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In Search Of Insight Podcast

In Search Of Insight | A Nootropics Depot Podcast

INTRODUCING THE NOOTROPICS DEPOT PODCAST

IN SEARCH OF INSIGHT

In Search Of Insight | A Nootropics Depot Podcast

INTRODUCING THE NOOTROPICS DEPOT PODCAST

IN SEARCH OF INSIGHT

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#007 | Are Men and Women Different? Should Men and Women Treat Supplements Differently?

Summary

In Search Of Insight Episode #007

On this episode of In search of Insight, we dive into the fascinating world of hormones. We pay particular attention to female hormones, and how women can use their hormonal fluctuations throughout the month to their advantage! If you would like to get a brief summary of what Erika and Emiel discuss in this episode, then keep reading because we’ve condensed the podcast down into a brief summary.

Estrogens

A big portion of this podcast is about estrogens, a class of hormones which is abundantly present in both men and women. There are four different types of estrogens, however, in this episode we pay particular attention to one of the main estrogens, estradiol.

Estrogens have major effects on multiple critical systems throughout the body and brain. For example, estrogens control bone remineralization, blood flow, neurotransmitter balances and overall cognitive function.

The importance of the estrogens is further highlighted during menopause and in post-menopausal women. This is due to the fact that women loose most of the granulosa cells in their ovaries during menopause. The granulosa cells are highly important as they contain a large amount of aromatase, an enzyme which converts testosterone to estrogen. Since the majority of estrogen in women is derived from testosterone, it means a loss in granulosa cells leads to a massive decrease in estrogen production. In a lot of women, this estrogen deficiency then leads to issues with mood, blood flow, bone health and overall cognitive function.

One of the reasons a reduction in estrogens can cause these negative effects, is because under normal circumstances, estrogen is a major neuromodulator. For example, estrogen can upregulate tyrosine hydroxylase, increase dopamine receptor density, decrease dopamine reuptake, upregulate tryptophan hydroxylase and increase overall serotonin levels. These important cognitive effects of estrogen are clearly visible during the menstrual cycle.

The Menstrual Cycle

In the podcast, we discuss the following image of the menstrual cycle in great detail:

Figure 1. The Menstrual Cycle

While looking at the above image, it can be seen that estrogen levels spike in the late follicular phase. This peak in estrogen levels also often results in a peak in mood and cognitive function. This can be traced back to estrogen's neuromodulatory function.

It’s also clear that progesterone levels peak significantly during the luteal phase. This brings with it quite a few problems. Progesterone is rapidly converted into allopregnanolone, which is a powerful neurosteroid. Allopregnenolone binds to the benzodiazepine site of the GABA-A receptor and through this pathway, causes an initial bout of pleasant relaxation. However, allopregnanolone also increases alpha-4 GABA subunit density, which does not respond to benzodiazepine site stimulation. The net result is that after 24 hours of allopregnanolone exposure, the relaxing effects fade and directly opposing effects take its place. This can lead to a short period of irritability.
The irritability then reverses, as long term exposure to allopregnanolone regains the relaxing effects. However, this also causes a big problem in the late luteal phase when progesterone levels plummet. This then causes a withdrawal type effect from the allopregnanolone, which can lead to major negative mood effects.

The Aging Hormone System

We also go quite in depth about how the hormonal landscape changes as we age. This hormonal aging can cause major issues for both men and women. For men, testosterone levels gradually decrease as we age, which can lead to issues with mood, energy levels, physical strength and libido.

For women, the changes in hormonal landscape are a little bit more extreme as age advances, leading to major reductions in both estrogen and testosterone levels. Interestingly enough though, due to the reductions seen in estrogen levels, the male and female hormonal profile actually starts to converge as we age.

Fertility

Another topic we cover on this podcast is female fertility and the aging ovaries. As we experience major socio-economic changes, and we finally see more equal opportunities for women in education and the workplace, many women are choosing to have children later in life. This can be somewhat problematic as fertility gradually declines in our 30’s. However, we discuss some strategies of how to ensure healthier ovarian aging, which may help prolong fertility.

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#006 | Joe Rogan’s Favorite Testosterone Supplements | Does Tongkat Ali Work? Is Fadogia Agrestis Toxic?

Podcast Transcript

Erika

Hi, and welcome to In Search of Insight, Nootropics Depot's monthly podcast. I'm your host, Erika or u/NootropicsDepotGuru on Reddit. And sitting next to me is our product specialist, Emiel.

Emiel

Hey, everyone. And you might know me as u/Pretty-Chill on Reddit.

