Dr. Rhonda Patrick: In your opinion, like let's say someone is in the deficient range of vitamin D, they have inadequate magnesium, perhaps their zinc is, maybe okay or in the inadequate range. Would getting to that sufficient status really move the needle with respect to like testosterone?

Derek: I think if you were on the low end of the reference range or literally hypogonadal and you were clinically low or deficient for those depending if it's all three or not because obviously there would be an additive effect.

Dr. Rhonda Patrick: Most of them are at least vitamin D and magnesium pretty commonly deficient.

Derek: Yeah, I would say you're looking at a potential incremental difference of 100 to 150 total T. It kind of depends on the person, of course. I've seen a more robust response in some studies, but I also don't want to overexaggerate the expectations. It is meaningful, and some of it can't be directly measured either. We're talking about the total T number, but how do you know how much deficient vitamin D is impacting your ability to use it correctly? And then, even if you had sufficient vitamin D, there is magnesium's impact on all that and the DNA interactions and whatnot. You would be speculating at best. And then there are some other, more tangential supplements that are not as obvious no-brainers. They're helpful, but they're facilitating mechanisms. They're not like a vitamin you need almost regardless of what your test levels were.

Dr. Rhonda Patrick: Yeah, I'd love to talk about those. you hear some of these herbal supplements and like some of the ashwagandha fenugreek with Tongkat Ali let's dive into that like are they effective which ones are effective which ones are hype.

Derek: Yeah, I think one that would be worth mentioning, although the literature isn't super robust, is boron. It potentially has a suppressive effect on SHBG levels. There's some literature that looks promising, but I wouldn't hang my hat on it and say it's guaranteed to suppress your SHBG from the high end of the reference range to something much better. It may. It does seem to work for some people, and, in general, it can be a supporting adjunct. It's not something you typically get through your diet in significant quantities. Often, it will come in a multivitamin, but the quantity that moves the needle for SHBG, I believe, is 6 to 12 milligrams. It can be meaningful for liberating free testosterone, not for producing more total T. The other one that's probably worth mentioning is ashwagandha, specifically an extract standardized to a sufficient quantity of withanolides, not just your standard run-of-the-mill generic ashwagandha. You want to look for a patented form, ideally Sensoril or KSM-66. These are patented forms of ashwagandha standardized to a target yield, so you know that what you're getting is what you're supposed to be getting rather than relying on certificates of analysis from China for a generic extract.

Dr. Rhonda Patrick: What was that compound they're standardized to again.

Derek: Withanolides?

Dr. Rhonda Patrick: Okay.

Derek: It'll show right on the label. It will say something like, "Ashwagandha, standardized to X percent withanolides." KSM-66 is 5%; Sensoril is 10%. The reason you would pick one or the other is the total dose. You could use fewer milligrams of Sensoril because it has more withanolides per milligram in your product, but they're both impactful.

Dr. Rhonda Patrick: Impactful is that the active compound that affects testosterone or.

Derek: It seems to be and when I say testosterone it's like the indirect effect via suppressing cortisol seemingly and kind of like the stress response manipulations that it can induce which are favorable for people who are anxious who have very stressful lifestyles who could benefit from it but it is not a catch-all supplement that will benefit everyone and some people it will push them into anhedonia territory which is like a numbing of emotion. So, you don't want to.

Dr. Rhonda Patrick: Really.

Derek: Yeah. If you overdo it will like literally suppress your stress response so significantly that everything's just like black and white.

Dr. Rhonda Patrick: So, what's a dose that would be considered overdoing it? And what's a dose that would maybe be effective for suppressing the cortisol response and indirectly affecting testosterone by not having the cortisol decreasing the testosterone?

Derek: Like I would go with the clinically supported dose for something that's efficacious. I wouldn't necessarily suggest somebody take something that's lower than what I've seen to actually work, but in general, it seems to be a cumulative effect over time. Maybe there are some people who might push you over the edge sooner and like certainly it's something to be cautious of and be aware of as a disclaimer before you jump on any testosterone augmenting supplements. Just be aware of the mechanism of how it works based on your own individual biochemistry because this is not something like a vitamin D that you can just sequester into subcutaneous fat and just like get rid of at some point. It's like it could impact your mood regulation quite significantly for a bit depending on like what your neurotransmitter balances at baseline. If you are already borderline like emotionally numb as a person and you take ashwagandha like you might literally like cease to care about anything for all I know.

Dr. Rhonda Patrick: That sounds awful. Yeah, but for someone who is more of an anxious phenotype like.

