't deprioritize things that are hard if it needs them. The question is, what signals is the body getting to manufacture additional molecules of creatine? And can we overcome that by giving it exogenously or taking it? And does that provide additional benefit above and beyond? I think we're about to see that there are some people for whom this particular synthetic pathway of making creatine is going to be particularly taxing, but let's get into it.

SPEAKER_00 3:21

So here's what I want to cover today. First, we're gonna talk about why your body's creatine assembly line is draining methylation cycles, but what that actually means in real human terms, because I don't want to just like talk over your head, I want to be real. And then we're gonna talk about how the glycine that it burns through to make it is the same glycine that your body needs for connective tissue repair and for glutathione to actually detoxify. And finally, I want to talk about what actually changes when you supplement creatine and you shut that process down. Like, do we have to be concerned with that process never coming back online? So let's get rocking on this and hit that subscribe button. So your body makes about one gram of creatine per day on its own.

SPEAKER_01 3:53

It gets Okay, there's the answer to that question. It's roughly another gram from food, maybe more if you eat a I think probably most people who eat an animal-based rich diet could get more than a gram per day. I've heard up to maybe three, but I think you have to be pretty conscientious about your animal protein intake to get that level of creatine per day. Let's see what else.

SPEAKER_00 4:18

A lot of meat and fish. Your body builds creatine in two very simple steps arginine and glycine, two aminos combined in your kidneys to form a compound that is called guaninoacidate, okay, or GAA. That GAA travels to your liver. Okay. Now stick with me on this. I know it sounds complicated. I promise I'll make sense of it. I just gotta get the mechanisms right. The GAA travels to your liver. It gets methylated by what is called S adenosol methionine. Okay, so SAM. This is the body's primary methyl donor. Okay, this SAM is involved in everything: DNA methylation, neurotransmitter production, like dopamine, serotonin, all these, also detoxification in our body. It is one of the literal most important molecules and studied molecules in the human body. Creatine synthesis alone consumes about 40% of all of these SAM-derived methyl groups. So this very important thing, SAM, these methyl groups, right? Imagine what it would feel like if your body didn't have to do that. And it could free up 40% of those SAM-derived methyl groups. So there's a study in the American Journal of Physiology that found that the methylation of GAA to form creatine uses more of this SAM than any other methyltransferase reaction combined in the body. So one single reaction making creatine consumes more methyl groups than everything else your body uses methyl groups for put together. Like it's crazy. It also tells us how important creatine is. So if you've ever wondered why like your methylation cycle feels like overworked, which would feel like you're toxic or you're like neurotransmitters, like you just can't get happy, your mood is crap. This is probably why your body.

SPEAKER_01 5:41

This is really interesting. I was not aware that the formation of creatine was actually the methylation reaction that caused the most or that used the most methyl donation in in all of the body's biochemical processes. It'd be interesting to see that, see this verified or replicated somewhere, but let's just assume it's true. This has huge implications for patients who have methylation pathway problems. So that is anybody who has elevated homocysteine or an MTHFR mutation, that is one of the many enzymes that is related to the body's ability to methylate compounds. If, you know, one good thing is to give methylated B supplements for my patients with elevated homocysteine. We've talked about that on this channel before. And what if we decrease the burden on the methylation pathway by giving creatine? It has never occurred to me that this is actually potentially part of a therapeutic intervention for patients who have methylation defects or problems. I don't know whether independently creatine would contribute to lowering homocysteine, but I think it's a fascinating experiment. Now, most of my patients are taking creatine anyway for the purposes of supporting their resistance training. But I wonder if even those patients who were not doing resistance training, for whom I wasn't necessarily thinking, gosh, we should add in some creatine to make sure they're getting adequate power in their workouts to drive muscle protein synthesis. I wonder if we should be using creatine to help alleviate stress on the methylation cycle. Let's see if we get into that more.

SPEAKER_00 7:34

It drives DNA repair, which makes you feel good. And it drives liver detoxification, which definitely makes you feel good. So your feel-good is hinging on this. And if your body is pouring 40% of its methyl groups into creatine production, those other systems have to compete for what's left. So mood, your detox capacity, your gene expression, all of it is downstream and creatine's hogging it. So there's a second cost, though, on top of the methyl groups. And this ties directly into your joints, to your skin, like even to antioxidant defenses. Like, and again, it's super overlooked. It's one of the most important things. We're gonna talk about how that works because it ties in with glycine in our body, right? Creatine is cheap too. Like you can get it anywhere. There's just a lot of cruddy quality ones. So just do your research.