Erika

So today, Emiel and I are diving into an exciting conversation all about testosterone supplements. We're going to be talking about tongkat ali. We're going to be talking about cistanche tubulosa and fadogia agrestis. And for those of you who are interested in testosterone supplementation, you have already heard these names floating around on the Internet, on bodybuilding websites, tips for your workouts, and how to promote mood and endurance. And so we're going to get really, really deep into the science behind these testosterone supplements, why you should consider taking some of them, and why you should think twice before taking others of them. Hint, hint. It's fadogia agrestis.

Emiel

And on that note, we'll be talking about some controversial topics on this podcast, one of those being testosterone supplementation in women and other controversial topic, of course, being Joe Rogan, who's in the title of this podcast. And boy, that really stirred up some controversy even before we released it.

Erika

Ruffled some feathers, shall we say?

Emiel

Yeah. Seems like a lot of you guys don't really like Joe Rogan, which is completely understandable. He's a very controversial person. He has recently said some stuff that is, frankly, flat-out dangerous. But he also has one of the biggest platforms where we can learn for free about supplements. And I think because of Joe Rogan's podcast, we are all a lot more aware of supplements and what they can do. And he's brought on some really important people like Andrew Huberman, Rhonda Patrick, and a whole host of other giants in our industry. So it's a really good platform, and we feel like we should be interacting with it a little bit because in this podcast with Andrew Huberman and Joe Rogan, some very interesting things were said, but some controversial and maybe not entirely safe recommendations were made. So we'll be touching on that a little bit as well.

Erika

We also wanted to let you know that to set the record straight, we're not associated with Joe Rogan in any way, personally or professionally. But we did want to basically open up the conversation about what other people in the supplement industry are talking about when it comes to testosterone supplementation. And we wanted to give you the valuable and essential information, scientifically-backed information, so that you're informed about the best way to approach testosterone supplementation for yourself and to consider what to look out for when shopping for testosterone supplements on the market in general. But specifically, what Nootropics Depots testosterone supplements might be able to do for you.

Emiel

Yeah. And that will really be the focus here. So we want to keep it on that. Joe Rogan is coming in here because we just have to address it.

Erika

Coming in here in topic, but not physically coming into the podcast. So don't worry.

Emiel

Yeah, it's just going to be us like it always is. But we'll be talking a little bit about Joe Rogan and Andrew Huberman more specifically actually, because he is the one who made some of these recommendations. And actually we were selling tongkat ali long before this podcast happened. And it's always been on our radar. I've actually been taking tongkat ali probably for about seven years or so on and off here and there. So I was really excited for us to get a tongkat ali supplement. And when we got it a few months or maybe even a year or two later, this podcast came out and our sales just shot through the roof, like 900% increase on sales for tongkat ali. And we had no idea what was causing this. When something like that happens oftentimes, you can trace it to a single event. When such a big increase happens, it doesn't feel very organic. So we looked around and we found this podcast, and it's a really interesting podcast. So this is also a bit of a response to that podcast and maybe a continuation and going a little bit deeper because the podcast, it's a three hour long podcast, and the part about tongkat ali is really only like a five-minute section of it. The rest is interesting and entertaining to listen to. But we want to go a little bit more in depth about what exactly tongkat ali is, what exactly fadogia agrestis is, and why you probably don't really actually want to be taking fadogia agrestis. And I have to say, Andrew Huberman, if you are listening, I respect your work, but I don't really understand your fadogia agrestis recommendation because you are very strong on human clinical research and all of the things you recommend. Like recently, you recommended Apigenin for sleep, Magnesium Threonate for sleep, and theanine for sleep. And there's a lot of human research on these things and human research on these things for these purposes. Fadogia agrestis though as far as I can tell, there are no human clinical trials on it. And that's a big problem because we're not entirely sure of it's safety profile.

Erika

And this brings us to a really important point in general that I feel I need to share right now in the podcast, which is that a lot of you who are listening to the podcast have been following Nootropics Depot for years, and maybe some of you are new to our brand. But what we want you to know and we want to say to you directly is that the quality control standards of the supplement industry are quite horrible. And we at Nootropics Depot believe that this needs to change. And so though there aren't a ton of issues in the world that we can directly change, in effect, as individuals, we at Nootropics Depot feel very strongly about providing safe and effective supplements and making that change every single day. And this is a part of the reason why we're addressing fadogia agrestis specifically because of this lack of research and also lack of safety.

Emiel

Absolutely. And really honestly, a lack of evidence for any sort of effects that are being discussed on this on the Joe Rogan podcast. And the interesting thing is there are some other things like fadogia agrestis that do the same thing, but actually have human clinical trials done on them, some human evidence for safety and just a much longer history of use. And one of those things is cistanche. So we'll talk about that.

Erika

So, Emiel, what is tongkat ali?

