#340 - AMA #69: Scrutinizing supplements: creatine, fish oil, vitamin D, and more—a framework for understanding effectiveness, quality, and individual need

Hey everyone, welcome to a sneak peek, ask me anything or AMA episode of the drive podcast. I'm your host, Peter Atiyah.
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So without further delay, here's today's sneak peek of the Ask Me Anything episode. Welcome to Ask Me Anything AMA episode number 69.
In today's episode, we cover supplements. As this is a very complex topic, we wanted to approach it first by proposing a framework that you can use to evaluate supplements that we can't make blanket recommendations on since everyone has their own individual health circumstances.
To me, the framework is very important here because if I were to just dive into this podcast and give you my point of view on a random collection of supplements, it would be akin to giving you a bunch of fish when in reality, what I want to do is make sure you, of course, know how to fish. But not just giving you the framework, we also want to give you a few fish.
And so we want to use the framework to cover a handful of studies for some popular supplements. We covered creatine, fish oil, vitamin D, vitamin B, or many of the vitamin Bs, and ashwagandha.
We also talk about how to look at supplement quality, and we hope that this episode gives you an ability to take said framework and apply it to any supplement you encounter in the future. If you're a subscriber and you want to watch the full video of this podcast, you can find it on the show notes page.
If you're not a subscriber, you can watch the sneak peek on our YouTube page. So without further delay, I hope you'll enjoy AMA 69.
Peter, welcome to another AMA. How are you doing? Great.
Thank you for having me again. Always, always welcome.
I know sometimes it's tough to get you to clear your schedule, but we're always happy you show up. Haven't missed one yet, so that's always a good thing.
So today we're hitting a topic, which is one we get asked about a lot, which is supplements. And this can vary greatly depending on the person, depending on the supplements.
And the hard part with supplements is that while everyone is

interested in it, it's so variable person to person and not even all your patients are taking

the same supplements or the same amount and all of that. And so it's really hard to talk about it