SPEAKER_01 8:17

Uh, I would say creatine is cheap and it's available everywhere. Please just get a cheap creatine monohydrate powdered supplement. As much as I would love to support Tom here, um, you don't really want you grabbing the gummies that have uh eight carbohydrates and 60 calories that you don't need unless you are really taking that intentionally for the glucose load to help some of the creatine absorption. He has talked about that in another video. If you are doing that on purpose, again, uh for the hydration and and process support, okay, I get that. Uh, but don't take gummies because gummies are convenient. Do it intentionally, not because uh you need to bribe yourself to have candy to get your supplements in, please. And thank you.

SPEAKER_00 9:01

Try to look for ones that have the creapure label on it. That's real German creatine. There's a lot of like these kind of Chinese creatines that are not particularly good. There's been a lot of third-party tests that have shown that a lot of creatines are not actually having the creatine they say they have in them.

SPEAKER_01 9:13

Personally, again, if you go back to my supplement video, we talk a lot about the third-party testing. The creatine in particular, again, because it's such a heavy, you heavily used supplement in the athletic industry, many of the best ones are NSF sport certified. That is the label I would use to verify that your creatine is what it says it is. Creatine monohydrate is great. Creapure is fine, but if it has that NSF sport label on it, you can be reassured that it is what you want.

SPEAKER_00 9:44

The one I use is called Create. If you want to try them out, I'll pop a link down below. It's a pretty aggressive discount, too. It's 54% off if you want to check them out. They have gummies that are sweetened with allulose, and then they have very simple unsweetened stick packs or unflavored stick packs. I use both because the gummies have allulose, so it cancels out the sugar that's in the gummy, which is also required for the creatine to really get into absorption very well. So it's a really cool combination, very science-backed in terms of how they formulated it. And I also just love this guy. I've known the founder for a very long time. His name's Dan. He's a good dude. Bottom line, it's real. It's creapure brand, so it's actually got like the real patented creatine, and that's a 54% discount link. So just check them out if you don't have a creatine that you already love and enjoy. But I think this one's worth a shot. Okay, so if we come to this glycine piece, this is gonna help us understand when we should take creatine and how much we should take it too. Because glycine is consumed during creatine synthesis, the whole glycine amino acid. And glycine is not just an obscure amino acid that your body has plenty of. Dr. Brad Stanfield actually found that your body needs about 10 grams of glycine per day just for collagen turnover alone. You synthesize about three grams on your own, and a typical diet on the average person is gonna give you two to five. So you're roughly looking at like a five gram daily shortfall before you account for everything else that glycine does. Glycine does a lot, by the way. Okay, it's a precursor to glutathione, which is your body's master antioxidant. It's the most abundant amino acid in collagen, so it's very essential for your joints, your skin, your hair, your connective tissue. And it's also used for bioacid conjugation and detoxification. There's a lot of researchers that even argue that it should be reclassified as possibly even conditionally essential or fully essential in many ways, because endogenous production simply cannot keep up with demand. We probably used to eat more glycine, so it was fine, but we don't eat connective tissue anymore. So every molecule of glycine that your body burns through to make creatine is a molecule that is not going towards your glutathione. It's not going towards your collagen, and it's not going towards your detox pathways. So when you're already running a daily deficit, that's really bad. Because if your skin has been losing like elasticity, or maybe your joints just don't feel good anymore, your recovery's garbage, right? The glycine shortfall could absolutely positively be a part of that.

SPEAKER_01 11:34

So if you're already The piece of this that he hasn't mentioned yet is sleep. So glycine taken before bed, again, about five grams, can actually very much support sleep. And it's hypothesized it's one of the reasons that magnesium glycinate or bisglycinate, depending on you know how you're buying it, is actually really useful. And it's not so much because it helps the magnesium or it's the particular formulation, because during digestion and metabolism, the magnesium ion will actually decouple from its chelate, which is the glycinate. So you're getting magnesium, which is great, but you're also getting glycine. And we wonder, some of us, if the you know, real reason that everybody likes to use magnesium glycinate for sleep is not, again, because it's some kind of special penetration into your sleep center, but actually because you're getting additional glycine. Uh, some people will supplement this separately for sleep, and that is another really interesting application. Certainly, again, this is an argument for bone broth, for you know, sort of eating nose to tail and trying to get as much of the connective tissue if you eat animal products that you can. And again, complete amino acid sources if you don't, trying to ensure that you're getting adequate versions of all of the different amino acids that are represented in various proteins.