Emiel

Okay, so a little bit of background here. I grew up in Malaysia, and tongkat ali is a Malaysian root. The plant is actually called Eurycoma longifolia. It's also known as long Jack or tongkat ali. And it's really popular in Malaysia. I remember as a little kid driving around and seeing these billboards with old men on them with canes and these little sachets of tongkat ali-infused coffee. I was always curious what it was later in life, I got into this and now I'm very aware of what it was. So that's kind of a fascinating thing for me. And tongkat ali has always been really interesting. And this is something Andrew Huberman actually mentioned on the Joe Rogan Experience podcast, is that other countries are much more advanced at hormonal regulation using plant substances. It's something we are way behind in the Western world. And clearly, if you look at something like tongkat ali, which has been used for maybe hundreds of years in Malaysia or in Southeast Asia in general, we are a little bit behind because we've only really started to discover tongkat ali in the last decade, maybe two decades, and especially in the last year or two, tongkat ali has become really famous. But anyways, the plant Eurycoma longifolia, the roots of it contain a plethora of different compounds, different peptides, and proteins and carbohydrates and starches, and things like that. But what we're really interested in is eurycomanone, and that's the compound we'll be talking about extensively during this podcast.

Erika

And that's also the compound that we standardize our Nootropics Depot, tongkat ali extracts for, right?

Emiel

Absolutely. So we have two different tongkat alis. We have a 2% eurycomanone, and then a 10% eurycomanone extract. So two different purposes. And I guess we can get into the differences between those real quick here, too.

Erika

Absolutely. I personally have been taking both the 2% and the 10 % tongkat ali extracts because I was really curious for myself, as a woman, to take these extracts because I know that they're supposed to support testosterone. Right. And testosterone in women can sound like "OOH controversial" and maybe even a scary conversation to even start. But because I'm interested and I'm open and I'm excited to try out some different supplements for myself, and I also have experienced a lot of benefits from some testosterone supporting supplements, prior to taking these, I was like, I'm game, let's go. I'm curious to see how these two different extracts compare. And in my experience, the 2% extract was really interesting. I took this one first and just by itself in the morning on an empty stomach, no other supplements, no caffeine interactions, just 2% tongkat ali extract all by itself. One thing I noticed is it took about 30, 35 minutes to start to kick in for me to start to feel those perceptible benefits. And then once it did, there was maybe about ten to 15 minutes of slight nausea. And I felt really tired for about 15 to 20 minutes along with that nausea. I was thinking, this is interesting. Okay. And then at that 20 minutes mark or so, the nausea went away and the tiredness went away. And then I felt this kind of sense of general calm. There was somewhat of a nootropic-like cognition supporting element to it, but kind of hard to put my finger on.

Emiel

And I would say this is a similar experience for me with the 2%. And something I hear from a lot of you guys, too is that the 2% is a little bit more calming, it's a little bit more cognitively noticeable and perceptible. And it still has some of those testosterone effects and confidence effects and muscle building effects overall. But it's an interesting one. And it's interesting because when we standardize for different compounds in an extract, we basically delete other stuff and concentrate the main active compound. In this case, eurycomanone. So what we're doing is we are stripping away other compounds slowly and concentrating eurycomanone. And you can imagine with the 2%, when we concentrate for the eurycomanone there, we don't have to delete as much other stuff. So it's 2% eurycomanone likely in a matrix of other supporting bioactive compounds that drastically changes the effects.

Erika

And one way to describe this, which I've learned from Emiel, is that the 2% has a more full-spectrum effect.

Emiel

Correct, absolutely. And when you move up to the 10%, it becomes more selective. So with the 10%, you get more of those effects of eurycomanone without some of the other stuff in tongkat ali. So, Erika, what did you experience on the 10%?

Erika

Well, it's pretty funny because after taking the 2%, I was like, this is kind of cool, but I'm not sure if it's that much of a standout product that I would want to take every day unless I really wanted it for the longer term testosterone benefits. On the other hand, when I took the 10% tongkat ali extract, oh, boy, I was really excited by this. I was not only excited by it, I was motivated by it. I was inspired by it. I felt honestly way more sarcastic and aggressive and sort of, I don't know, would antagonistic be the right word to describe it?

Emiel

I would say masculine energy because...

Erika

If masculine energy exists, that is what I felt from the tongkat ali 10% extract. And it was significant and it was really noticeable. And that effect lasted actually throughout the day. I couldn't necessarily feel the onset like I did with the 2% because I find the 10% has less physical, like, sensation effects. But the attitude and sort of the mood effects were very, very obvious to me as soon as it started kicking in. I would say probably about 45 minutes after taking it, but I didn't feel it come up. It was just all of a sudden I was like, boom, this is what's happening. This is what I need to do. Get out of my way. Let's go.

