Peter Attia MD291 ‒ Role of testosterone in men & women, performance-enhancing drugs, sustainable fat loss, & more
EVERY SPOKEN WORD
150 min read · 30,005 words- 0:00 – 0:11
Intro
- PAPeter Attia
[upbeat music] Hey, everyone. Welcome to the Drive Podcast. I'm your host, Peter Attia. [upbeat music]
- 0:11 – 7:38
Testosterone and DHT: mechanisms of action, regulation of muscle growth, and influence on male and female characteristics
- PAPeter Attia
Derek, good to see you again.
- DEDerek
Well, thanks for having me again, Peter. Appreciate it.
- PAPeter Attia
Yeah, so last time we spoke, we covered a lot of ground, and yet somehow at the end of it, we felt like there was still a lot to talk about.
- DEDerek
Yeah.
- PAPeter Attia
So, uh, hence we're back. Um, and I'm gonna do something unusual, which is I'm just gonna tell you, "Hey, what do you wanna talk about?" As opposed to, um, driving down my agenda. I have a bunch of things that I wanna talk about, but curious as to where you think we should pick things up.
- DEDerek
Um, yeah. I think that a lot of stuff we covered at a surface level, and maybe there might be some unanswered questions or ambiguity on some specifics when it comes to, you know, am I a good candidate for hormone replacement? How would I assess that? You know, should I be worried before I get on it? What kind of things should I look for? Um, I feel like kind of getting clear on that might be worthwhile 'cause a lot of people are kind of in that boat where they don't know who to trust, they don't know who to listen to, and I know even yourself, you're kind of like teetering on the thought of maybe exploring it. So I feel like even seeing what your thought process is going into evaluating is it viable for you would be super valuable.
- PAPeter Attia
Yeah. So, um, let's maybe back up a little bit and give folks a, a, a quick primer on the topic, right? So, um, l- let's just start by just talking about testosterone. Um, uh, I don't know if it's just that I'm more attentive to it or there's truly been an increase in marketing efforts, but it really seems like the last decade-
- DEDerek
Yeah
- PAPeter Attia
... um, and, and presumably it's also just the explosion of social media and, and more channels through which this information comes at you. Um, but, but clearly there's been a lot more attention, uh, brought, brought forth to this idea. Um, and it's very interesting because there's historically been kind of a, a negative connotation associated with testosterone, a natural hormone. We can talk all about that. Um, but of course its role in drugs, uh, a- as a drug of abuse in, in sports, um, has, has sort of tarnished it in a way that we don't see in, on the female side, right? So when we talk about hormone replacement for women with estrogen and progesterone, that doesn't come with the same performance-enhancing benefits.
- DEDerek
Which is odd, eh? How, like, it's viewed as such a taboo thing even though at the end of the day it is just a natural hormone that you produce.
- PAPeter Attia
Right. And so it's interesting, of course, that estrogen and progesterone are not scheduled, uh, drugs. They're not, they're not... They're hormones. They're... You know, you prescribe them without any limitation. They're unscheduled by the FDA, uh, the DEA. Um, conversely, testosterone is scheduled and much more highly regulated. And again, the, the suggestion here is that there's potential for abuse that we presumably don't see with estrogen and progesterone, and, and, you know, that's neither here nor there. It just is what it is. Um, so, so maybe let's just talk really briefly about testosterone, androgen receptors, how they work, the role of DHT, and what, what this does for muscle protein synthesis. Maybe just a kinda quick background on that.
- DEDerek
Yeah. So in general, most people are aware of testosterone as the primary masculine hormone, but in reality it's produced in significant quantities in both genders, just proportionally more so in men. It's to the magnitude of 10X that of females, I believe. Um, and also both men and women produce estradiol and DHT as well. They just have differing proportions and binding proteins and whatnot, but at the end of the day, the action in the body is the exact same. It still binds to the androgen receptor and, uh, induces gene expression and causes muscle protein synthesis and other anabolic actions in bone, psychoactive effects in the brain, um, et cetera. And just the magnitude to which it happens differs between sexes, and it also is what essentially determines how you sexually mature and differentiate as you enter adolescence. So you could realistically manually manipulate it, too, and you see this in-
- PAPeter Attia
Yeah
- DEDerek
... sport, you know, doping scenarios, bodybuilding males versus female. Like, you see it all the time. So ultimately, this is the primary androgen that dictates muscle growth and anabolic activity in tissues, and the metabolites of it kind of regulate a bunch of other things in the body, which we could get into. But to keep it, like, high level simple, it is the main primary androgen that men and women alike rely on, just at differing amounts.
- PAPeter Attia
And I think we talked... I can't remember if you and I talked about it on our previous podcast. I know it's been discussed on the podcast, so I won't... Re- We'll, we'll link to it in the show notes where I go into great detail mechanistically about what happens when testosterone binds to the androgen receptor and how that gets into the nucleus and how that in- impacts, um, gene translation or transcription into translation for a protein. Um, what's interesting, of course, is that you did mention DHT. DHT has a significantly higher affinity for the androgen receptor. Um, anything else you wanna say about the role of DHT versus testosterone in... And we can just talk about it in one gender. We don't have to necessarily break it down.
- DEDerek
Sure, yeah. So the spectrum of just what... I s- I said androgen. I didn't really elaborate what that even means. It's kinda like, as far as I know, the definition is to essentially to be male or to make male or something related to masculine characteristics ultimately is kinda what you derive from androgens. And the further on this spectrum of androgenicity it goes, the more masculine and viralizing potentially in women it could be. So DHT is that hormone essentially that drives this pathway to the extreme and is what is responsible alongside testosterone for, like, maximal sexual differentiation, maturation in adolescence like I mentioned. But, you know, you see mutations in the gene that encodes for 5-alpha reductase, which is the enzyme that makes DHT, and you'll note that certain, um, pseudohermaphrodites who don't have DHT will end up, you know, lesser developed-
- PAPeter Attia
Right
- DEDerek
... in the masculine spectrum than a normal functioning human with full DHT production. So this is just kinda like an example of the spectrum of on one side you have males producing 10X the testosterone and more DHT subsequent to that, and then females, much more estrogen proportionally to males. Well, somewhat, depending on, you know, where they're at in their cycle and whatnot. And then 10X lower the testosterone and also much less DHT. And this ratio of androgens to estrogen essentially is what dictates are you going to, you know, have male characteristics or female characteristics, and how much are those characteristics going to get exaggerated? 'Cause even if you're a full-grown female, if you exposed yourself manually to these hormones, you could very much push yourself in that direction. So DHT, a lot of people are know, people know about it for its responsibility in, like, what it does for hair loss and some, like, the common side effects associated with it. But it is an important hormone that does regulate how masculine you become as you grow up. So I think that's the best way to put it.
- PAPeter Attia
Yeah. And, and there's a critical window of exposure, too.
- DEDerek
Mm-hmm.
- PAPeter Attia
So embryologically, obviously, exposure to testosterone and DHT have an enormous impact on sexual differentiation, um, later in life.
- 7:38 – 22:08
TRT in women: the complexities and potential risks associated with testosterone use in women
- PAPeter Attia
I mean, I give you an example. I, I, uh, have a patient, a female patient, who's on testosterone and, um, she accidentally for a period of about a month just didn't read the directions, uh, correctly and was taking 10X the dose.
- DEDerek
And that's not that hard to mess up when you're-
- PAPeter Attia
It's very easy to do. It's, yeah, this is not, like, uh, uh, this is, this is something you have to be very careful with, um, because the doses are so, so small for women.
- DEDerek
And there's no FDA-approved women's testosterone as well.
- PAPeter Attia
Right. You could have it compounded, in theory, uh, at a lower concentration. But regardless, she t- she, for about a month, ended up taking 10X the dose, which means she was taking a male physiologic dose of testosterone.
- DEDerek
What was her total test, do you know, by chance?
- PAPeter Attia
We didn't even bo- the, the symptoms immediately-
- DEDerek
Yeah
- PAPeter Attia
... said, "There's something going wrong here." Um, but, you know, the symptom, the first symptom interesting that she noted, um ... You know, I would have expected hair growth to be the biggest issue. Uh, but sh- it was clitoral enlargement.
- DEDerek
Hmm.
- PAPeter Attia
In, within just a period of a month.
- DEDerek
Yeah.
- PAPeter Attia
Um, the good news is, completely reversible once the, the dose was restored to the 10th that it should have been. Um, but do y- I, I don't know anything about really, I don't really follow bodybuilding closely enough, but I assume that female bodybuilders are routinely using doses of that nature?
- DEDerek
Yeah. They are, depending on their guidance, somewhat or very aware of the masculinizing potential of what they're using, and some will avoid testosterone entirely because of that, 'cause it is essentially equal anabolic as it is androgenic. So it begs the question, why would you be using testosterone as a female if you're trying to achieve super physiologic muscle growth? You kinda know in order to push it to that extent, you're probably gonna end up in male characteristic territory. Um, so oftentimes they will defer to compounds like oxandrolone, which is Anavar. They'll use things like primobolan sometimes, o- um, metenolone and-
- PAPeter Attia
So meaning much more anabolic-
- DEDerek
Yeah
- PAPeter Attia
... much less androgenic.
- DEDerek
Yeah, so these are synthetic compounds that have been manipulated to be more tissue selective, as in more anabolic activity relative to the male viralizing component. Unfortunately, you can't segregate the two entirely, but they do what they can. And the best thing they can do is keep an eye on the side effects as they manifest in very, very real time, keeping a close eye on it. I know some women who even have a, uh, like a decibel voice recorder.
- PAPeter Attia
Yep.
- DEDerek
And they will monitor if their, like, tone is getting lower or not-
- PAPeter Attia
Yep
- DEDerek
... in real time, 'cause in, it's-
- PAPeter Attia
Is that potentially an irreversible-
- DEDerek
Yeah
- PAPeter Attia
... um, change, if voice-
- DEDerek
Yeah
- PAPeter Attia
... is changing?
- DEDerek
Yeah, so you have to be super careful, especially, even in TRT, if you were gonna do TRT as a female, a lot of the clinics nowadays will advertise and market testosterone in a way that is highlighting how great it is for libido, quality of life, you know, uh, I dunno, glucose management, muscle growth. Like, there's a lot of things that sound attractive about it that are an easy sell to a female who, you know, may be asexual and, like, perimenopause or something. And I've seen standards being promoted as cookie cutter, everyone should have a 200 nanogram per deciliter total test.
- PAPeter Attia
Wow.
- DEDerek
Which is crazy.
- 22:08 – 28:38
DHEA supplementation: exploring the benefits and risks for women, and the differing effects on men vs. women
- PAPeter Attia
Um, let's talk for a moment about DHEA. So that's the other thing that seems to be all the rave today.
- DEDerek
Mm-hmm.