SPEAKER_00 12:56

Already taking collagen, or maybe you're taking direct glycine, as long as your body is still making its own creatine, a good portion of the glycine you are taking is getting diverted to creatine synthesis instead of actually going to where you want it to go. Okay, which brings us to what happens when you shut the whole thing down. And I want to get into that because that's really important. But I would recommend if you're over the age of 30 that you go up to 10 grams of creatine if you're dealing with connective tissue stuff too. Okay, because what's happening is you're gonna have more connective tissue potential risk of not turning over when you're older. So you're over 30, collagen plus creatine kind of becomes a must, in my opinion. At the very least, consuming foods that are rich in collagen or glycine. So bone broth, ground beef with the gristle. Okay, like you don't have to take a collagen supplement. Like I do here and there, I mix and match it, but 10 grams of creatine, five grams almost minimum, if you're really over 30. And you know, there's different things that you can do to kind of test it out. You can split it up throughout the day. That's what a lot of people are saying, because it's actually gonna like stabilize maybe this methylation process. So you're like kind of dosing it throughout the day, because that's a fast response. It's not something you just necessarily load up on. So almost try micro-dosing a couple grams multiple times throughout the day or just put it in your water and sip on it in your water. But let's talk really quick when you shut this whole thing down. Okay, when you supplement creatine monohydrate, your body recognizes that it no longer needs to manufacture its own. That sounds scary because if it's like testosterone, like you wouldn't want to shut that down, it'd be hard to come back up. There was a study in the British Journal of Nutrition that showed that creatine supplementation downregulates the enzyme that kicks off creatine synthesis in the body. So your body body like actually shuts down the assembly line.

SPEAKER_01 14:11

And when that happens That shouldn't really come as a surprise. Unlike testosterone, creatine is not a hormone, so it doesn't have quite as robust a you know feedback loop and receptor pathway synthesis, I don't think. On the other hand, every biologic drive, coming back to my first point, is driven by demand. So if you supply the creatine that your body is looking for to carry out essential processes, there's not, it shouldn't come as a surprise that your natural mechanism will shut that down. You know, the hormone pathways are really subject to receptor downregulation and that kind of thing. If you're providing the exogenous creatine, you're not going to downregulate that as much. But I'm curious to know exactly what we think happens with chronic supplementation.

SPEAKER_00 14:58

Two things change. First, all those methyl groups that were being consumed actually radically become available for other reactions. You have more SAM for DNA methylation, so you have better gene expression, you have more neurotransmittersynthesis, more serotonin, more dopamine, you have more liver detoxification. You're not adding methyl groups by taking creatine, you're literally stopping the biggest brain on them. The thing is, is the moment you stop taking creatine, your body still has a demand. So it just goes right back to creatine it again. You don't actually create a deficit. Okay, you don't create this issue where you don't produce creatine anymore. You would have to potentially be taking ridiculous amounts all the time, constantly. Like that's and even then, we don't have the cohort to even test that that would be a problem. This whole thing has a direct downstream effect on homocysteine, which is probably something you've seen on your lab work before. Okay, and if that sounds complicated, it might sound like it, but homocysteine is just a very good indicator of how we're doing with methylation.

SPEAKER_01 15:38

Every time Again, if you have not seen homocysteine in your lab work before, please ask your clinician to get that ordered for you. We talk about it here on this channel a lot. It is directly related to risks for heart attack and stroke. And again, we've talked about the methylation pathway, how homocysteine will build up if you are not converting your inactivated forms of B vitamins to the activated forms. SAM or SAM-E is another supplement that can also be used. TMG or trimethylglycine, again, there's that glycine, is also part of that in many patients. And uh let's see what else Tom is going to say about homocysteine.

SPEAKER_00 16:15

Time that SAM donates a methyl group, it produces homocysteine as a byproduct. Because creatine synthesis is the single largest consumer of SAM, it is responsible for a huge proportion of homocysteine production. Now, if we look at a study that was in the American Journal of Physiology, it showed that creatine supplementation reduced GAA levels and lowered homocysteine from that pathway. So we're seeing this stuff. It's powerful. If your homocysteine has ever come back elevated, it's worth paying attention to. Now, secondly, the glycine that was being consumed to build creatine is now freed up. So more glycine for glutathione means better antioxidant effects, better skin. You look clearer, you're detoxified, you have more for collagen, so you have better skin, better connective tissue, better joints, right? Possibly better hair.