Emiel

And this is honestly why I say a little bit of masculine energy, because I spend a lot of time with Erika working on these podcasts, and she hadn't told me that she took 10%. And I was thinking something is a little bit off with Erika. She's so much more.

Erika

No, not off, on!

Emiel

Yeah, on. But for me, at first it was a little bit I had to get used to. You were so much more direct and confident in telling me what to do, and this is what you don't do, and we got to do this. It was actually a nice experience once I warmed up to it because you were so much more confident. And I noticed the same thing for myself. I recently jumped on a meeting right after taking some tongkat ali, and I was fired up. I really had to tone things down because I just had so much more confidence. And I think this is something that everyone experiences with tongkat ali.

Erika

And it's specifically the 10% extract that we have.

Emiel

Yes. And this is actually why I personally like the 2% more, because the 2%, I get that similar aggressive kind of mindset and more confidence and more in your face attitude, but it's toned down and it's nice and relaxed, like what you were saying. It mellows you out a little bit more, but you can still notice that confidence, whereas with the 10% you have much less of that calming effect. So the aggression and the confidence comes through a lot more. An interesting thing to note, though, and this is where we immediately jumped into some controversial material, because you just heard a woman talk about taking a testosterone supplement and having a very great experience with it. And if I look over at Erika right now, she's not standing next to me with a giant beard or a mustache. There is no facial hair. She doesn't have an Adam's Apple. This is not how testosterone works in women. And women need testosterone as well. And I think Erika can probably attest to that fact.

Erika

Sure. I've taken a handful of supplements from Nootropics Depot that are testosterone-supporting supplements.

Emiel

Which ones, by the way?

Erika

The one that I've been taking for a while is cistanche, the cistanche tablets which I really, really like. I find that to be particularly calming, and I really like the cognitive benefits of that. I'm now taking and probably will continue to take the tongkat ali 10% because I just can't get over how much more effective I feel in general.

Emiel

And both of us took it before this podcast, by the way. So if you do notice actually in our voices and in our demeanor that we're a little bit more confident than direct, it probably actually is the tongkat ali, and it has a pretty profound effect. I do have a theory, though, because Erika and I both take cistanche daily, but we don't take tongkat ali daily. So I've had a little bit more of an experiment with tongkat ali. I took just tongkat ali by itself, and then I took tongkat ali and cistanche by itself. And then one time I even took cistanche, tongkat ali, DHEA and pregnenalone, Shilajit and zinc, creatine as well. I felt great on that.

Erika

That's like the motherload or perhaps the father-load.

Emiel

Yeah, maybe that was a little bit too intense. But what I've noticed now is I'm just taking cistanche every day. And now when I add some tongkat ali, it's like hitting the boost button. Everything is working fine and I'm nice and confident. And now when I add tongkat ali on top of my chronically supplemented cistanche, it just rocks it up to another level. So we'll talk about this a little bit more, but I think this is a really interesting way in which to utilize tongkat ali.

Erika

Absolutely. So before we get into all that juicy information about what to stack with tongkat ali or how you can incorporate tongkat ali into your everyday testosterone supplementation, I'm really curious to learn a little bit more about what eurycomanone does specifically because I know there are some of you out there who want that nitty-gritty mechanism information. So what is eurycomanone doing? What systems in the body does it act on and what are the pathways of its actions?

Emiel

It acts through a pretty complex set of pathways originating in the brain and kind of ending in the testes for men. And for women, it actually ends in the ovaries and in the adrenal glands. So for men, most testosterone is synthesized in the testes, and it's synthesized by cells called Ledig cells. These Ledig cells respond to signals that you get from the hypothalamus. So in the hypothalamus, you have a hormone called gonadotropin-releasing hormone GNRH that stimulates the production of luteinizing hormone LH and FSH, which I always forget exactly what that stands for. Yeah. Follicle stimulating hormone. So luteinizing hormone and follicle stimulating hormone get induced by the release of Gonadotropin releasing hormone from hypothalamus. And the FSH and LH increases happen in the pituitary. Then this LH and FSH from the pituitary stimulates the testes to produce testosterone in these ledig cells. But then there is a negative feedback loop when a lot of testosterone gets produced, there is an enzyme that aromatizes this testosterone, which then turns testosterone into estrogen. And then that estrogen can act on estradiol receptors that are in the hypothalamus and pituitary, and they actually kind of regulate how much testosterone can be produced. So it's a bit of a self-regulating system. We're going in with tongkat ali and we are dysregulating the system allowing more testosterone to be produced kind of overriding that self-regulating off signal. So by that we can achieve in people with normal testosterone levels, we can achieve higher than normal testosterone levels. And in people with slightly lower testosterone levels, we can see a normalization of testosterone levels and maybe even a little bit of an increase. And Andrew Huberman in the Joe Rogan Experience podcast, actually, and I'm not sure if it can get that significant because Andrew Huberman is saying that tongkat ali has been shown to increase testosterone levels by 100 to 200 points, which is a quite large increase. It's not a crazy increase that you might see with other illicit things, but it is quite a big increase. And actually, we have seen some blood tests of people on Reddit and we have seen such large increases, I wouldn't expect such a large increase to happen for everyone. But the takeaway point here is that tongkat ali causes quite a significant increase in testosterone production. And this is where fadogia agrestis also comes in because as you can see, luteinizing hormone is an essential part of the step of increasing testosterone production. And Andrew Huberman is suggesting fadogia agrestis because it significantly upregulates luteinizing hormone levels, which luteinizing hormone levels also control the amount and density of ledig cells and it controls the activity of these ledig cells. So luteinizing hormone is a really important part of the equation here.