- PAPeter Attia
Um, a lot of my female patients are asking to be put on DHEA. And, um, I'm not sure where this came from because DHEA has been around forever.
- DEDerek
Mm.
- PAPeter Attia
Um, it's one of the few hormones that's available over the counter. Uh, that's a relatively unique situation to the United States. Very few countries-
- DEDerek
Not in Canada, though. Don't bring it back to Canada, or else you get [laughs]
- PAPeter Attia
That's my point. Yeah.
- DEDerek
Yeah [laughs]
- PAPeter Attia
So even, even across the border with our, you know, neighbors that we're otherwise pretty similar to, DHEA-
- DEDerek
It's Schedule I
- PAPeter Attia
... is, yeah. It's, like, Schedule I?
- DEDerek
Yeah. It's r- if you have that, you're doing something more illegal than having anabolic steroids.
- PAPeter Attia
Wow. I did not know it was Schedule I, and yet here it is. Go on Amazon-
- DEDerek
Yeah
- PAPeter Attia
... and you can fill your boots with it.
- DEDerek
Yeah.
- PAPeter Attia
Um-
- DEDerek
Which makes no sense.
- PAPeter Attia
No, it makes no sense, I mean, uh, until you understand the, uh, the regula- like, you understand there's, there's a political, there's a dirty political story as to why that's the case.
- DEDerek
There's some really backwards compound selections, though, that are banned. Like, for example, you can buy ephedrine in GNC in Canada. It's like, why? It's literally used to make meth.
- PAPeter Attia
Mm-hmm.
- DEDerek
And then here, it's a lot harder to get ephedrine. But then you can get yohimbine here, which is a fat burner we'll talk about later, and in Canada it's banned. And it's like, wh- who's selecting-
- PAPeter Attia
Yeah
- DEDerek
... what gets banned?
- PAPeter Attia
A lot of women, for some reason, have recently, like in the past few months, been-
- DEDerek
Okay
- PAPeter Attia
... sort of saying, "I wanna be on DHEA, I wanna be on DHEA." And, you know, they're somehow being led to believe this is the elixir of life.
- DEDerek
Mm.
- PAPeter Attia
And I'm sort of trying to scratch my head and understand why they're saying that. Presumably they're saying, "If my DHEA levels are low, it could explain my low testosterone, and this is a, quote-unquote, 'more natural way to increase my testosterone.'" I haven't seen any compelling data that DHEA does much of anything. Um, what, what did the data say? I haven't looked in a decade, by the way. So a decade ago, when I was really beci- beginning to get interested in hormone tinkering-
- DEDerek
Mm-hmm
- 28:38 – 38:32
The role of progesterone in both men and women, pros and cons of supplementation, the importance of tailored doses, and more
- PAPeter Attia
of progesterone? What, what do you think the role of progesterone is in, uh, both men and women for, um, you know, d- outside of reproduction, right? So putting reproduction aside. Um, [clears throat] you know, one of the things that we're doing a lot more with our patients, um, we used to be pretty quick to abandon progesterone systemically if women were having, you know, any mood symptoms associated with a full dose of it, and we would just very quickly adopt a Mirena, you know, a progesterone-coated IUD to give the endometrial, uh, counterbalance to the estradiol to prevent the hyperplasia and obviously reduce the risk of endometrial cancer with unopposed estrogen. Um, but you know, we're really seeing a lot of women in the middle ground who maybe can't tolerate a full 200 dose, a 200 milligram dose of progesterone, which would be kind of the, the full dose-
- DEDerek
Mm-hmm
- PAPeter Attia
... um, but feel great at 50 to 100. And so, y- you know, in many ways what we're trying to do is just find every woman's dose and, like what's the amount of, that you can tolerate? And if it's sufficient, great. If it's insufficient, we'll backstop it with a Mirena.
- DEDerek
Mm.
- PAPeter Attia
Um, w- why do you think that is? Why, why do you think progesterone is so important for women?
- DEDerek
Outside of reproductive, like standard utility, I think that it's more... Like if you look at a steroidogenesis cascade, which is like in layman's terms I guess if you took cholesterol and then all of the different things it could turn into when you cleave it and through enzymatic pathways turn it into, you know, a um, glucocorticoids or like downstream to adrenal steroids and downstream to testosterone and DHT and estradiol and estrone and all that stuff like that is called steroidogenesis, the synthesis of all these steroid hormones in your body. And some of you guys might've seen this chart before, and I'm sure you've showed it on the podcast. It's like this big messy thing that has like 7,000 different pathways and it looks overwhelming. But up near the top where you start to have like, uh, you know, cortisol production, you have some of this stuff upstream for, um, like glucocorticoids as well as where pregnenolone branches from like to actual androgens and upward to like adrenal hormones. At the top you have this, uh, downstream cascade from progesterone that leads to an array of metabolite hormones that are like pro-anxiolytic as in they will be like anti-anxiety, kind of balance out the sympathetic drive that you might get from androgens and also help you get to sleep. So that's why progesterone is so useful at night and it's kinda why it's placed at that time for dosing as well. And taking it orally also is like impactful on the way it's metabolized out to get some of these proportional metabolites too, 'cause if you had it in a cream or an injection, not only maybe is it harder to get the dose you want out of it, but the metabolite content that you get is totally different when you have a first pass metabolism versus you skip it. So with progesterone in particular, it produces an array of different things, including but not limited to, one is called allopregnanolone, which is seemingly implicated to some extent in post-finasteride syndrome, but also very much in postpartum depression, and they've even created like a synthetic analog of it now that they use to treat postpartum depression, which is interesting. But all of those different metabolites cumulatively c- if you are deficient in, you know, some amount of them, depending on the individual's biochemistry and genetic predispositions, could result in like a, you know, more anxious human than otherwise. So the dose required to balance out, you know, the, uh, androgenic signaling relative to all this other stuff going on, I, you know, it's ... I would expect it would vary quite significantly female to female and especially when you are backfilling hormones from a shut down state. Like it's not endogenously regulated the same way when you have feedback mechanisms, so you're kinda just manually shooting stuff at your liver and hoping it's gonna spit out the right amount of stuff, and you can only really do that through some sort of titration/experimentation and what dosages seem to produce, you know, repeatable outcomes in the literature we have available. So I would imagine a lot of women would, you know, have a dose that is far less to achieve the outcome they want or much higher or perhaps don't respond at all 'cause it's not what they need. Depends, but I, I think that would be my, my educated guess.
- PAPeter Attia
Is there a role for progesterone use by men?
- DEDerek
Yeah, so I said this last time and you seemed baffled, and it definitely does not have like an approved use in men. There's no like literature that points to it as this is something you should use in men or replace. But I do believe and see it play out where it could be useful to balance out some of that sympathetic drive and whatnot. And it kinda ... You know, you could look at blood work and kind of see, okay, in my like minimal negligible amount, should I be pushing that to the top of a negligible amount that is my threshold or-
- PAPeter Attia
And what, what doses do you see people using here?
- DEDerek
The same doses, like 50 to 200.
- PAPeter Attia
W- that high?
- DEDerek
Yeah. Yeah.
- PAPeter Attia
And what are the side effects of that?
- DEDerek
So if you are not on exogenous hormones, it is, it does have negative feedback. So similarly to most people are very familiar with how estrogen has negative feedback to the hypothalamus pituitary testicular axis and testosterone through androgen receptors, but what often goes overlooked is some of the other hormones like progesterone. So progesterone isn't as potent of a negative feedback regulator that I've seen, but it definitely is and it seems to h- maybe even have anti-androgenic activity as well. And if it does that through, you know, competitive inhibition or like I don't really know off the top of my head, I don't recall how it does it, but it does seem to produce anti-androgen-like effects, and some of it may be mediated through the negative feedback and some of it may be inhibited through actual like transcriptional activity. But ultimately it's something that will lower your ability to have like, you know, androgen-like effects in the body to some extent.
- PAPeter Attia
But if you're on TRT-
- DEDerek
Yeah, it doesn't, doesn't matter because you're already shut down.
- PAPeter Attia
Correct. So what would be the benefits when you're on TRT, um, what is it helping you balance out clinically?
- DEDerek
I think very common we will see disproportionately high free androgen levels in men, especially when you look at ... A lot of guys will look at their total testosterone, their free testosterone, their SHBG, but what often goes overlooked is SHBG binds DHT with I believe it's a five times higher affinity than testosterone.
- PAPeter Attia
Mm-hmm.
- DEDerek
It might be 10, I think it's five though. Whatever it is, it's much higher. And that ratio of DHT to testosterone to estrogen that's freely circulating, like your regulating mechanism in the body, the primary one, 'cause SHBG is like the main thing that determines how male you are essentially, that is ... Well, besides the actual production of the hormones, but DHT binds, gets bound up with five times higher affinity than test, which is like 20 times higher than estrogen. So if you have that regulatory framework kinda like ... dro- driven down through either a dose of testosterone that is higher than you need or like a, I don't know, super infrequent dosing pattern that results in, like, a disproportionate drop on certain days or an array of different things, you could end up in this, like, free androgen dominant environment where your sympathetic drive is kind of, like, keyed up perpetually. And because you have a long ester compound in your system, you don't have the luxury of endogenous manipulation of your hormones going up when you need them and down when you need them. Like, the pulsatile framework of your natural production is nonexistent. You're just, like, getting a big spike whenever you inject, and then it's slowly gonna diminish out of your system until you want to inject again. And a lot of guys, even when they're doing, you know, twice a week or something, you're still getting, like, some level of spike and then dips and then spike and dips, where if you were a natural with normal natural testosterone production, it would be, like, very pulsatile with a diurnal rhythm, with natural dips and valleys and peaks, and it would not fluctuate where it's like bam, bam. And if you look at a steroid plotter, you can kind of see how this looks, and you want to compare a steroid plotter to, like, your actual rhythm naturally. It's, like, not really the same. So that's kind of where you get into, you know, more frequent dosing might be better. But at the end of the day, a lot of people are overlooking how dominant the free androgen profile could be in a guy on TRT. 'Cause you'll see your total testosterone, and it might be 700 when you measure it, but you're measuring it three days after your injection. You're looking only at free testosterone. Your DHT has not been evaluated. Your free DHT surely hasn't been evaluated. I don't necessarily think everyone has to spend hundreds of dollars to check those, by the way. But just be aware that if your SHBG is lower than it was before you started TRT, like, there is a disproportionate regulating mechanism in play here now that you have to perhaps account for if you're in, like, a state of anxiety. Like, that might be a factor or if you have trouble getting to sleep. Like, there are certain cues I would look to as to, am I, you know, a little bit too red-lined right now?