in a way that makes it applicable to everyone without being like, take this, don't take this, which is something that you've never really done because of how you look at this topic. What we decided to do today was instead look at a framework for how you think about supplements and then go through case studies of a variety of supplements to talk through it to hopefully allow the person listening or watching to then be able to apply it in their own life so they can just get a better understanding, be smarter when it comes to this topic.
So we tried to pick ones that we get asked about a lot for the case studies, which is creatine, fish oil, vitamin D, B vitamins, and ashwagandha. So the hope is after this, not only will people understand those specific supplements better that we're going to do the case studies on, but also how they can apply this framework to their own life.
With all that said, when patients come into the practice, what percent of the supplements are they taking that you recommend they continue to take? Obviously, any patient that's coming into the practice, we're trying to gather as much information about them as we can through their medical history. An important component of that is understanding all medications, supplements, hormones, anything they take.
I call this the bucket of exogenous molecules. So generally we know this on the way in, and there's a ton of variety.
There's people who come in who are taking nothing. They don't take any medicine by prescription.
They don't take any supplements. Conversely, there are patients who come in on no medications, but a list of supplements that might be two pages long and everything in between.
Our view is generally to approach this the way the kidney approaches the filtration of glucose, sodium, and potassium, which is you dump everything out and then ask the question, what should be added back in? And I don't mean we literally stop everything, but I'm saying that's kind of the mental model for how we go about thinking about it. Because a lot of times when we ask patients, why are you taking this or why are you taking that? They don't know.
They just say, oh, you know, I started this a couple of years ago because I saw somebody on Instagram talking about it. Or, you know, I saw this doctor a few years ago who told me to take this, but I have no idea why.
So there's just a couple of things worth acknowledging before we jump into this. And it comes from discussions that I've had many times, which goes something like this.
Hey, I don't believe in taking any medicine, just so you know, only natural supplements. Now, my response to that is, tell me the difference.
There is a difference, but I just want to make sure you as the consumer of this understand the difference. And it's really a question of regulation.
So supplements are not regulated. By definition, the FDA has tacitly referred to them as generally regarded as safe, but the process by which that's determined is not entirely that rigorous.
And pharmaceutical products, while far from perfect, do have more in the way of regulation and oversight. There are places where these overlap.
I'll encounter a patient who says, listen, I will never take a statin to lower my ApoB, but I will definitely happily take red rice yeast, at which point you have to sort of explain to them that a very high dose of red rice yeast is effectively a modest dose of pravastatin. So I think it's just helpful for patients not to get ideologically wrapped up in the idea of over-the-counter supplement versus pharmaceutical agent, and instead to just analyze any molecule you put in your body through the framework we're going to talk about today.
Today, we're going to limit it to over-the-counter supplements because these are the things we get asked the most questions about. And frankly, it's the area in which it's harder to do the type of analysis we're doing today.
So the type of analysis we're doing today is so much easier to do in the pharma space because of the regulatory hurdles that must be cleared by a drug to be approved. So it's almost like shooting fish in a barrel.
It's still a great exercise to do, but doing it the way we're going to do it today is really how you develop the muscle for doing this type of work. I think with that said, do you just want to run over real quick the questions you asked to determine whether or not a supplement is worthwhile? And I think just giving this overview will be helpful because as we said in the beginning, when we go through the case studies, we'll stick to these questions and answer them along the way.
And so to kick it off, do you just want to run through what those questions are? I think this is the single most important thing I'm hopefully transmitting throughout this episode. I mean, the heavy lifting is actually showing you how we go through this, but this is the punchline.
Anytime you're considering taking a supplement or someone is suggesting a supplement, you should ask the following questions or something that approximates them. So the first question I'm asking is, are you taking this to correct a deficiency or are you trying to achieve supranormal levels of fill in the blank? Second question, are you taking this molecule because you believe that it's going to improve your lifespan or your healthspan or potentially both? The third question is, if it is lifespan, is it because this molecule is targeting a specific disease and presumably reducing your risk of that disease? Or do we believe it's more broadly geroprotective? In the supplement landscape, that's pretty rare to find, but obviously you can see examples in the pharma space where we might see certain drugs that we think have gyroprotective benefits versus those that have lifespan benefits, but only on one disease.
Of course, the other question that is the corollary of that is if you're taking it for health span, can you speak to which apparatus of health span? Do you think this is something that is improving physical performance, cognitive performance, or emotional health? The fourth question is, is there a biomarker that you can track to suggest that you are getting the appropriate amount of the supplement or that you might be in the therapeutic window? The fifth question is, do you understand the mechanism of action? Now, again, I want to be clear. You don't have to answer every one of these questions in the affirmative for it to make sense.
For example, there are countless things that we use for which we might not fully understand the mechanism of action, but we might feel confident enough on some of these other dimensions to move forward. The final question is, what is the balance of risk to reward, including potential side effects, the magnitude of the effect, the confidence we have in the data that speak to its safety, and the quality of the supplement itself.
And this last point is especially important here. We know from previous podcasts that I've done, including the one with Catherine Eban, that even in the pharma world, the quality of the drug is not to be taken as a given.