SPEAKER_01 16:48

You're already That is all a nice mechanism, if it's true. We don't I I haven't seen him present data for us yet that in fact taking your 10 grams instead of five of creatine a day and adding your glycine supplementation actually produces any of those things. It makes great sense. I don't think there's much harm in it, but just be aware that right now we have sort of exceeded the boundaries of the evidence that has been presented to us. And again, I was waiting for him to say that giving SAM or giving creatine would actually lower homocysteine. Maybe we'll pop into that paper a little bit after he's done with his video and check that out for ourselves and see if we can find any evidence for that.

SPEAKER_00 17:33

Already running a five gram shortfall with glycine. So every molecule you're not burning on creatine goes towards closing that gap. So if you're taking collagen already, just add creatine to it. Most people think of creatine as something you're adding, helping you get more energy, helping you build more muscle. That is all true. But it's more about what it is freeing up so that your body can do what it does best. Your body doesn't need you to add muscle or add fat. It knows how to do that if you give it the tools. So your liver gets a break, your connective tissue gets what they need. You're letting your body come back to a natural homeostasis, a natural baseline. Now, if you're focused on the longevity piece, like on reducing inflammation, on supporting methylation cycles, creatine is just almost a must, right? So five grams to 10 grams per day, split throughout the day if you can. You don't need to load it. That's not important anymore. You don't need a fancy form of it. Monohydrate is simple. I would also recommend adding glycine, adding collagen, eating ground beef, eating or consuming bone broth. N-acetylcysteine is also a really good thing to take as well, alongside this, because Nacetylcysteine stacks up this well. Glycine and cysteine are both precursors to glutathione. So freeing up glycine through creatine supports glutathione production from both directions. And then NAC kind of helps this process too. Now, if you want to make sure the creatine you're taking is actually getting absorbed properly, I did a video talking about how to get creatine to absorb better because actually, if you combine it with a certain kind of mineral, it can increase creatine absorption up to 3x and actually gets in your system the way that you want it. So I put a link to that video right here. It's a great one to watch next to learn how to use creatine properly. And as always, I'll see you tomorrow.