- PAPeter Attia
G-
- 38:32 – 43:42
Measuring levels of free testosterone
- PAPeter Attia
given that free testosterone is typically estimated, I guess we can talk a little bit about testosterone measurements. You were mentioning earlier that there's a direct way to measure free testosterone. I was unaware of that. Um, do you look at free androgen index, where you're just taking the ratio of testosterone to SHBG, so you're taking the ratio of two things that are directly measured? Is that a better proxy for what's happening physiologically than this indirect, uh, calculation of free testosterone? Which, I mean, again, if, if my memory serves me correctly, free testosterone is a calculation based on testosterone, SHBG, and albumin. Is there anything else that factors into it?
- DEDerek
Yeah, I'm pretty sure the free direct measurement via LabCorp is just based on those binding proteins. I don't think there's anything more to it. But with the equilibrium dialysis, it is separating it and measuring it directly and-
- PAPeter Attia
Does LabCorp do an equilibrium dialysis?
- DEDerek
Yeah. It's just more cost-prohibitive. So the good news is a lot of these tests t- when they evaluate them against it as a gold standard track pretty closely with it, so you can use them as proxies that are relatively accurate. It does get skewed when you get into trying to measure, like, hypogonadal men that might have... You need to be a bit more, I don't know, uh, lower concentrations, and you want to make sure you get it right. It's not just tracking trends as much. Or individuals who are using synthetic androgens, it will for sure cross-detect if you're using a immunoassay-
- PAPeter Attia
Yeah
- DEDerek
... or a calculation, um, 'cause it's gonna be based on the cross-detection of the total testosterone presumably as well if you use that. So yeah, in general, if you wanted to use the gold standard, it would be equilibrium dialysis. I don't know if it's always necessary. However, at a baseline measurement for people who are trying to get as ideal and accurate of blood work as possible, I would typically always go with the highest sensitivity, and that's... Like, even with your blood work, it's not like it was wildly different on some of the metrics, but, like, it was significant enough that it makes you-
- PAPeter Attia
Y- yeah, let's talk about that. So I wrote my values down. So for my last blood test, I did it... I had LabCorp run them both. I had them run the, um, immunoassay, which is not the gold standard. That's the cheaper test for both testosterone and estradiol, and then the LC-MS, which is the gold standard. And so here's the difference. So the enzyme-based immunoassay for testosterone was 502, but the LC-MS was 381.
- DEDerek
So for people who wanna know how to tell if the test is that one, it says Roche ECLIA right beside it.
- PAPeter Attia
Yeah, so Roche is the company that provides the, the, the-
- DEDerek
Yeah
- PAPeter Attia
... the, uh, the assay for them.
- DEDerek
But that's, like, the only thing I think it says underneath it to identify.
- PAPeter Attia
Yeah.
- DEDerek
Yeah.
- PAPeter Attia
So that's a pretty big difference, right? I mean, that's a-
- DEDerek
Yeah
- PAPeter Attia
... 25% difference. Uh, and, and-
- DEDerek
Yeah, like I, I think it's significant enough to justify getting-
- PAPeter Attia
Yeah
- DEDerek
... the accurate one.
- PAPeter Attia
Yeah, yeah. This is... And that's the only one we do, but I just wanted to see what the, what the difference was. So the, the, the accurate test read 381 to the inaccurate 502. Here's what's more telling was the estradiol.
- DEDerek
Mm.
- PAPeter Attia
So the estradiol on the accurate test, the LC-MS, was 18.3.
- DEDerek
Mm.
- PAPeter Attia
And on the, um, enzyme-based test, it was 41.3, so that's more than a 2X difference.
- DEDerek
Yeah, the enzyme-based testing will cross-detect estrone, synthetic estrogens as estradiol, and it's, uh, annoying. [laughs]
- PAPeter Attia
I... Why do you... I mean, that still seems really high, right? Given that my estrone, my estriol, they should be very low. I'm obviously not taking any synthetic estrogens. Why do you think it's off by more than 2X? And by the way, I see this in other patients as well.
- DEDerek
Um, [sighs] yeah. I, that would be tough for me to speculate without seeing the full gamut.
- PAPeter Attia
I, I think it's picking up something in my supplements. Like, I think there's-
- DEDerek
Oh, probably. Yeah
- 43:42 – 48:00
The trend towards earlier interest in TRT, and the risks of underground sources of testosterone
- PAPeter Attia
Okay, so let's now kinda shift over to, to sort of the, the testosterone replacement decision-making in, in, in, in a male. Um, so it seems to me that younger and younger men are seeking out testosterone replacement therapy. Um, is there any data on that, or is that just sort of our perception?
- DEDerek
No, you are right. Like, as far as marketing efforts and exposure, if you look at just Google Trends and you type in TRT, it's like, the graph of how many searches are on Google has, like, skyrocketed over the past decade.
- PAPeter Attia
Where, where do most men get their TRT? How much of it is done kind of, um, from an endocrinologist, for example, like someone who presumably, you know, spent a lot of time understanding the system? How much of it is done from, you know, clinics that only do testosterone as an ex- as, as the other extreme example, right?
- DEDerek
Yeah. Yeah, it's tough because countries will differ in their scrutiny on this stuff to such a varying degree that if I speak, I could speak to the US and give some sort of ballpark, and I, I feel that's probably the most useful. Um, and again, this is not based on some sort of survey or anything. This is just [laughs] my, my speculation as to what I would imagine is happening from trends I've seen. Underground market is still the most easily accessible with the cheapest barrier to entry, and with the, you know, advent of internet e-commerce stores, it's not that difficult to find a website that sells testosterone or other anabolics and get some Bitcoin and buy it. So there's a lot of people that will get it from their gym bros or online. It's very accessible now. And the cost, aside from the prescription barriers of finding a doctor who you actually think will give you the prescription and not necessarily knowing when you go into that consultation or whatever that they're gonna be, you know, the flexible doctor that you need, it's just easier for a lot of guys to get it, you know, black market. So there's a significant amount of guys, at least in the fitness industry, that are suppressed from their hormone use that will be on TRT underground. So I would say that probably the majority of them are on not scripted TRT, even, like, lenient phar- like, telemed clinics. I don't think most-
- PAPeter Attia
Yeah
- DEDerek
... I would say a majority are still using underground.
- PAPeter Attia
And they, I mean, like, presumably crypto is what enables that because otherwise the DEA would shut these things down. Or is it, or is it too much of a game of Whac-A-Mole or there's too many of these around?
- DEDerek
Yeah, Whac-A-Mole, yeah. So there's a lot that sell an amount of volume presumably that is not significant enough to focus on, or it's just like, it's so hard to track 'cause even if you shut one down, another one pops up. It's based in some country that's not even the US supposedly, and they drop ship it, and they use crypto, so it's harder to track the currency. It's like...
- PAPeter Attia
Got it.
- DEDerek
Yeah.
- PAPeter Attia
And what kind of testosterone are these guys getting? Are they actually getting branded Depo testosterone? Are they getting some knockoff from China?
- DEDerek
Often it's underground, but there are resellers of pharmaceutical grade too, and sometimes these guys will have connections with people in, you know, Europe, in certain countries where you can just walk into a pharmacy and buy, you know, whatever you want for one-tenth of the price, and then they will mark it up and then sell it to you in the US, and yeah. So there's an array of different options, but typically it is a, you know, a underground lab that is producing it and making, you know, what they're advertising as a accurately dosed sterile product that is branded under their, like, you know, underground lab brand essentially.
- PAPeter Attia
Got it. Um, okay. So for folks that wanna do this kind of in a little bit more of a responsible way and go and see a doctor, um, y- you know, there are a lot of these kind of, uh, doc-in-a-box operations where they're basically just T docs. Um, I don't know how they're operating. I assume that a lot of this is telemedicine. I don't know how much longer that will be in existence. Um, I do believe that a lot of that stuff's gonna be shut down. Um,
- 48:00 – 56:46
The complexities and considerations surrounding the use of Clomid, E-Clomid, and hCG in TRT
- PAPeter Attia
but for the time being, um, y- you wanna just talk maybe a little bit, I know we talked a bit about this, but anything else you wanna say on the, uh, Clomid, E-Clomid, hCG T trade-offs?
- DEDerek
Yeah. That is, um... [sighs] I think when you are trying to restore fertility in the short term- And you're averse to injections and, you know, there's a lot of factors that could lead me to say Clomid might be viable. But in general, if you're looking at something long-term, I would say typically Clomid or Enclomiphene, which is, you know, a more progressive version of the drug, albeit not FDA approved, um, neither of those I think are viable long-term, at least from a risk perspective. You are essentially putting yourself in a position of long-term estrogen receptor antagonism in certain tissues, meaning you're gonna be missing out on estrogen receptor activity in certain areas of your body that down the line could manifest an array of issues. Like, if you look at the side effects of SERMs, you'll see weird stuff depending on the compound. Sometimes it's ocular issues or-
- PAPeter Attia
What, what do we know about the long-term use of Clomid? 'Cause that's ... We've got more data for Clomid than we do Enclomiphene, which is, as you said, just a very, very close derivative of it, but they both work the same way. They both block estradiol ... The, the estradiol receptor of the hypothalamus, correct?
- DEDerek
Yeah, and then the Zuclomiphene component of Clomid, which is, has two drugs essentially in it, 'cause they will have differing effects, that component of it is more anti-gonadotropic, I believe. So it's, like, something that will, um ... Like, the Enclomiphene component is far more specific to the SERM activity you are seeking in the hypothalamus. The Zuclomiphene is longer half-life, less efficacious, doesn't even really represent the target therapy of the drug. So in general, even if, if you're looking at Clomid, that's the only one that has approval, so you would-
- PAPeter Attia
Yeah
- DEDerek
... potentially have the data. But I, off the top of my head, don't know of any studies that are going decades long to evaluate something like that. I don't know if it exists. I would be kinda doubtful it exists, to be honest. But I would think in the ... From what I've seen, at least anecdotally, take from that what you will, is typically no one ends up with a stable mood long-term or an ability to, like ... It's, it's not a sustainable therapy long-term, in my opinion, for the vitality component you seek from replacement therapy to begin with. So perhaps on paper your testosterone looks good, but it's more of a, a metric that you're using to justify the drug, because you are achieving the target, which is, "Look, my testosterone's better now," but at the expense of literally tricking your brain through inhibiting very, very necessary mechanisms. So it's not like you are stimulating production through a means that is directly targeted. It is more like you are trading off the health of one part of your body to get an outcome that is potentially, uh, ROI-justifying in another aspect of your body. So at the expense of estrogen receptors working everywhere in the body, you're getting more testosterone.
- PAPeter Attia
And is it blocking estrogen receptors everywhere or just centrally?
- DEDerek
Yeah, it is selective, hence SERM, but it's not perfect, as we talked about last time. You are going to get, um ... Like, we could just Google Clomid side effects and you'll see an array of different things, I believe including but not limited to skewing of lipid parameters. You were the one who taught me about-
- PAPeter Attia
Yeah
- DEDerek
... doing some effects.