That episode, which is several years old and we'll link to it, really called into question the quality of some of the pharmacologic agents out there, especially generic brands. But whatever amount of nefarious behavior exists over there, I think you're safe multiplying that by 10 or 100 to understand the magnitude by which that's happening in the supplement space.
So I guess before we jump into this, Nick, I just want to make sure we've pulled together a lot of information on the six supplements you mentioned. For the sake of time, flow, making this conversational, I'm not going to go deep into each study that we talk about.
Rather, I'm going to try to cover the important details, but we will heavily cite, link to, and explain the details of the studies in the show notes. So if you're listening to this because you just want to see how the framework works, great.
But if you're like, actually for those supplements, I want to go deeper, the show notes is where to go. Perfect.
So I think let's get started with the first one, creatine. Going through the questions in the framework, are you using creatine to correct for deficiency or trying to achieve super maximal levels? With creatine, it's clearly the latter.
I'm sure there's somebody walking around out there with a creatine deficiency, but that's not really the use case. So when people like myself and I do take creatine, it's because we believe that supra-physiologic levels are preferential.
We take this primarily to improve athletic performance, potentially increasing lean mass slightly. There are some emerging studies that suggest that it may also ameliorate cognitive decline.
And basically research shows that once muscle stores are fully maximized, which can be achieved with three to five grams per day, you've flattened out that curve. In other words, you don't need to go much beyond that.
Although, as we've talked about on this podcast, there was a day for those of us that are old enough to remember when the zeitgeist was to do a period of loading at much, much higher doses in the neighborhood of 20 grams per day before falling to a maintenance dose of five. But today, people that are taking it are usually just taking three to five grams per day.
As far as taking it for lifespan, healthspan, which one are people usually taking it for? Well, we certainly see no direct evidence on lifespan. I think most people who would take this, if being confronted with the granularity of this question in this way, would say, look, I'm taking this for healthspan.
I'm maximizing the benefits of my exercise, especially with respect to resistance training and maybe potentially warding off cognitive impairment. Now, of course, indirectly, I would say that those are also benefits on lifespan, but I would say that that's probably the way to think about this.
And you kind of talked about this earlier on, but is there a specific biomarker that people can use to track to see if the supplement's quote unquote working or not? No, there's not a biomarker for this. And again, what do I mean by a biomarker that people can use to track to see if the supplement's quote-unquote working or not? No, there's not a biomarker for this.
And again, what do I mean by a biomarker? Well, if you're taking a medication to lower your blood pressure, measuring your blood pressure actually becomes a biomarker for the thing you're taking. Am I taking enough or too much? If you're taking a drug that lowers your ApoB, the ApoB itself serves as the biomarker.
We don't have a way outside of a lab commercially to measure tissue creatine levels, so we do not have a biomarker for this, and that's why people who take it are just sort of adhering to a protocol. On the mechanism of action, do we have any understanding of the mechanism of action for creatine, whether it relates to the physical or the cognitive side? On the physical side, meaning on the muscle performance side, it's certainly pretty clear.
People will recall how energy currency is delivered. So ATP, adenosine triphosphate, is the richest form of energy currency, and it liberates energy.
So it's spent by liberating a phosphate. So ATP becomes adenosine diphosphate, ADP.
Of course, that process works in reverse. So as we want to build up and replenish our ATP stores, we need a phosphate donor.
And this is where phosphocreatine comes in. So we do naturally have phosphocreatine.
In fact, when you start to think about the various energy systems, if I asked you, Nick, to do something that was an all-out effort for 10 seconds, that would not require oxygen. You're not tapping into your VO2 max or your oxygen delivery system.
It's frankly not even an anaerobic activity, meaning you're not actually turning glucose into pyruvate, into lactate, etc. If you're doing something that is such a short burst of activity, you are really relying on the phosphocreatine system to generate the ATP for that activity.
So if you're doing a 40-yard dash, you're relying on phosphocreatine. But of course, phosphocreatine itself is a phosphate donor, and therefore anything that boosts the supply of phosphocreatine boosts the supply of ATP.
And it's our belief that that's effectively what it is doing, and therefore that it's helpful with anything that requires bursts of activity, but even beyond just the super short extending into the anaerobic. I don't know that there are really any proven benefits that this augments aerobic performance.
So once you get into the purely oxidative phosphorylation pathway, I mean, maybe someone will correct us, but I'm not really aware that there are benefits of creatine in that regard. I think it's more in the first two energy systems, the phosphocreatine system and the anaerobic system.
On the cognitive side, we know that a small amount of creatine is synthesized in the brain and that creatine can cross the blood-brain barrier, but the brain certainly does not take up creatine to the same extent as the muscles do. So while we have, again, some evidence to suggest that creatine is efficacious for cognitive function, it might turn out to be the case that you need higher doses of it.
I think that's still an open question as far as I'm concerned. You mentioned earlier that we'll put a lot of more detailed information on the data in the show notes, but looking at a high level, what does the data around creatine say about efficacy of it? This is a supplement that has been quite readily studied.
There's reasonable evidence to suggest, and again, we'll link to lots of it, that creatine does help improve various parameters of muscle performance. And it's not that subtle.
I mean, it's typically in the range of 5, 10, maybe even 15%. So these include things like power and hypertrophy.
Again, the power shouldn't be that surprising when you understand the mechanism of action. The hypertrophy seems to be due to not just the increase in the myofibril thickness, but also in the retention of water within the muscle.
And of course, that's still considered lean mass. As I alluded to, kind of physical performance in short, intense burst activities, and potentially some benefits in slowing down the aging phenotype of muscle mass.
Again, like I said, it's really probably best suited for high intensity and anaerobic activities, but the one meta-analysis we'll cite to found that creatine did not really improve endurance events in trained athletes. Again,