Erika

So in theory, the idea of suggesting fadogia agrestis makes sense because it's helping support luteinizing hormone levels, right?

Emiel

Correct. So fadogia agrestis, one of its main effects is that it enhances luteinizing hormone levels. And because the effects of tongkat ali depend quite a bit on this luteinizing hormone upping the luteinizing hormone levels a little bit more with fadogia agrestis causes a synergistic effect between tongkat ali and fadogia agrestis. And the combined effect should in theory, and this hasn't really been verified with human clinical trials or anything, but in theory, it should further enhance the testosterone increases that we see from tongkat ali. So this is why fadogia agrestis is being promoted for this by Andrew Huberman. The interesting thing, though, is there are no human clinical trials on Fadogia. And the animal trials that exist are a little bit conflicting in their safety reports. So one thing on the Joe Rogan experience that is talked about is that fadogia agrestis makes your testicles big. And like Joe Rogan said, who doesn't want big testicles? Well, for one, I don't necessarily want big testicles because it would make sitting a little bit harder but on the other hand, when your testicles are growing that much, it might not be a very good thing. And in these studies, actually, that seems to be the thing that is a little bit questionable. So the increase in testicular size could certainly increase because of this extra luteinizing hormone. And this seems to be the case to a certain degree.

Erika

But I'm curious, is it doing anything effective for testosterone?

Emiel

For sure. It's very effective for testosterone. There is absolutely no question about that. And in these studies, you see massive increases in testosterone, and it's good. Okay. So for that effect, great. The thing that is a little bit concerning is that it also affects a lot of different enzymes and processes within the testes, and it seems to be transiently toxic to the testes and testicular cells.

Erika

Can you be a little more specific? What do you mean by transiently?

Emiel

It means that it isn't permanent. There's no permanent damage that they can see. But after 30 days, there is minor damage and a decrease in function of the testes, which is not good.

Erika

No.

Emiel

After seizing supplementation, this does seem to correct itself, but this is after 30 days in an animal model, and we're not really sure what would happen after a year in the human model. And if your testicular function is down during this year, how good or bad is that?

Erika

So at this point, we're saying not worth the risk.

Emiel

We are saying not worth the risk, and a lot of people are saying not worth the risk. Another thing with fadogia agrestis is, and it was an interesting part of the Joe Rogan experience, too, is that this is a Nigerian shrub. And in our experience, a lot of supplements that are coming from the African continent are much less well understood than their Southeast Asian counterparts or Asian counterparts from China and India, where there's well documented historical use and thousands of years of use and very well documented. And lots of people who are still practicing this and who have brought this knowledge over to the Western world, translated a lot of these texts into English so we can understand it. And then there's a lot of Western studies and studies from all over the world that have proven how these things work and their safety profiles. And there's a lot of human clinical trials. I mean, just think about things like ginseng and ashwagandha and a lot of those types of herbs, very popular ones, very well understood. The herbs from the African continent are extremely interesting, and I really want to dive into those a lot more. One of those is Kanna, something we have carried in the past and will hopefully carry again in the future. A very interesting plant from South Africa. But fadogia agrestis is also from the African continent. The main sources seem to be South Africa, and like Kanna, it's very hard to source high-quality materials in good amounts outside of South Africa or maybe Nigeria. So the stuff we are getting here, we don't really know is it fadogia agrestis? There's been a really large uptick in interest for it. So it probably means some people are slinging some fake Fadogia. So when we consider the full picture, questionable safety and questionable availability and questionable knowledge about how to grow Fadogia, how to properly process Fadogia and those sort of things on a more commercial scale makes it a very tricky product to look into, to source, to sell.

Erika

And to standardize for, I can imagine.

Emiel

And to standardize for it. Yeah. There will be likely issues getting reference standards and things like that. So this is one of the reasons why we are looking into Fadogia, but we've kind of put it on the back burner because it just doesn't seem worth it, especially when there are other options.