- PAPeter Attia
Desmosterol.
- DEDerek
Yeah, and, like, that's sketchy, and [laughs] like, I wouldn't wanna have that long-term. Um, like, there's stuff you'd have to track that are very unknown variables. At least we kind of know what to expect when you have natural testosterone increasing, like what happens at a, you know, lipid perspective or a negative feedback perspective, or you're not dealing with some, I don't know, nebulous activity in different tissues and having to account for it. So s- like, actual brain inhibition, you know, is, uh, sketchy to me, and from what I've seen, people end up, uh, I don't know, not in a good state of mind long-term on it. But I suppose it's possible you could.
- PAPeter Attia
What doses are you seeing people use in the wild?
- DEDerek
Um-
- PAPeter Attia
Like 50 milligrams daily, 50 milligrams three times a week, 25 daily?
- DEDerek
Yeah, around 50. Yeah. It ... Obviously in the bodybuilding world, I told you about the absurd PCT regimens, post cycle therapy, where guys are using 100 per day-
- PAPeter Attia
Mm-hmm
- DEDerek
... for, you know, shorter timeframes, but it's, uh, you know, super high doses.
- PAPeter Attia
Now, I, I think we're going to see a big increase in the use of Clomid and E-Clomid even beyond what we're seeing now just based on the regulatory environment, which is to say that, you know, there will be no use of telemedicine for the prescription of any scheduled compounds. So that means that testosterone and hCG, which we'll talk about again in a second, um, can only be prescribed in person, at least if you're adhering to the law, whereas via telemedicine you could still use Clomid or potentially, uh, E-Clomid. So, you know, that just sorta suggests that we're gonna see, uh, you know, hCG kinda plummet and, uh, Clomid go up. Um, so I, I think the implications of understanding this are actually pretty significant, and I'd really like to see this studied better.
- DEDerek
Yeah.
- PAPeter Attia
Um, because everything about Clomid is easier to use, right? You're gonna have this ... You're gonna get over the regulatory issue. Um, it's oral. It's a pill. You don't have to inject it.
- DEDerek
Mm-hmm.
- PAPeter Attia
You know, hCG, as we've talked about, is a bit more difficult to use because it needs to be refrigerated. It's a very fragile peptide, and it's probably more expensive than both testosterone and Clomid put together, right?
- DEDerek
Oh, yeah, for sure.
- PAPeter Attia
Um, anything you wanna just say about hCG that we didn't cover last time?
- DEDerek
Um, I think that if you are looking to restore natural production and assess t- or assess your testicular response in general before you decide to go down the TRT pathway could be a worthwhile thing to do. So if you're considering TRT, you have a total testosterone of 300 or and you're symptomatic
- PAPeter Attia
381
- DEDerek
Yeah. And let's just say you're symptomatic, you're, you know, you haven't, don't even remember the last time you had morning wood. Um, you know, your energy levels are much lower. It's much more difficult to retain muscle, et cetera, et cetera. F- actually looking at your blood work to assess what is the release from my pituitary down to my gonads to actually produce the testosterone, what is that signal and is it sufficient? So do I have a in range, high normal, like what does it look like on my blood work of my luteinizing hormone, LH and FSH? And if it looks to be adequate or even high would be even more indicating if something's wrong, you could determine from there why are my testes not responding to it. And then from there, that, it, there's a way to delineate down to-
- PAPeter Attia
Yeah, so but here Clomid and, and, um, I mean, Clomid gives you two pieces of information, right?
- DEDerek
Yeah.
- 56:46 – 1:07:44
Low testosterone: diagnosis, potential causes, treatment options, and other considerations
- DEDerek
my testes first.
- PAPeter Attia
Yeah. But let's say you learn this, okay? So let's say, um, with my [clears throat] testosterone of 381, I, I take hCG-
- DEDerek
Uh-huh
- PAPeter Attia
... and my testosterone goes to 1,200.
- DEDerek
Mm-hmm.
- PAPeter Attia
1,000, 1,200. Like it goes to upper end of the range. So we've learned that, hey, my hypogonadism is central. It's not peripheral, right?
- DEDerek
Mm-hmm.
- PAPeter Attia
That somehow my pituitary isn't making enough signal because clearly my testes can make enough testosterone.
- DEDerek
Mm-hmm.
- PAPeter Attia
With, armed with that information, what, what is the best course of action? Is it to stay the course and just say, "Well, hey, keep taking hCG because at least your testes are responding to it," or, you know, is there some obvious problem-solving? And, and I'm thinking about this even in my case, right? Because, you know, like when I think of all the things that would normally impair pituitary function, the first thing that comes to my mind is sleep disruption.
- DEDerek
Yeah.
- PAPeter Attia
And, you know, knock on wood, that's one thing I've pretty much got down in the toolkit. My sleep is, is great.
- DEDerek
Mm-hmm.
- PAPeter Attia
Um, maybe stress. Pr- you know, probably hypercortisolemia, maybe not so great. Um, training, over-training, under-training. Like y- you know, what are, what are the, what are the things you would look at to, to brainstorm if that scenario were the case? I don't know if that's the case, by the way, but that's an experiment that is probably worth doing to see, hey, where, why is my T low? Is it low because my brain isn't saying the right thing or is it low because my body can't do it?
- DEDerek
Yeah. I think there is multi- multiple factors here that could be fleshed out before you ended up on a hCG to even figure out, you know, what's my response at the testes level. Figuring out if you can top out the natural signal I feel is the first thing to do pending your blood work looks like, you know, gonadotropins are low to mid-range and I'm still not, you know, wh- why am I only getting a 381 response out of that? It would be to look to many of the things you just said, which obviously you're pretty dialed on. And then above and beyond that, it would be assessing the basics like micronutrient intake, macros. Are you eating enough to recover relative to your training stimulus? Um, I'm not gonna say a lot of people over-train too much. Maybe they're just under-recovering and their sleep is bad. That's probably a more realistic outcome. But in general, there is, not in your case, but in many other individuals, micronutrient deficiencies across the board. Zinc intake's not meeting adequate amounts. Magnesium intake's super low, and that's impactful as well. Um, an array of things, vitamin D being low, also very impactful. And these things can all move the needle like 100 plus nanograms per deciliter potentially, depending how deficient you are. So some of these low-hanging fruits with the sleep, micronutrients, minerals, actual macro intake. Some people are eating ultra garbage processed foods, no micronutrient density. They're undereating. Maybe they're on semaglutide and they're, you know, super calorie deprived and they have very low protein or something. That's also impactful. All of these assessments, do I have an adequate energy intake? And of that energy intake, high quality nutrient value in that energy relative to my demands? Am I training hard enough to actually maximize testosterone too? 'Cause that's also a factor is your resistance training regimen. And the sleep, all of these things in concordance will ultimately dictate what is your output. And then let's just say you've had that all dialed in. At that point, if it's still either suboptimal signaling, so, you know, low, low normal, whatever it is, or even normal gonadotropin output, and then you're still getting an inadequate response, you could then potentially discern partly that you're not gonna be able to get the signal you need out of your pituitary to optimize, or you actually have some degradation of response at the receptor level in the testes themself, which is an age deteriorated- ... thing as well unfortunately. Like, I would love to just say everyone's testes are gonna retain perfect function forever, but that's not the case. So similar to the signal, there's also the health of the actual organ. So if those things are all optimized, like you've kinda done your due diligence, it's just making sure you actually know what the due diligence is and you didn't just-
- PAPeter Attia
And if those things are optimized and you're at 381 and you take hCG and your T goes up-
- DEDerek
Yeah
- PAPeter Attia
... what, what, what, what does, what does that imply? That there's some other factor that we're unaware of that's impairing-
- DEDerek
Yeah, I would-
- PAPeter Attia
... central stimulus
- DEDerek
... yeah, I would be like, "What's your GnRH output then?" Not that I know how you could even measure that.
- PAPeter Attia
Yeah, yeah.
- DEDerek
But presumably that may be low, or the receptor response to the GnRH is suboptimal too.
- PAPeter Attia
Yeah, interesting.
- DEDerek
So it's like a whole upstream [laughs]
- PAPeter Attia
Yeah, that's interesting. That's the, that's the problem with these. Uh, is there anything that-
- DEDerek
You could use a GnRH agonist and even test out what your pituitary output is from there, but that's like good luck finding a doctor who understands the-
- PAPeter Attia
Yeah
- DEDerek
... nuance of not castrating you with that.
- PAPeter Attia
Yeah, although what you could do is then you could use Clomid.
- 1:07:44 – 1:20:00
Growth hormone-releasing peptides: rationale and implications of the recent FDA categorization as high-risk substances
- PAPeter Attia
When we last spoke, we talked about a whole bunch of peptides.
- DEDerek
Mm-hmm.
- PAPeter Attia
And so just recently, meaning after we spoke but before this recording-
- DEDerek
Yeah, the wild time in [laughs]
- PAPeter Attia
... yeah.
- DEDerek
Yeah.
- PAPeter Attia
The FDA came out and took a list of about 30 peptides and put them on a list called Category 2. Now, this included six of the peptides we discussed, including BPC-157 and, um, oh, what is it? CJC-
- DEDerek
CJC-1295.
- PAPeter Attia
Yeah. Have, uh-
- DEDerek
Ipamorelin.
- PAPeter Attia
That's right. So a bunch of the things we talked about-
- DEDerek
MK-677
- PAPeter Attia
... that's right, are now on this Category 2 list, and I've been doing my best to understand what that means. My interpretation of what it means to be Category 2 is they, these can't be sold, compounding pharmacies cannot make them, and any interstate commerce of these things is a felony. Um, that said, I've noticed that there are still sites selling these peptides, and they seem to be suggesting that they're selling them for research purposes, which is clearly bullshit.
- DEDerek
Mm-hmm.
- PAPeter Attia
Um, is, what's your understanding of this FDA ruling?
- DEDerek
I think that the ruling has basically put them on a, uh, like a super high risk list essentially, whereby they're not outright banned, but you will invite heavy scrutiny and perhaps legal action should you decide to make them, 'cause you will essentially have to ... Uh, I don't think it's too d- maybe it's not comparable, but in the dietary supplement world, they have a advisory list, and they will pick certain things they think are high risk and add them to this list. And then if you continue to make or sell these, you may receive a warning letter, at which point you have to either discontinue immediately or they will take you to court and you have to prove why it's DSHEA compliant and legal to sell. And you could have a court appearance where you could try and make your case, but you will lose essentially. So I don't know if this is gonna be the exact same outcome, 'cause it's, you know, pharma stuff too, so it's probably, you know, heavier scrutiny. But from the people I've talked to in the compounding world, people who even are in the business of selling peptides, they seem to think it's ... I don't know. The commonality that I'm seeing is it is very risky. It was already risky to begin with, but it's very risky. And you are inviting scrutiny, but it's not necessarily actually illegal.