you always could argue, well, maybe it's because they were really well-trained and their mitochondria

were well-honed, but it's possible that there's a study where you took completely untrained

athletes, had them do an aerobic task with and without creatine, and you might indeed see a

benefit there. So again, I think we're still kind of in early days on some of this stuff.

There was a 2017 review that got quite a bit of attention that we'll link to that concluded that creatine may help with the prevention and recovery from injury. And there have been a number of meta-analyses looking at cognition.
The most recent one, which was this year, looked at 16 RCTs and found that creatine had a positive effect on memory. I would say long and short of it is a lot of this stuff looks very promising.
There's also some evidence that women in particular might benefit more than even men. Women have lower stores because muscle mass is the predominant store.
Women have less muscle, therefore less stores, but there might also be less consumption through diet. So it, again, at least leads to the hypothesis that women may benefit even disproportionately to men.
There's some, I think, rather weak data that suggests that it may help reduce depression in women. And there's some evidence to suggest that it may be helpful during periods of rapid hormonal change.
And that could be within the monthly period of a menstrual cycle, pregnancy, perimenopause, and menopause. So you might ask, why is that the case? Well, the creatine and phosphocreatine pathways are impacted by hormonal changes.
And of course, during all of those periods that I just mentioned, you're seeing rapid hormonal changes. So it's not really that surprising that supplementing to supernormal levels of creatine could offset some of those impacts.
Pregnancy is a question I get asked about a lot, Nick. I would say I remain a little bit unclear and would probably suggest that it's probably safe during pregnancy, but we just don't have enough human data to form a strong point of view.
So in my mind, the wise thing to do is to avoid anything that is not absolutely necessary during pregnancy. So just to give an example, when we have women in our practice that are preparing for pregnancy or pregnant themselves, I mean, no matter what they're taking, if they're taking medication for something that they can live without for nine months, we would absolutely stop it.
So yeah, I would say women should probably dose it at about the same doses as men, but of course they'll get more bang for that buck because they're on average smaller. Rounding out everything we talked about with creatine, what is the balance of risk reward to how you see it? It seems like a lot of stuff we talked about was a lot of reward, but how do you think about this to summarize it? I would put this in the low risk, modest reward category.
We do have, I think, really robust safety data here, and it looks good. If the muscle stores are already full, the liver is probably going to metabolize the delta.
The kidneys will clear the excess. There is one thing to keep in mind.
If you're a person who doesn't have perfect kidney function, you do probably want to talk with your doctor before you take it. And this is very important.
You want to make sure that they know you're taking it before they do any blood tests to measure your creatinine because high doses of Creatine can impact serum doses of creatinine, which we would use as one of the metrics to determine kidney function. So in our patients that have anything but perfect kidney function, if they're taking creatine, we typically have them stop for a couple of weeks before we do a blood test.
Creatine monohydrate really is the version to take. I don't even know if they sell anything else.
They used to sell a creatine phosphate a long time ago. I don't think that there's anybody selling that anymore.
I don't think it matters, but there's just no evidence that you need to be taking anything other than creatine monohydrate. It's wildly inexpensive and you should be looking for the purest product only that has nothing in it.
The only ingredient should be creatine monohydrate, no fillers, no extra ingredients, unless there's some flavoring agent that you want. But I just mix this in with an electrolyte drink.
So I want nothing other than the creatine monohydrate in the sample. Anything else you want to say on creatine before we move to the next one, which is fish oil.
Nope. Perfect.
Fish oil, another supplement that we get asked about a ton. We've done some podcasts on it.
A lot of questions on it. It seems like a lot of people take it.
And so going through the questions with fish oil, first one is, are you correcting for deficiency or are you trying to achieve super maximal levels when it comes to fish oil? Thank you for listening to today's sneak peek AMA episode of The Drive. If you're interested in hearing the complete version of this AMA, you'll want to become a premium member.
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