Erika

Of course, and tongkat ali being one of the standby options that people have been familiar with and

Emiel

Moreso an option that synergizes with tongkat ali, because that's what fadogia agrestis is for.

Erika

Okay.

Emiel

So tongkat ali will always be there. It's solid. It works really well by itself.

Erika

But we're trying to get to this segue, which I think you were hinting at earlier, which is that there are alternatives to Fadogia that will synergize with tongkat ali, and the one we're going to talk about is cistanche tubulosa.

Emiel

Yes. Because cistanche tubulosa does the exact same thing. It enhances luteinizing hormone levels, but furthermore, it also upregulates all of the testosterone synthesis enzymes that exist in the testes. And some of these are the CYP enzymes. And a lot of these enzymes get upregulated by cistanche. And this is why cistanche is actually a really good standing option for Fadogia. The first reason being that cistanche tubulosa has a very long history of human use in traditional Chinese practices. So we have a lot of evidence that it works, how it works, that it's safe. Furthermore, in the last year or two, there's actually been a few clinical trials, human clinical trials, high quality ones on cistanche, where they also evaluate its safety. And it's safe. So we know it's safe. There's a long history of its use. There's a long history of its cultivation practices and extraction practices and things like that. And there are well-established sourcing options and trade routes and stuff for cistanche. So this makes it a really good option to have when you compare to fadogia agrestis. We have human data, it does pretty much the same thing. It's easy to get and reference standards exist so we can actually test for it and we can standardize it properly and we can be assured of its safety and efficacy, which is always what we want.

Erika

Absolutely. So I'm curious, then, what's the benefit of stacking cistanche and tongkat ali, like, if you were to compare just tongkat ali by itself, versus tongkat ali with cistanche, what else do you gain from cistanche?

Emiel

So what you gain from cistanche is the same thing that you would gain from fadogia agrestis, which is enhanced luteinizing hormone expression. And when you have enhanced luteinizing hormone expression in the context of tongkat ali supplementation, then the testosterone-increasing effects of tongkat ali should go further, which is why Andrew Huberman recommends that you take fadogia agrestis together with tongkat ali. But in our opinion, as we've talked about in-depth now, cistanche is actually the better option here. And in my opinion, it's also the better option because cistanche has a trick up its sleeve. And this trick is that it enhances growth hormone secretions, too. So not only are you getting the muscle building and anabolic effects from the enhanced testosterone levels that you might get from tongkat ali and cistanche in combination, and even just tongkat ali by itself or cistanche by itself, but furthermore, you are getting testosterone and growth hormone. Growth hormone also being very important for muscle building. So in my opinion, this makes cistanche the superior option when compared to Fadogia.

Erika

Well, that's a pretty strong statement. So I think now that we have a really good understanding of the mechanisms and where cistanche and tongkat ali are from and the concerns and the issues with fadogia agrestis, I have a much better understanding of just the benefits of this kind of testosterone supplementation. But I also want to know for everybody out there who's wondering what's going to happen, what would happen if I'm making changes or taking supplements that are affecting my hormones? If I'm a man, how are they going to affect my testosterone versus my estrogen levels? If I'm a woman, how are they going to affect testosterone and estrogen? Are there any other hormones in the mix here that we should be thinking about when it comes to the effects of tongkat ali and cistanche?

Emiel

Yeah, and this is where the whole hormone thing gets very complex. And I would actually recommend some of you go and listen to some of Andrew Huberman's fantastic podcasts that go very in-depth about hormones. Andrew Huberman is a fantastic researcher when it comes to hormones. And he has a lab at Stanford. And actually, in college, I learned a lot about brain development surrounding testosterone. And a lot of this research was from Andrew Huberman. So if you are interested in diving really deep into the hormone thing, look at some of his podcasts, too. But within this podcast, I can go into depth a little bit too. When we are enhancing luteinizing hormone levels, we're actually also enhancing our estrogen levels a little bit too, which is a good thing. We need estrogen. Men need estrogen. Women need estrogen. We don't just want to tank estrogen levels. Tongkat ali does have a slight aromatization effect, so it will prevent some of the testosterone from turning into estrogen, which is part of how it also enhances testosterone production. In addition to actually blocking some of these estradiol receptors that turn off testosterone synthesis. So there is also a strong estrogenic part to this, which is good. We need it. This is part of the process. And when we're looking at that too, a big one is actually prolactin. And we've heard a lot of concerns about "If I'm taking something that enhances testosterone levels, then that must mean I'm also getting more estrogen levels. And because of that, if I'm a man, I might start developing breast tissue." This is actually not something that's super related to estrogen or testosterone. It's actually related to prolactin.