SPEAKER_01 18:54

Thank you. Let's give that video a like. And how about we go find that paper and see what we can find out about creatine and homocysteine? Let's see if open evidence can help us answer the question about whether taking creatine will lower homocysteine. So here you can see I've asked the question, our evidence grade is B minus, moderate evidence. That's actually a new feature of open evidence that is kind of interesting. But let's see what we actually have to say here. Theoretical rationale is biochemically sound, but the human clinical evidence is mixed. Creatine supplementation consistently reduces GAA, that's the molecule made in the kidney that goes to the liver that Tom DeLauer was talking about, which confirms downregulation of endogenous creatine synthesis and methyl group sparing. Yet it says it does not reliably lower plasma homocysteine in the general human population, despite robust effects in animal models. I'm gonna skip through the biochemical rationale because that's what we just spent a couple of minutes looking at with Tom. But let's see what the animal data say and then we'll go through the human studies. It says animal data are strongly supportive. In rats, creatine supplemented diets reduced plasma homocysteine by about 25%, while GAA supplemented diets, which increased methylation demand, raised homocysteine by 50%. So that's really good proof that the mechanism that we've talked about is in fact what is at play here, at least in rats. In uremic rats, which have elevated levels of urea nitrogen and who have kidney dysfunction, creatine supplementation lowered homocysteine from 15.4 to 12.1 micromoles per liter, with an inverse correlation between plasma creatine and homocysteine. So the more creatine they had, the lower the homocysteine dropped. Similar reductions were seen in other models. But it says human data are more nuanced. The largest and most rigorous trial, which had 458 patients double-blinded in Bangladeshi adults, which only did three grams of creatine per day for 12 weeks, found that creatine significantly lowered plasma GAA about 10%, but did not lower plasma homocysteine on average. However, among participants who received creatine and folic acid, those who experienced a decline in GAA also had a correlated decline in homocysteine, suggesting the methyl sparing mechanism operates, but maybe insufficient alone to move total homocysteine in humans. Maybe that, or maybe the dose was too low. Next study in vegan subjects with hyperhomocysteinemia in about 50 patients, five grams a day of creatine for three weeks, normalized homocysteine in the hyperhomocysteinemic subgroup, suggesting that the effect might be more pronounced in populations with elevated baseline homocysteine, which is really what we're talking about here anyway, or low dietary creatine intake. And lastly, a case report of an NTHFR 677 T T homogein. Homozygote, so somebody with that mutation who does not methylate well at all showed a dramatic drop in homocysteine from a baseline of 33 wow, yikes, to 17 micromoles per liter after one month. 17, by the way, still too high, but that's almost a 50% drop. That is incredible. Uh, after one month of five grams a day, where wild type and heterozygous individuals showed no benefit. And again, proposed mechanism is that spared methyl groups increase SAM availability for alternative remethylation pathways, like the ones that are betane-dependent, which may be particularly relevant when folate-dependent remethylation is impaired. Okay, so the key takeaways if you have baseline elevated homocysteine, you do not eat a lot of creatine in your diet, or you have an MTHFR mutation, which truly, like that's really the population I was asking about. Uh, that seems to be potentially a very valuable thing to add. So, what I'd like to do, because the the takeaway here from open evidence is sort of saying, well, the data are really mixed. We don't know whether this is um, you know, we just they're they're wishy-washy about it, right? They don't say that it's universally helpful. And largely that's because the big randomized controlled trial didn't find that creatine supplementation by itself lowered homocysteine. But let's take a look at that study and see what they actually found. The title of this paper, Low Dose Creatine Supplementation Lowers Plasma GAA, but not plasma homocysteine, in a double-blind, randomized, placebo-controlled trial. This was published in the Journal of Nutrition in 2015. Authors are as shown, Mary Gamble is the senior author here. Let's take a look and see what they really did. This is the abstract. We're gonna go into the body of the paper itself. Here is a nice uh graphic showing you that synthetic pathway that we've talked about. We're not gonna go into detail about that, lest I start to have PTSD from biochemistry. And here we go. Study participants. So folic acid and creatine trial has been described elsewhere. Participants for this trial were selected from health effects of arsenic longitudinal study, which was a prospective cohort, over 20,000 adults from Bangladesh. We had uh patients between the ages of 20 and 65. Inclusion in the study. Participants were randomly selected. Pregnant women, individuals taking nutritional supplements, protein in their urine, and known kidney disease, diabetes, or GI or other health problems were excluded from the study. All right. 622 participants were recruited for the study and assigned to one of five treatments. The analyses in this paper concentrate on those randomly assigned to receive placebo, three grams a day of creatine, 400 micrograms per day of folic acid, or three grams a day of creatine plus 400 micrograms of folic acid. And those were supplied by Douglas Laboratories. Participants randomly selected to receive 800 micrograms of folic acid were excluded from this analysis because there was no comparable creatine group. Okay. The creatine dosage is based on the estimations of Brosnan et al. that a 20 to 39-year-old 70 kilogram man loses 14.6 millimoles of creatine per day, which is about two grams, with the mean creatine losses for women about 80% that of men. We therefore concluded that three grams a day should be sufficient to downregulate endogenous creatine synthesis. This dose is also considered safe by the European Food Safety Authority, and the folic acid dosage is based on the US RDA for adults. So again, randomized double-blind placebo-controlled trial, basically the gold standard for clinical trials. They're going to talk about the blocked randomization, gender strata. Again, all of these are just good basic practices. And they have a pharmacist who's distributing the assigned treatments. All participants received arsenic water filters. Okay, that's