- PAPeter Attia
I see.
- DEDerek
So they could easily prove it probably if they wanted to and took you to court, but I don't know that all of them are going to get, you know, Whac-A-Mole-d. I feel like it might be a sort of a scenario like that. And when you look at these research chemical sites, they are no different than they were months ago. Like, these are the same sites that have been operating with their pseudo research chemical use only, you know, fake umbrella the whole time. Like, those companies exist to try and sell whatever with no prescription, no compounding pharmaceutical standards. Like, at least in compounding, there is some level of oversight where you, you know, have to be plus minus some amount of potency. You should be submitting it for microbial testing and stuff. And in this world it's, you know, you buy it from Alibaba, private label it, and then you sell it online. That's what these research chemical sites are. So maybe some of them are doing HPLC testing, but that's like, you know, the, the really responsible ones, if you wanna call it that, like relative to the rest of them that are just straight up buying it, repackaging it, and selling it.
- PAPeter Attia
And yet I think, do people buy there with a credit card? Or they're not having to use crypto to buy through these sites, are they?
- DEDerek
I think it depends on how big the company is, 'cause sometimes you could get away with credit card processing up to a certain amount until, you know, Stripe or whatever your processor is determines you're doing something high risk that's not a part of their, you know, compliant activities. And up until that point, oftentimes they're accepting credit cards. So the bigger companies will do Bitcoin only or other, you know, more loophole ways of paying, MoneyGram, Western Union, stuff like that. Uh, t- typically crypto. But, um, yeah, some companies do credit card too. Yeah.
- PAPeter Attia
So the, the rationale for putting these 30 peptides on this Category 2 list, uh, the, provided by the FDA is, is it's a safety question, right? So the question was, um, we don't have, you know, sufficient data on the safety of these things, so we're gonna, we're gonna sort of schedule them in a way. Um, was there anything else to it? I mean, is, is, is, is there any reason to believe that these things were, were harmful? Or y- you know, I, I guess I just don't really understand, um, what the, what the rationale was. A- and I'm, by the way, I'm not saying I necessarily disagree with it. I just, I'm trying to understand what, what's being communicated in this ruling with respect to these peptides.
- DEDerek
I think publicly what they're saying is it's a safety concern, and there's no actual FDA approval to justify the, uh, production of these and prescription of them, which- Is not the most unreasonable conclusion, I suppose, given that a lot of these are research chemicals at the end of the day. Like, it's not like melanotan II has a, you know, application right now for somebody who's too white, you know? So [laughs] it's, uh, some of this stuff is very, you know, fudged at the end of the day anyways with compounds that got abandoned in the middle of a pipeline, but people had a demand for it, so the research chemical companies have never stopped selling it, and then compounding pharmacies, the ones that are willing to risk it for the biscuit will, you know, make a certain amount [laughs] since in quantities that they deem is, uh, you know, enough to satisfy the perceived demand, but not enough to get whack-a-mole potentially. So yeah, it's, it's really weird 'cause you would think it'd be black and white. You don't make it or you make it illegally, and that's kinda it. And I think a lot of people do believe that it's gray area enough that it is still legal to make, and there are small combi- compounding pharmacies that are gonna do business as usual. I think, um, some of them are looking to other abandoned, you know, pipeline products now to replace the existing ones 'cause those aren't on the list-
- PAPeter Attia
Mm-hmm
- DEDerek
... even though they're similar mechanism of action or whatnot. Um, and you could find like, you know, a catalog of Frankenstein compounds that a pharma company didn't want and get it from China, and then do the whole process over again 'cause, you know, there's endless amounts of those.
- PAPeter Attia
Why do you think there, there, there's such an epidemic of interest in this stuff? I, I, I'm constantly amazed at the frequency with which people forward me, you know, links to these bizarre molecules that, you know, they've heard some influencer talking about on social media, and they're, they're, they're asking me like, you know, should they be on it? And, and I, I g- I gotta tell you, it j- my patience for it is so-
- DEDerek
Yeah
- PAPeter Attia
... so low. It's so thin.
- DEDerek
Yeah.
- PAPeter Attia
When it's like, you know, if you would spend, I don't know, take half the amount of time you scroll social media looking for obscure molecules that idiotic influencers think you should be taking and maybe put it into working out-
- DEDerek
Yeah
- 1:20:00 – 1:39:53
Follistatin gene therapy and myostatin inhibition for increasing muscle mass: the recent hype online, human and animal data, and the need for more research
- PAPeter Attia
Yeah. You mentioned myostatin a second ago, which of course reminds me of, uh, something that's been going around social media lately, which is, uh, this interesting discussion about a gene therapy for-
- DEDerek
Mm
- PAPeter Attia
... follistatin. Um, so for folks listening to us who haven't been following this, um, I guess there's a, there's a gene therapy out there where, um, you, you introduce a vector to somebody, and you ... I don't think you fully silence, but you, you clearly attenuate ... Uh, actually no, I'm sorry. You activate the gene for follistatin. That makes more of the follistatin protein, which inhibits, uh, the expression of the myostatin gene, or maybe inhibits the protein myostatin, one or the other. And this, of course, is theoretically interesting because of what we know about the actions of myostatin. Um, m- I... When I think back to images that stand out from my first year of medical school, clearly on the top 10 list-
- DEDerek
You haven't even said it and I already know what you're talking about.
- PAPeter Attia
Yeah, you know what I'm talking about, right?
- DEDerek
Yeah. [laughs]
- PAPeter Attia
This is still like 25, more than 25 years ago.
- DEDerek
Yeah.
- PAPeter Attia
I still remember sitting in class when they showed the myostatin knockout mice and cattle.
- DEDerek
Yeah.
- PAPeter Attia
And do you wanna just tell people what a myostatin knockout looks like?
- DEDerek
Yeah. So it produces a double muscle phenotype, is what they call it, and if you look at these cattle, it's like you would think it's Photoshopped by how absurd it looks. This is like the Mr. Olympia of cattle, essentially. Like, there would be no chance anyone would come close in, you know, cattle sport, [laughs] if you, whatever. Um, and then the mice, same deal. They have, uh, like a ... Literally they call it double muscle essentially 'cause it's, you literally have double the muscle fibers as, uh, you know-
- PAPeter Attia
The wild type.
- DEDerek
Yeah. The reference. So-
- PAPeter Attia
And, and I remember, like, the chickens, the mice, the cattle.
- DEDerek
Yeah.
- PAPeter Attia
I mean, it was truly remarkable.
- DEDerek
There, there was this dog too, super jacked dog. Forget, forget what type it is, but, uh-
- PAPeter Attia
Yeah
- DEDerek
... it was the same myos-
- PAPeter Attia
And so, so, so my roommate and I spent the rest of medical school just talking about we've got to figure out a way to inhibit our myostatin.
- DEDerek
[laughs] Yeah, yeah.
- PAPeter Attia
Okay. So apparently now someone's working on this, and they're claiming that for just, I don't know, $25,000 for your first shot, and maybe 25,000 for every subsequent shot, you can get a gene therapy that will activate and produce more of a protein called follistatin that inhibits myostatin. And so that should be good, right?
- DEDerek
Yeah, yeah. It seems like, at least in the literature in animals, you see this, uh, you know, the myostatin knockouts and you see this, you know, double muscle phenotype. You would, you know, assume ... And you, there is actual rodent data too where you see follistatin administration does enhance muscle. Like, it does happen. Um, and I guess as a result of that, there was ... A lot of these research chemical companies were very quick to come out with, you know, a freeze-dried, like lyophilized follistatin product that had one milligram per, per vial, and you would buy it for, you know, hundreds of dollars. And then you would basically like shoot a vial a day or something of that nature and spend thousands over the course of a cycle, which was based on, you know, no data at all.
- PAPeter Attia
Now, this was, this, this was made ... H- how did this peptide get created? Is this an FDA-approved drug, or is this one of those-
- DEDerek
No
- PAPeter Attia
... you know-
- DEDerek
It was like-
- PAPeter Attia
This is-
- DEDerek
... we know what the chemical structure is. Let's go get a Alibaba chemist to make it.
- 1:39:53 – 1:48:32
Simple tips for lowering calorie intake and losing fat
- PAPeter Attia
Um, okay, I wanna pivot a little bit to talk about something. You made a video a while ago. I thought it was a great video. Um, I don't know how long ago you made it, though. It was all about kind of appetite suppression tricks that bodybuilders use that... I, and I think the purpose of the video is, hey, for those of you, most of you, who are not bodybuilders watching this who still wanna shed a few lbs, these are some kind of tricks that, that, that can be used, dietary tricks. So do, do you remember some of that list?
- DEDerek
Yeah, and I do wanna preface when I say this that when bodybuilders are trying to get very lean, it gets to a point where you're pulling out all the stops to an extent whereby it's not necessarily reflective of what is the optimal healthy diet.
- PAPeter Attia
For sure.
- DEDerek
Sometimes it's to the extent of short of any attempt at micronutrient density, how do I hit my protein and satiate myself to the maximum extent and fuel my training with enough carbs and have enough fat that I don't have hormone suppression? And that's like, those, those are the metrics once you get to the end of a dieting phase. Now, that's not necessarily indicative of what everyone's gonna do, 'cause most people just wanna see, you know, a sh- a hint of abs for the first time. So, you know, you don't need to take this to the extreme.
- PAPeter Attia
Yeah, I mean, I, I didn't... I interpreted your video as this is the full suite of things you have.
- DEDerek
Sure.
- PAPeter Attia
You wouldn't do all of them simultaneously. You kind of pick and choose from this list with what works, but-
- DEDerek
Correct. Um, yeah, I, I guess I just definitely wanna make sure 'cause people watching your stuff know what high-quality food is, and I do not necessarily advocate for these in all circumstances. But, like, diet soda, quite useful for calorie restriction in my opinion, for maintaining some, you know, satisfied s- uh, sweet tooth. Um, I think Layne has published a really good video recently highlighting that even compared to water, it... I'm not suggesting replace it with water, but in a state of calorie deficiency, if you have a craving, you're probably better off drinking a diet soda than you are eating some, you know, calorie-rich, fat-laden, sugar bomb dessert. Like, even some of the keto treats that you see that are marketed as, you know, healthy and, you know, diet conducive, oftentimes, like, look at the nutrition facts. You'll note the calorie component is horrendous. So just because the sugar content might be low-
- PAPeter Attia
Right
- DEDerek
... the fat content proportionally to make it taste good is, like, far more-
- PAPeter Attia
Right
- DEDerek
... destructive to your actual body composition goals. So that is something of note as well. Um, some of the first things I do typically that are low-hanging fruit are try to maintain the same volume of food on my plate but just replace with more calorie-light options. So as much as I love the micronutrient density of red meat, and it is one of my go-tos, I will consider swapping some of it to chicken breast, for example. Not necessarily saying to do that long term, but it is certainly an easy way to maintain if I'm having a six-ounce portion of meat in a meal to hit my protein needs, having a, you know, lean chicken breast as opposed to my, you know, ground beef that I had at the grocery store. The difference in calorie to protein content is pretty significant. So that's one of the first low-hanging fruit things I do is see how can I replace what to me perceivably is the same amount of food, but just with lighter options.