Erika

That comes as a surprise to me because I think I can only speak for myself. But as a person with less knowledge of the hormone systems, I always assumed that estrogen, more estrogen or changing estrogen would have these, quote, estrogenic effects, which I might associate with growing breasts or gaining weight in different places.

Emiel

And estrogen definitely does that. But in men, it seems like prolactin is actually the bigger stimulator of breast tissue.

Erika

So what is prolactin exactly?

Emiel

Well, if you consider the name pro, what?

Erika

Oh, lact, lactose, lactate,

Emiel

Yeah. So what do you think it's mostly doing in women?

Erika

Oh, it's a lactation hormone.

Emiel

Yeah.

Erika

Got you. That makes sense.

Emiel

But it also plays a role in men. And part of it is the ability to ejaculate and to achieve orgasm is related to prolactin. And people with very high prolactin levels may have issues in this area. So dampening prolactin levels can be positive for libido, it can be positive for preventing some of the breast tissue growth in men. And this seems to be the one thing that's often overlooked and especially overlooked in testosterone supplementation. So some people might actually have some issues related to prolactin and tongkat ali might exacerbate this. So I wanted to find a good option for this. And one very common option in some different worlds is that you block or actually, sorry, you don't block. You activate dopamine D2 receptors. And this activation of dopamine D2 receptors blocks prolactin production. So we want something that activates dopamine D2.

Erika

Okay, that makes sense. And this is reminding me of something we spoke about in a previous podcast. I can't remember which one it is, but we were talking about the hormonal changes that women experience throughout their menstrual cycle and the fact that right before the menstrual cycle actually begins, dopamine D2 receptors are activated, which causes mood changes and physical changes and basically prepares the body for menstruation.

Emiel

Correct, yeah. I can't remember what podcast that was in either. But we were talking a little bit about some exotic dancers in that.

Erika

Yeah, definitely. So if you're curious about that, go search on YouTube. It's going to be tagged in our chapters that we have, so exotic dancers related to dopamine D2. Fun facts, but we'll let you do the searching.

Emiel

But let's keep talking about this Dopamine D2, because it's really interesting. And it's interesting. A lot of you are interested in it from a nootropic standpoint, because it will help with motivation and overall cognitive function and things like that. And it helps drop prolactin levels, which can be positive, especially when we are trying to enhance testosterone levels. And we're trying to build muscle and we're trying to build muscle while not growing like flabby, fluffy breast tissue. So one thing you can actually take it looks like is apigenin, which we recently just released, which seems to be one pretty significant Dopamine D2 agonist, which actually is a bit of a surprise to me. I noticed that there is like a smooth, stimulating, relaxing thing going on with apigenin. This seems to kind of be why it acts as a Dopamine D2 agonist. And there's actually a study that is showing chamomile syrup that has some level of apigenin in it is quite effective at lowering prolactin levels. And these researchers thought that this is likely from apigenin because apigenin is a dopamine D2 agonist. So this would be a really interesting compound to actually add to the overall stack. So if you're taking tongkat ali and you're taking cistanche, then maybe also consider adding some apigenin.

Erika

And apigenin would be added specifically to address the prolactin issues that you might experience when taking tongkat ali and cistanche together, so that you get the best benefits for supporting your testosterone levels from tongkat ali and cistanche. And you get less of the maybe the unwanted effects or the less than desirable effects by managing prolactin.

Emiel

Yeah. And in addition to that, testosterone, and we haven't really touched on this yet. Testosterone is also an important one for libido. It's important for male and female libido, and especially later in age. It seems to be very important for female libido.

Erika

Especially around menopause and perimenopause.

Emiel

Absolutely. So actually a new strategy for post menopausal women who are having libido issues is actually to increase testosterone levels slightly. But prolactin is also important for overall libido and achieving orgasm and ejaculation in men. So lowering prolactin levels, in addition to increasing testosterone levels, could have a very broad spectrum libido enhancing effect.

Erika

Wink, wink, if you get our drift.

Emiel

Yes. And actually prolactin is one of the things that prevents men from achieving multiple orgasms. So prolactin increases after an orgasm. So lowering prolactin might prevent some of that from happening, too, for anyone who is really going for the endurance thing.

Erika

Okay, so let me get this straight. Lowering prolactin may have benefits for male orgasms with the potential to increase the chance that you could have multiple orgasms, is that correct?

Emiel

Yes. And actually, I have heard through some of my research that I've been doing that in porn stars, taking a very strong Dopamine D2 agonist is a very popular thing to take before shoots for this exact reason.