Derek: I think 600 milligrams is the dose, but double-check that because I might be misremembering. I'm pretty sure. And that is seemingly impactful to the tune of upwards of another 100 points. I could be misremembering exactly, but I think it's pretty reliably in the triple digits for those who can benefit from it. For some people, it's a game-changing supplement that improves their quality of life outside of its testosterone-enhancing capacity. Some people deal with a lot of stress and need that extra resilience or suppression of how much it affects their mental state. Some people can't even get to sleep because they're ruminating and constantly anxious. Having that suppressed stress response can be very beneficial. On top of that, it improves their sleep and also improves their testosterone through the reduction of glucocorticoid responses. It works for sure. The literature seems sound on it. Some of it is funded by companies that have the patented extract, so be aware of that. But at least from what I've seen anecdotally in blood work, it seems to work. Tongkat Ali is another very notable one. It works through a different mechanism. How it works seems to be a bit more speculative, but it potentially does a few things. One is minor SERM activity, and this is more speculative. SERM means selective estrogen receptor modulator: something that binds to estrogen receptors and either positively or negatively modulates them in selective tissues. There are certain tissues where selectively inhibiting certain hormones would be more favorable, versus others where it would be detrimental. You wouldn't want to inhibit estrogen's activity in bone, for example, because that would cause bone degradation. Depending on the person, inhibition at the hypothalamus may help increase testosterone via inhibition of that feedback loop. I don't necessarily think it is a SERM. That's just a tertiary potential mechanism, and it is speculative. The main mechanisms people seem to agree on are suppression of SHBG to some extent and upregulation of steroidogenesis intratesticularly. Locally, I believe it upregulates steroidogenic acute regulatory protein, which incorporates cholesterol into the mitochondria to undergo the enzymatic cleavage sequences that result in testosterone production. It seems to help upregulate the process that enzymatically produces testosterone locally. That seems to work well for individuals who have high SHBG levels or potentially higher estrogen levels than are otherwise fixable through basic lifestyle changes. Everyone has their own proportion of metabolism at the end of the day. It's not always going to be optimal, even if you otherwise have a great diet and lifestyle. I think it's for people for whom everything looks adequate on paper but whose SHBG might be a bit high, or who could use a little boost. It seems to work to the tune of 100 to 200 nanograms per deciliter for some people, depending on how potent a standardized extract you get. You want one that is HPLC-tested for eurycomanone. That's the active ingredient in Tongkat Ali that has the bioactive effect you're looking for. Many Tongkat Ali supplements just say "Tongkat Ali," or "Tongkat Ali 100-to-1" or "10-to-1." From what I understand, those are kind of meaningless numbers. You're not going to get a 200-to-1 version of Tongkat Ali, and even if you did, there's no indication that there's any eurycomanone in it. Similar to ashwagandha, you want something that says how much of the literal ingredient that does what you're looking for is in it, with a third-party test to verify it.

Dr. Rhonda Patrick: And what was that ingredient called again?

Derek: Eurycomanone.

Dr. Rhonda Patrick: Got it.

Derek: E U R Y A C O M A N O N E, I think.

Dr. Rhonda Patrick: Now, how does Tongkat Ali compared to like boron? Is it sounds like for men it might be like you're getting a bigger bang because it's doing it's working in two different ways.

Derek: Yeah, it's a good question. Boron is a mineral. Mechanistically, I wouldn't be able to say for certain what the difference is or how they affect the SHBG binding complex. I might misremember, and I don't want to misspeak.

Dr. Rhonda Patrick: Okay. Well, yeah, it's just kind of interesting. But would Tongkat Ali work in women as well, just through SHBG? Or maybe boron? I don't know which. Just off topic here, boron has also been thought to potentially be a longevity molecule. There's some evidence that boron may be involved in improving aging. So when you said boron, I thought, "Oh, really? That sounds interesting."

Derek: Yeah. I feel like that's almost like a lower-hanging fruit thing cuz it's just typically part of a multivitamin that may just not be dosed high enough and you can just like stack on top and see if it has an incremental decrease to SHBG. And then the Tongkat is like more of a speculative one that you don't want to just like take until you've exhausted some of the other options, but is like the more exotic kind of like hammer that you might want to take to the situation if it's like your last resort before I've tried everything. My lifestyle's perfect. My diet's dialed, my micronutrients are accounted for, my sleep is good, I don't drink, I don't smoke, and my total T is still inadequate and I don't feel that great. Should I try some of this like one of these exotic things that seems to have a reasonable safety profile and like an efficacious, impact in men and young healthy men at that like there are literature showing the effects in young healthy men, not just like age- related like declined men. So notable. Now, as far as its impact on women, I would think mechanistically it would do a similar thing, but like I don't have a study I could point to that says it's the same. So, I would think, but I don't know.

Dr. Rhonda Patrick: Are there any others? I hear about, the fenugreek and then the some of these like D-aspartic acid or are there any others that are notable or would you say more hype?

Derek: I think a lot of those have been disproven like tribulus, D-aspartic acid, fenugreek. One that is notable that might do something is shilajit. If you get a high quality shilajit, it may provide enough like the actual capacity of your organ to respond to hormones is partly conditional on its ability to tolerate stress and reactive oxygen species locally too. So if you have more than you can deal with and you introduce a potent antioxidant to the equation, you may be able to like attenuate and neutralize the kind of like decrement to performance and kind of like net out more local hormone yield. So, shilajit seems to be impactful on intratesticular antioxidant activity, but I wouldn't it's another one that requires like careful sourcing and it's also one that's like more speculative and indirect cuz like there are probably better ways to manage your oxidant like your antioxidant profile I would think. So.

Dr. Rhonda Patrick: So your top four supplements for testosterone would be.

Derek: Zinc, magnesium, vitamin D. Not in order, just the top three, I would say. And then, for impact, I would probably say Tongkat Ali, but boron would be my safer next choice based on its safety profile.