- PAPeter Attia
Mm-hmm.
- DEDerek
So that will be going from, you know, a ... fat-filled Greek yogurt to maybe a more fat-free Greek yogurt, and it doesn't taste exactly the same as you remember it, but it's pretty damn close, and the calories are perhaps, you know, a fraction as much, and you're still getting proportionally the protein you need. Um, swapping some red meats to whites. Um, eggs, going from some eggs with egg yolks. If you sprinkle in some egg whites with it as opposed to just all whole eggs, you can still get yolks in and get your micronutrients, but it almost tastes indiscernibly different when you have just maybe, like, one or two of them replaced with egg whites as opposed to the whole egg. Like, there are little things that are just noticeable, but not enough for you to consider it, "Oh my God, I'm in a deep deficit right now," and it's like I'm starving. You almost don't notice. And that in itself, just even three things I mentioned, you probably could have chopped off 500, 600 calories from your-
- PAPeter Attia
That much?
- DEDerek
Yeah, an egg is 80 calories per large egg, I believe. Could be even higher, depending on how large it is, and then an egg white for the proportional amount of protein I think is, like, 30 off the top of my head.
- PAPeter Attia
Hmm.
- DEDerek
Could be wrong on that.
- PAPeter Attia
Yeah, yeah. But directionally-
- DEDerek
But some- something like that. Um, you know, chicken breast, I think it's, like, 30 calories per cooked ounce, depending on, you know.
- PAPeter Attia
This is why I like, uh, wild game, because you're still getting red meat, but it's super lean.
- DEDerek
Yeah. That's, this is one thing I was gonna ask you on our, uh, podcast for my channel, too, is, like, you pound these venison steaks that are so lean and great. Like, how would you as a budget-friendly person go about getting your protein with the most lean, uh, cuts? 'Cause it's not always the most, like... You know, it's pretty cost-prohibitive to get the really good bison, venison, stuff like that.
- PAPeter Attia
Yeah, I mean, it, I, uh, one option is if you want red meat and you wanna be able to do it, I think you just, you, you go hunting, right?
- DEDerek
Hmm.
- PAPeter Attia
Like, if you think about it, like, if you, if you shoot one large deer, one, you know, elk, that's gonna feed your family for more than a year.
- DEDerek
See, this is unconventional advice, but that is, like, actually practically applicable advice for what is budget-friendly.
- PAPeter Attia
Yeah, and by the way, like, if you... Y- you know, people would say, "Oh my God," like, "How do you shoot an elk?" I mean, you know, it's impossible to get elk tags to shoot big elk. Well, guess what? It can be a cow elk. Like, a cow elk, a female elk, like, those tags are over the counter. Anybody can get them. These are not... You know, you're not trophy hunting, so nobody, like, there's no... You go- States regulate how much you can hunt. Um, you get incredible meat from the cow. Um, I would argue that's the healthiest thing you could eat, frankly, is, is, is wild game, because these animals are completely unstressed. Um, so anyway, I think, I think there's, I think those are, those are options if you're sort of doing it on a budget because, um, you know, the amount of meat you would get out of a cow would more than feed you and your family for a year.
- DEDerek
Hmm. What would you think... I don't even know if this is the right question to ask, but, 'cause I've never hunted, so I don't know what this looks like as far as, you know, the cost to get your, uh, what you need to hunt with, um, whatever licensing you need-
- PAPeter Attia
Yeah
- DEDerek
... how many states this is viable in, and then also skill level. Like, does it take a long time to even get to a point where you could successfully achieve-
- 1:48:32 – 2:05:11
Methods of sustainable fat loss with muscle preservation: insights gleaned from bodybuilders
- PAPeter Attia
how much of a... Um, I mean, like, uh, what's your advice to somebody who's trying to lose weight, um, but in a sustainable way? So not, like... In some ways, when bodybuilders are doing it, it's not really sustainable, because they're really starving themselves down to a competition.
- DEDerek
Yeah.
- PAPeter Attia
And the way that they're eating during that period of time is, y- you know, it's, it's so catabolic, um, that, that they're destroying their endocrine system along the way, but it's short-lived, and they're gonna re-feed when they're done. And, and so while we can talk about all of the different things that they, they might stack and do all simultaneously, um, w- you know, what's your view on the sustainable way to lose 10 pounds and keep it off i- in terms of deficit?
- DEDerek
I think your perception of what bodybuilders do as far as aggression towards their diet is o- hinged on their final outcome and how steep it is to get there- Cumulatively, but the way they arrive there, no one is more mindful of preserving tissue than bodybuilders. So-
- PAPeter Attia
So in other words, they're not dram-
- DEDerek
The-
- PAPeter Attia
They're not creating huge deficits at any one point in time?
- DEDerek
Eventually they are, at the point that they absolutely need to, but they're more careful than any human I know in-
- PAPeter Attia
Oh, yeah, I would, I would believe that
- DEDerek
... so if you were to try and take away from a bodybuilder, how would I apply this when they're stepping on stage at literally diced to the socks 5% body fat, it's not that you're getting there, it's that you're stopping at, like, the eight-week-out-from-competition mark of a bodybuilder. Maybe not 8, maybe, like, 10 or 12, but the process they took to get even there was very staggered, calculated.
- PAPeter Attia
Yeah.
- DEDerek
They would not reduce-
- PAPeter Attia
And by the way, 10 to 12 weeks out, what's their body fat relative to that 5 they're gonna step on stage?
- DEDerek
Like, it depends at what level and how on track they are, but-
- PAPeter Attia
Yeah
- DEDerek
... some of them are starting at, like, you know, 12% body fat, so perhaps that's not... You know, everyone has different goals of what they consider good.
- PAPeter Attia
Yeah, yeah.
- DEDerek
So maybe this is, like, my skewed fitness perception saying, "10-week-out bodybuilder is what you should shoot for." But just in general, the process they take to get from their peak body fat percentage to stage lean, no one is more mindful of titrating accordingly the macronutrient and micronutrient input to sustain training volume too, 'cause they need to actually make sure their training doesn't deteriorate, 'cause if it does, they're gonna lose tissue. So-
- PAPeter Attia
Yeah
- DEDerek
... taking from that, you see them at least hitting one gram per pound body weight in protein, like, without fail.
- PAPeter Attia
And they will hold that until the stage?
- DEDerek
Unless there is some, like... Maybe on the week of, they're already at their target body fat, and then at that point they're trying to do tactics to make their stomach as, you know, not full of anything as possible. So what they do on the last week doesn't really count.
- PAPeter Attia
Okay, okay.
- DEDerek
Up un- up until a week out, yeah.
- PAPeter Attia
Up until a week out, they would still be taking one gram of protein per pound of body weight.
- DEDerek
Typically.
- PAPeter Attia
And to your point, at this point, you can't be doing that with steaks 'cause there's... it's way too caloric. So you are on the chicken breast, protein powders.
- DEDerek
Depending on the person, though. And I guess it depends on, again, the quality of your meat, 'cause it's like I've seen the m- macros on your venison and it's ins- insane.
- PAPeter Attia
Yeah, it's basically just protein, yeah.
- DEDerek
Yeah. So, um, basically the staggered approach you wanna take is that you don't really wanna lose more than, I think, typically it's, like, 1% of your body weight per week as a general rule of thumb, which is... I guess could be, depending how obese you are, could be a little bit aggressive. But even let's just say a pound a week maybe-
- 2:05:11 – 2:06:56
Could prolonged fasting impact testosterone levels?
- PAPeter Attia
I sometimes wonder if my low testosterone is in response to how much fasting I used to do. 'Cause I used to always do a, a check of testosterone pre... I, I would do full blood work before-
- DEDerek
Mm-hmm
- PAPeter Attia
... and after a fast. So if I was doing a 7 to 10-day water-only fast, which I was doing once a quarter-
- DEDerek
Mm-hmm
- PAPeter Attia
... um, the, the change in hormone levels after 7 to 10 days of nothing was profound. So if my testosterone started out at 500 to 600-
- DEDerek
Mm-hmm
- PAPeter Attia
... it would probably end at 100 to 200-
- DEDerek
Yeah
- PAPeter Attia
... total T. If my TSH was, you know, 2, it would go to 4. If my... It might be even higher, maybe even 6. But free T3 and reverse T3, if free T3 was, you know, 2.5 to 3 and reverse T3 was 12... So the, you know, f- the, the higher the free T3 and the lower the reverse T3, the better thyroid function you have.
- DEDerek
Hmm.
- PAPeter Attia
Post-fast, that free T3 would go maybe from 3 down to 1.5, and the reverse T3 would go from 12 to 32.
- DEDerek
Damn. Yeah, not surprising, yeah.
- PAPeter Attia
Um, and so I just wonder if, you know, repeating that cycle over and over and over again, um, has, has, has maybe impacted, um, endogenous production. Although interestingly, my, my thyroid function looks stone-cold normal, uh, but it's just that, you know, my T is very low.
- DEDerek
Yeah, I would be interested to see, like, what your gonadotropins did when you went back to normal dieting at that point, and then how you responded from there. 'Cause if you could see, like, a trend in your testicular response, too, and how your brain-
- PAPeter Attia
Yeah
- DEDerek
... was shooting things out, that would be, that'd be interesting. But,
- 2:06:56 – 2:12:36
High-protein ice cream
- DEDerek
you know.
- PAPeter Attia
What about things like carnitine, caffeine? What, what role do these play in, in, uh, weight cutting?
- DEDerek
Not nearly as much as good diet choices. So I would love to get into the fat loss pharmacology momentarily, but one thing... There's a lot of diet hacks that, you know, we could take all day talking about, so I don't wanna bore the audience. But one thing I do wanna mention that is super impactful is protein ice cream. I don't know if you've ever had this stuff, but there's this thing called a Ninja CREAMi, and it's basically a mixing device-
- PAPeter Attia
The Ninjas, like the, like the blender.
- DEDerek
Sure.
- PAPeter Attia
Yeah.
- DEDerek
Yeah. But this one in particular is very popular lately because of the consistency of ice cream that it creates.
- PAPeter Attia
What's it called?
- DEDerek
Ninja CREAMi, like C-R-E-A-M-I.
- PAPeter Attia
So it's not the blender. It's a device that's different from their blender?