because that's a part of a bigger study. Ten participants were dropped from these groups over the course of study for various reasons, including adverse events. Always an important thing to keep in mind in a supplement or a medication trial. So we had one in the placebo group for abdominal cramps, one in the folic acid group for high blood pressure, one in the creatine group for severe vertigo, and uh three people dropped out for pregnancy, one each in the creatine, folic acid, and combined creatine and folic acid groups. There were some missing samples, one from placebo, one from creatine, and dropout not otherwise specified, one from placebo and one from folic acid. So total sample size by treatment group was about 101 patients, placebo, 153 in folic acid, 101 in the creatine group, and about 103 in the combined group. Plasma homocysteine was the primary outcome of interest for this analysis. Secondary outcomes were plasma creatine and creatinine, GIA, blood SAM, and SAH, and plasma total cysteine. Sample handling, I'm gonna skip through some of this. Whole blood SAM, plasma folate, and B12 were measured. They don't specify whether the folic acid that was given was methyl hydrotetrafolate, which is what you would get in a methylated B vitamin or a methylated B complex. I mean, I guess that folic acid is just folic acid by itself and the unmethylated version of that. Um, you can overwhelm the methylation pathway by providing increased inactive substrate, but it's a harder, it's a bigger lift for the body to do it that way. Um, if I'm gonna give patients who have methylation issues supplements, I will try to give them the activated form. Sample size considerations. Uh I think I'm gonna skip through that. There are their statistical analyses. Let's just get to the data. Okay, results. We have some baseline characteristics. So average age, late 30s, about half were men. BMI is in the 20s, about 20 to 30 percent were ever smokers. Um, arsenic levels are measured here, plasma folate levels are measured, and about 210, 15 to 20 percent of the population was folate deficient. And here is our baseline plasma homocysteine levels, which are a bit elevated, right? So optimal or good is less than 10, optimal will be less than 8. And we're looking here at you know, 12 to 14 as an average level. And I don't know what their cutoff is, but they're calling over half of their cohort as hyperhomocysteinemia. So good. That means we should be able to detect a change and see some real impact if creatine is going to help. And that was my first concern with this paper was what if we're already looking at a cohort that has, you know, levels that are 10, 11, maybe we won't see a big drop. If we're starting in the 12 to 13 range, 12 to 14, I think that's a reasonable starting place to actually see a change. Okay, so what do they actually see in terms of the decrease here? So plasma creatine and creatinine is here, plasma GAA is here, blood SAM. All right, plasma, total homocysteine. So in the placebo group, we have baseline is 12, week 12 is 12% change. This is gonna be what we really want here, and with a 95% confidence interval. And if that confidence interval includes zero, then we are gonna say that there's no significant change here. So in the placebo group, uh the percent change is negative 1.3%, but confidence interval goes from negative 0.5 up to 3.1, so that's not significant. Our next group, sorry, I'm gonna scroll up here for a second because I didn't see groups ahead of time. Okay, creatine and folic acid and then combined. Okay. So in the creatine-only group, the percent change was minus 4.3%, but again, we're going from negative 9 to positive 0.7, so that is not significant. The folic acid group is significant. This is minus 23%, so a confidence interval from negative 27 to negative 19. And the combined group is also significant, negative 21% from negative 25 to negative 16. So folic acid alone and creatine plus folic acid were significant, but creatine by itself here was not. All right. So I agree that this is why open evidence was a little bit lukewarm on whether creatine supplementation is going to provide a lot of benefit by itself, but said maybe in the presence of folic acid. But if what I'm doing for my patients with elevated homocysteine is giving everybody the methylated vitamins anyway, right? So folic acid or metro methyl tetrahydrofolate or methylcobalamin, sorry, and methylcobalamin, TNG, trimethylglycine, betane, right? We have all of these components to a good, complete methylated supplement. Then does creatine on top of that help? Answer maybe not, at least not based on this study, right? Because in fact, here the combined group was really not that different than the folic acid-only group. It was a little less, honestly. So, you know, maybe if you're not able to get a methylated B vitamin, or I'm gonna bring up something else I'm not prepared to talk about today, but if you have a COMT mutation and you don't tolerate methylated B vitamins very well, maybe creatine would help. Again, that's based on the other studies that were mentioned, right? The vegan patients who did well and the patient who had an MTHFR mutation who dropped from 33 down to 17. Those are potentially scenarios in which that's helpful. But again, I wouldn't restrict the methylated supplements to the for people who were otherwise able to take them. I have to say, like, I'm not gonna really gonna go through the rest of this paper in great detail. Um, I'll just highlight this one line. Although plasma total homocysteine was lowered in the creatine group, mean within-person change was not statistically different from that in the placebo group, right? And that's really the bottom line. So creatine by itself, not different than placebo, had to be with folic acid to do anything. And really, folic acid was doing the heavy lifting here. I was I was prepared to say that this might be practice changing for me, right? That I might start adding creatine to everybody. I don't think it's a bad idea. I think creatine is a really interesting supplement, and there are some other pieces about creatine in the brain that I would really like to explore with you guys in another video, another time. But right now, I still believe, based on at least this trial, that methylated B supplementation is probably still the mainstay, foundational therapy that I'm offering my patients with elevated homocysteine. Creatine has a lot of other great benefits and should be used, but I think using it to drive homocysteine down by itself, probably not the be all and end all that I was hoping it might be. Let me know what questions you guys have about this down in the comments below. 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