- DEDerek
Correct.
- PAPeter Attia
Okay.
- DEDerek
So this thing mixes what is already blended into an ice cream. So you would put it in the freezer, blend it, and then you put it into this thing, and it would turn it into an ice cream consistency.
- PAPeter Attia
Got it. And what do you put in it? How do you make it?
- DEDerek
Um, well, it depends what you want to put in it, 'cause you could make this as healthy as you want, which is essentially just, like, whey isolate plus some non-calorie filled, like, sweetener that you deem, you know-
- PAPeter Attia
Yeah, yeah
- DEDerek
... if you, if you wanna risk it. Um, maybe some, uh, sugar-free pudding mixture in there too, like a chocolate or something. And from there you could have something that is, like, you know, 300 calories, if even, and is as good tasting as horrible ice cream, but hits, you know, like a 60 gram protein hit with super high quality stuff, minimal sugar content, is, like, 80% as good as something you would buy in a store almost. Like, the consistently makes all-
- PAPeter Attia
Wow
- DEDerek
... consistency makes all the difference here, 'cause it's like typically, and this was, this was how it worked when I was younger and I first tried all this stuff, is perhaps there was a similar device, but at the time I was using a standard, I think it was a... I forget which blender it was from Costco, but I, I've tried a Ninja, a different one before, another one. I used to put in, like, huge amounts of ice. Um, fruit, you could do fruit too obviously and make it. But basically the consistency I got out of it was not that attractive. So it was not like... You could tell it wasn't ice cream. You're kinda eating, like, this sludgy, like, healthy thing. But this, it's like you could make it near, not identical, but pretty damn close to a point that I would... Like, I'm actually derailing our conversation to come back to it. Like, that's how significant it is.
- PAPeter Attia
[laughs]
- DEDerek
So, so for people who are wanting that sweet tooth that-
- PAPeter Attia
But, but if I make a protein shake-
- DEDerek
Yeah
- PAPeter Attia
... what I'm gonna use is real simple. I'm gonna use, um, almond milk-
- DEDerek
Yeah
- PAPeter Attia
... or cashew milk, sh- so as my wife calls them, nut juice.
- DEDerek
Yeah.
- PAPeter Attia
Um, f- like a whey protein.
- DEDerek
Yeah.
- PAPeter Attia
And I mix, I'll typically mix the unflavored, um... What's it called? Oh, God. Promix.
- 2:12:36 – 2:23:57
Exploring fat loss supplements and drugs: L-carnitine, yohimbine, and more
- DEDerek
Yeah.
- PAPeter Attia
Okay, so let's talk about some of the, the, the fat last pharmacopeia, uh, the fat loss pharmacopeia. So, um, I have friends that swear up and down by carnitine, L-carnitine. I think they inject it. Is that-
- DEDerek
Mm-hmm.
- PAPeter Attia
So tell me about that.
- DEDerek
So the L-carnitine is, um, present in red meat, and depending on your diet, you may or may not be deficient in it, and it is something that can help, uh, um, incorporate free fatty acids into the mitochondria and help you produce energy, and it also is implicated in certain indirect processes like AR content in the muscle, which is some of the more fringe literature. But it seems to, in the presence of sufficient anabolic stimulation, actually increase the expression of what you can get out of your testosterone input. So this is the main reason why people I know use it, and presumably why a lot of people use it that you know too, is it's often advertised as get more out of less androgen, essentially.
- PAPeter Attia
But does this work if you are getting sufficient carnitine in your diet?
- DEDerek
Yeah.
- PAPeter Attia
Like, do you need super, super physiologic doses?
- DEDerek
Well, in general, if you're injecting 500 milligrams, for example, like you will be supra. So it's not something... Similar to creatine, you can make the argument that endogenously or through your diet, you maybe get enough to satisfy, um, like maybe you're not gonna saturate muscle stores, but I mean, it is, it's not analogous to creatine, but it seems to be at least in supplemental form-
- PAPeter Attia
And this is something you inject sub-Q daily?
- DEDerek
Depending on the volume, 'cause it is, depending where you get it, could be 200 milligrams a milliliter, 500 a milliliter, and you can only put so much oil sub-Q or water, sorry, it's water-based sub-Q, before you s- have lumps. So even though it's more easily absorbed, it's still not something you wanna be injecting milliliters of.
- PAPeter Attia
Yeah.
- DEDerek
Like, typically sub-Q shots you want-
- PAPeter Attia
So are we back in the same problem of like, where are people getting this stuff?
- DEDerek
Typically compounding pharmacies or online, or they're making it themselves 'cause it is just an amino acid that you could just buy anyways. So home brew sometimes. But the reason they're injecting it typically is because-
- PAPeter Attia
Wait, home brew. How are they sterilizing the water and-
- DEDerek
I'm not g- [laughs] I'm not a chemist who's gonna explain really how you would do it, but it's the same process by which you would make your underground steroids presumably. So it's like-
- PAPeter Attia
Oh yeah. I mean, in other words, this is a bad idea.
- DEDerek
Yeah, yeah, yeah. Maybe.
- PAPeter Attia
Yeah, this is an awful idea.
- DEDerek
Unless you know what you're doing, 'cause some of them are like pretty, I don't know, intelligent, but I still wouldn't risk it even if I had the instruction manual personally.
- PAPeter Attia
Yeah.
- DEDerek
So in general, though, there is pharmaceutical, not grade, but like compounded versions that are made in an environment that's been at least fact-checked depending on the rigor of the pharmacy in question, of course, 'cause you've done many, uh, deep dives into compounding.
- PAPeter Attia
Yeah.
- DEDerek
Which I recommend people check out.
- PAPeter Attia
Yeah, we did a, I think we did an AMA where we covered the, the, the ins and outs of compounding. And even with compounding pharmacies, there have been enormous breaches of, um, of good manufacturing processes.
- DEDerek
Hmm.
- PAPeter Attia
And that results in contaminations of legitimate FDA-approved molecules like corticosteroids that have led to literally thousands of deaths. So, you know, it's one thing when people are compounding things without good manufacturing process that you'll take orally 'cause the gut is a lot more forgiving.
- DEDerek
Yeah.
- PAPeter Attia
Um, but the moment you start talking about things that are injectable and now you are injecting something in yourself that's dirty, you know, that could be a huge compromise. So yeah. Anyway, I, I, I, uh, I, I hope there are ways for people to vet that stuff.
- 2:23:57 – 2:31:17
Potential remedies for individuals experiencing metabolic dysfunction due to hypercortisolemia
- PAPeter Attia
One of the clinical scenarios that I, I see a lot of that I think plays a significant role in, um, the state of overnutrition, right? So, y- you know, again, I've talked about this. When I look at somebody, I wanna know these three things really quickly, right? Are you overnourished or undernourished or adequately nourished? Are you adequately muscled or undermuscled? Uh, are you metabolically healthy or not? Um, and depending on where you fall in that matrix, like you have to decide whether calories need to stay the same, up, or go down. Now, o- one of the scenarios that is m- I think most clinically vexing is the person who is, uh, overnourished, typically metabolically unhealthy, typically undermuscled. So that's a pretty common phenotype, right?
- DEDerek
Mm-hmm.
- PAPeter Attia
You're a little too fat, you don't have enough muscle, and you're not metabolically healthy. Um, and a big part of the driver is the, uh, uh, basically the hypercortisolemia that accompanies sympathetic overdrive.
- DEDerek
Mm-hmm.
- PAPeter Attia
So an individual that is under so much stress, chronic stress, um, that you basically can't stop the glucocorticoids from chronically being catabolic to lean tissue and anabolic to fat tissue.
- DEDerek
Hmm.
- PAPeter Attia
Um, and you know, when you think about all the other endocrine scenarios, like we have ways to kind of manipulate them. This one we don't really, right? So, you know, you, there are certain things we can do. You can use ashwagandha. You can use phosphatidylserine. Um, they certainly help with sleep in that setting, but what, what... I mean, do you know anything or do you have any insights into ways to kind of manipulate that person's physiology in addition to pulling the important, the big three important levers around nutrition, sleep, and, um, and obviously exercise?
- DEDerek
Yeah. And by the way, the alpha-2 receptor antagonists yohimbine and alpha yohimbine, which is a bit better of a drug in my opinion, are definitely not the drugs you wanna take if you're in the hypercortisolemia [laughs] -
- PAPeter Attia
That's right
- DEDerek
... you know.
- PAPeter Attia
And that, that's what made me think of it is when you brought them up, I'm like, well, that's actually producing a phenotype that a lot-
- DEDerek
Yeah
- PAPeter Attia
... of people are in chronically.
- DEDerek
Yeah. Some people, the use case ... Again, it's not like it's indicated or anything, but some people get a significantly better appetite suppression effect out of those particular drugs, too, than something else. That might be where you would look. But anyway, that aside, as far as actual anti-catabolic action, the most potent thing I'm aware of is actually anabolics. There are certain ones that are more potent at antagonizing the glucocorticoid receptor and actually compete with glucocorticoids for binding, and that's where they get their anti-catabolic action in a deficit. So something like oxandrolone, not that you can get it now, which we could talk about. But [laughs] that in, like, burn victims, it is literally indicated for antagonizing the heightened cortisol, you know, glucocorticoid response that you get from being in that state. So it is one of the most potent anti-catabolic drugs.
- PAPeter Attia
Yeah, so what, what, what happened there? Oxandrolone was also ... Was oxandrolone scheduled, des- uh, it just banned altogether? What's the status of it?
- DEDerek
So my understanding, and I may be not entirely correct, but it was FDA-approved for-
- PAPeter Attia
Many indications.
- DEDerek
Yep.
- PAPeter Attia
Yep.
- DEDerek
And then basically the FDA determined based on, and this seemed like kind of a nonsense thing, but, uh, a meeting in the '80s where they determined that anabolics, in particular Anavar by extension, had no efficacy anymore, essentially. And for whatever reason, they determined that that decision back then ... If you go far back enough, you can find studies where they're like, "Anabolic steroids aren't performance-enhancing." And it's, like, obviously nonsense, but at that time, that was what the literature available showed. And it almost seems like they're leaning ... They're, you know, they're leaning on some of that in order to justify pulling it. We don't think it is useful for all of these approvals anymore. And then there's pressure from that for all of these companies that have generic-approved versions of it to subsequently pull it as well. What motivated that ex-
- PAPeter Attia
I'm sorry, so the FDA pulls Anavar, which is the branded version-
- DEDerek
Sorry
- PAPeter Attia
... of oxandrolone.
- DEDerek
Yeah, so Anavar is made by a pharmaceutical company, and I'm referring to oxandrolone the chemical, not Anavar.
- PAPeter Attia
Oh.
- DEDerek
So I'm, I'm sp-
- PAPeter Attia
Understood.
- DEDerek
Yeah.
- PAPeter Attia
But they're speaking to the molecule-
- DEDerek
Yeah, yeah
- 2:31:17 – 2:36:12
The cornerstones of body composition improvement remain nutrition and exercise, even in the presence of exogenous testosterone
- PAPeter Attia
listening to this, all roads point back to, like, nothing seems to matter more than what you eat when it comes to body composition. Uh-
- DEDerek
Yeah
- PAPeter Attia
... what you eat and how you exercise, right?
- DEDerek
Oh, for sure. Like, I could-
- PAPeter Attia
Like, all this other stuff is, like, a rounding. I mean, it's like it's 90%, um, exer- uh, exercise, diet, and testosterone. [laughs]
- DEDerek
[laughs]
- PAPeter Attia
And then it's 10% all of the other stuff.
- DEDerek
Yeah. And I think a good note to make, 'cause the last time we spoke, we had talked about, you know, the development of pharmacology and what is leading to the change in physiques as of recent. And I said in order it was, like, drugs and then, uh, diet and then training. I don't even remember what the order was of the last two, but that, you know, it almost doesn't matter when drugs are like that important for achieving the outcome on a Mr. Olympia stage. All but, and this is the caveat that I definitely wanna make clear here if I wasn't in the first one, just in case, what you just said, that 90% of it is this, like you do not achieve even the outcomes from anabolics without the support of a, like, great infrastructure of diet and training and sleep. So as much as it can be a band-aid for shitty, all those things, you will achieve a fraction of the results even on anabolics if those are not in check. Like I've seen ... I've even done it myself, as much as I don't wanna admit, but I've talked about this publicly. When I was younger, I thought, you know, what would it look like if I just did a ... Like, I've seen hyper-responder bodybuilders do fluff workouts and get crazy results. And being the guy who wants to experiment with everything, like maybe I'm just working too hard. Maybe I'll try like the fluff Phil Heath workout I saw or something on YouTube. Turns out it doesn't work for me at all, and I basically wasted, you know, a full cycle of exposure to these compounds to get almost nothing out of it 'cause my training was kind of half-assed. So having that baseline, regardless if you're natural or enhanced, it is the fuel to actually support the recovery that may be at an enhanced level with anabolics, but like it still doesn't exist without these things. So yeah, 100-
- PAPeter Attia
Has someone done the study of testosterone replacement therapy in an, in a non-active individual who doesn't change any behavior and how minimal the changes are?
- DEDerek
Yeah. So the Boston study, which is like the standard graded dose response study that everyone's familiar with, um, that one had from ... He had two different studies that were using 600 milligrams of testosterone. One of them was a graded dose response, and-
- PAPeter Attia
600 a week or every two weeks?
- DEDerek
A week.
- PAPeter Attia
Holy cow.
- DEDerek
So yeah.
- PAPeter Attia
Kind of six x physiologic dose.
- DEDerek
Essentially, yeah.
- PAPeter Attia
Yeah.
- DEDerek
And the other study that I think was done in the '90s was doing 600 milligrams of testosterone versus placebo in a non-training, training, and then also on the testosterone non-training, training individual.
- PAPeter Attia
So a two by two, yeah.
- DEDerek
Yeah. And what they found was that the, obviously the 600 group who trained got the best outcome, but the group that didn't train and took 600 test still had better lean body mass outcomes-
- PAPeter Attia
Than the training placebo group.
- DEDerek
Yeah, which kind of spits in the face of what I just said a little bit. But-
- PAPeter Attia
Although that's 600 milligrams.
- DEDerek
[laughs] 600 is ... Yeah. So as much as-
- PAPeter Attia
You almost need to see that on 100 because-
- DEDerek
Yeah, and you also have to draw it out over the span of a training career. Like, you're not gonna sustain-
- PAPeter Attia
Yeah
- DEDerek
... perpetual muscle growth, and some of that is ultimately when you take steroids for the first time, there is a temporary increase in lean body mass metrics that are essentially, and you could probably speak to this better than me, like unquantifiable by, you know, like standard metrics of measurement to body composition. 'Cause ultimately the way these work is not just through the production of, you know, uh, muscle protein synthesis and contractile tissue. It's also, like, the increased intracellular water that you would not hold otherwise, and the increased blood volume, and increased this. These are things that although they're not contractile, they are still making up your muscle, which is largely water. So even though they do try to account for, like, total body water that is not, you know, like muscle based, you are still some confounding level of, you know ... The drugs actually facilitate this as the desired outcome. So, you know, there's gonna be some of that in the outcome regardless. But I think, you know, it's, it's unquestionable that anabolics, you know, even if you're not training, will produce a level of muscle that is higher than if you had no hormones.
- PAPeter Attia
Yeah.
- DEDerek
Like, that's definitely an outcome. Yeah.
- 2:36:12 – 2:42:31
The importance of approaching health advice found online with a critical eye and a healthy dose of skepticism
- PAPeter Attia
To wrap up, any, any, um, influencers online you're particularly excited about as far as, [laughs] like, just the amount of buffoonery that's going on? Any- anyone that, uh, particularly has you excited? I mean, one of the things you're known for is kind of debunking, uh, the charlatans. You've done a, you've done some legendary work in this, which we'll, we'll link to some of your best videos on this.
- DEDerek
Oh, thanks.
- PAPeter Attia
But, but is there, is there anybody you're looking at now just sort of shaking your head at like w- how is this person fooling so many people?
- DEDerek
Yeah. Um, I guess we've talked about him briefly, Gary Brecka. Seems like he has, he has a lot of good information. Don't get me wrong. I don't wanna turn this into a shitting on him, you know, parade necessarily. But the guy very heavily emphasizes the importance of getting gene testing for, like, a limited amount of SNPs that are ultimately very common to find in general population, and then making wild extrapolated claims from that that assert all of your ailments and problems could be attributed to this. And then he has good information that's general about lifestyle, training, sleep hygiene, but then he'll sprinkle in these, like, aggressive claims about methylation. If you have, you know, you're homozygous for C677T MTHFR, which I am, and a lot of people are-
- PAPeter Attia
Almost everybody is
- DEDerek
... yeah, then you need to be taking this exact blend of methylated B vitamins and this ... And he speaks very articulately, eloquently, confidently, concisely, and it very much gives the impression that this guy knows something you don't know, and you should be following his advice because he ultimately is the one who transformed Dana White's physique too, and Dana White speaks very highly of him. And- I don't know, man. Like, some of the products he sells, it's like he has a $140,000 red light bed. He has, like, uh-
- PAPeter Attia
Does, does that improve methylation?
- DEDerek
Pfft, I don't know. I, I have no idea, to be honest. I, I would assume probably doesn't do a lot of anything, but I haven't even looked into it to see 'cause it just never even occurred to me as something worth looking into. But it seems a bit expensive, you know, objectively. Like, it's, you know, borderline you're in a, like, low-end exotic car territory essentially for a fucking bed that emits light on my face, so I'm a bit skeptical. And then, you know, he has other stuff, but in particular his gene testing. I don't know, man. Like, it's just like, it feels like-
- PAPeter Attia
How much, how much does the testing cost?
- DEDerek
I think it's, like, 600 bucks, so-
- PAPeter Attia
$600 for a gene test?
- DEDerek
Yeah. So it's, like, assessing, for example, if I got a 23andMe and I had my data, I could submit it to Rhonda Patrick or somebody who has one of these, like, automated reports and get something as comprehensive or more so with, you know, no suggestions to buy stuff after that either. Just like straight up, "Here's the interpretation based on everything we know about these SNPs." And it would tell me if I had methylation impairments and-
- PAPeter Attia
I mean, we basically, we do all of those tests as part of a standard blood panel, and it's basically free.
- DEDerek
Yeah, yeah. I've, uh, I know the, the MTHFR stuff is also in your, uh-
- PAPeter Attia
Yeah, it doesn't, doesn't cost anything. So I mean, $600 seems a lot given that-
- DEDerek
That's what I thought
- PAPeter Attia
... you can do a whole genome sequence now, 3 billion base pair. We're not talking SNPs. Whole genome sequence for $300 today.
- DEDerek
Damn. That's crazy. Yeah. Ah, I don't know, man. But then you get his, you know, interpretation of it, which is, you know, it almost feels like he's hoping you have one of the most aggressive methylation impairments so he could point to it and say, "Here's why you feel this way." Like, that feels like what I'm gathering from the content. Or, you know, "Oh, you clearly are a worrier because of your COMT polymorphism here. Like, this is why you are so concerned about, like, little problems that you shouldn't be ruminating over. All you need is some SAMe or whatever." And it's like, I don't think that's ... Like, I feel like even if you are right, you got a needle in a haystack 'cause there is so much that goes into genetics that is beyond these, like, maybe common SNPs that have some impact. Like, for example, if I'm the most methylation impaired, sure, I'll look at betaine or whatever to lower my homocysteine, like, totally reasonable. But, like, don't assert it's the root of my, you know, everything that's wrong with me. Or, I don't know, like, he highlights it as ... It, it just, like, comes across a little bit disingenuous to me, and I really do wonder how much of it is him perhaps deluding himself, 'cause he speaks so confidently it's hard to believe he's this good of an actor, or just genuinely doesn't know, which I think is unlikely. But I mean, like, he goes on the biggest podcast in the world and spits, you know, the complete misinformation, says that T4 is methylated in the gut to T3 and, like, all this-
- PAPeter Attia
What?
- DEDerek
Yeah. [laughs] So if, if you have a gene mutation, if, or if your MTHFR is messed up, like, you will not convert T4 to T3, and that's why you might have hypothyroidism. Like, that was an assertion made recently on Joe's podcast, which is pretty fucking wild to me 'cause Joe is actually hypothyroid and has been for a long time. So you're basically appealing to some, like, actual medical condition he has, saying you have the answer, and it's your, like, cheek swab thing, and it's like, I'm highly doubtful that's the case, and I'm nearly certain that methylation is not the thing that converts T4 to T3.
- PAPeter Attia
It, it absolutely most certainly is not. It's a, a series of enzymes called deiodinases that make those conversions, and, um-
- DEDerek
Yeah
- PAPeter Attia
... that, to my knowledge, has nothing to do with your MTHFR gene.
- DEDerek
Yeah, Chris Masterjohn had a really good video recently that kinda, like, summarized it all, and, um, I'd, I would recommend people check out his stuff if you wanna know anything about methylation. You've had him on before.
- PAPeter Attia
Yeah, I've had Chris on the podcast. Um-
- DEDerek
Super intensive and great podcast, by the way.
- PAPeter Attia
Yeah.
- DEDerek
Really enjoyed that one.
- PAPeter Attia
So we'll, we'll, we'll link to Chris's, uh, discussion on that.
- DEDerek
Yeah.
Episode duration: 2:48:55
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