Erika

Okay, this makes sense. And now we really have to implore you to go back and find that podcast about exotic dancers because we just touched on the exotic dancers and the benefits of this increase in Dopamine D2 receptor activity right before their menstruation, because it was basically allowing them to reach new heights with their performances. So this makes so much sense now that we're just diving head first into this hormonal conversation why porn stars would be taking these kinds of hormone supplements, because it helps you perform.

Emiel

Absolutely. And for someone who has to be on set for however many hours, this is an important thing to be able to maintain that ability.

Erika

Yeah. The endurance demands are quite extreme.

Emiel

Yes. prolactin. And that's a very extreme case. And they are taking very strong things that lower prolactin, and that's a whole other topic. But when we're looking at it in a more preventative or more supportive thing with supplements, then...

Erika

For all you out there who aren't porn stars.

Emiel

Yeah. And if you are, great, maybe this will work well. So take some Tongkat, cistanche and apigenin because you'll get increases in the good sex hormones like testosterone, and you'll get lower levels of prolactin, which might get in the way there. prolactin, by the way, also seems to underlie some of the effects of PMS symptoms and some of the pain symptoms that women experience during menstruation and some of the mood issues that women experience during menstruation. So in that context, it is also beneficial to lower overall prolactin levels. So Apigenin could work well, there.

Erika

That's exciting and I think now that we're having this conversation, I'm going to put a little mental note for myself just to explore and bioassay apigenin specifically for its benefits surrounding PMS, because I think this is something that we definitely want to talk about in some future podcasts. And I know for women out there who are curious, this is such an important and I think under-explored topic just in general, especially with nootropics and supplements. But I'm excited about it. So I just had to add that in there.

Emiel

Yeah. It's actually a really good one. It's one I've been taking daily since we came out with it. And I took it a lot during beta testing, too, of course, to make sure that the dosage was correct. And we did go for quite a high dosage, which should actually make those prolactin effects much more pronounced as well. But Apigenin actually also has some mild pain management effects and is slightly muscle relaxing. So it would likely be a really good one to take during menstruation and during periods where you have mood issues.

Erika

Okay. This is good to know. But we've been talking a lot about sort of the sexual and the erotic aspect of hormones and addressing hormones and changing and working with your hormones. But I know that there's a lot of people out there who are really curious about the benefits for your workouts and endurance just when it comes to muscle building and this world. So are there any other points to touch on when it comes to the benefits that people can experience in their workouts from taking this stack of tongkat ali and cistanche and Apigenin.

Emiel

Yes. So when you increase testosterone levels, you increase protein synthesis. And when you increase protein synthesis, you get more muscle growth and you get stronger and your muscles look bigger and more toned. So this is one big aspect of testosterone supplements that people are often after. If you take them, you'll likely become stronger and more effective at the gym and you can reach your goals a little bit faster. Or maybe you can reach your goals in a more sustainable way. Or, and this is an interesting thing, actually, that was discussed on the Joe Rogan podcast, too, is you have longevity just like your age longevity, but then you also have performance longevity. So even though you might live to 80, 90 years old, it might mean that you stop if you are a pro athlete, that maybe around age 70 or something, you become much less effective at being that athlete. And that's kind of the performance longevity. And the idea being if you supplement with testosterone a little bit, you can extend your performance longevity. So that's an interesting thing, too, for some of our older listeners, too, is maintaining that performance longevity could be a very interesting thing with testosterone enhancing supplements. But the main takeaway here being testosterone makes you stronger, but it also increases your drive. So it actually makes painful things feel more enjoyable and you want to do it. And it's why young men oftentimes also participate a lot in extreme sports. And I know I'm...

Erika

High-risk behavior, we would say.

Emiel

Yeah, and I have lots of injuries from skating back in the day, likely because I really wanted to push myself super hard. And then when I got into college, I started lifting weights and I got into powerlifting and Olympic lifting and really brutal stuff and really fun. And it felt really nice. And this is likely also from testosterone. And the more you have, the more drive, the more aggression you have, the higher you will likely perform in the gym. So this is a really good one.

Erika

And this makes sense because we all know that testosterone levels get lower with age in both men and women. But obviously the results and the examples in men are a little more obvious. So for those of you who are interested in continuing to maintain your testosterone levels as you age, supplementing with tongkat ali, cistanche, and Apigenan could be really effective for addressing this aspect of aging.

Emiel

Yeah. And actually to get to this aspect of aging a little bit deeper and also some other aspects of testosterone. One other thing that the older we get, the worse our sleep gets. And sleep is also very important for testosterone production and it's important for muscle protein synthesis and just overall recovery. And this is where Apigenin comes in, so you can definitely take tongkat ali, cistanche and and Apigenin at the same time, and it will have great effects and the prolactin effect will be there. But another thing you could do is taking tongkat ali and cistanche during the day and then taking Apigenin at night because apigenin actually helps enhance sleep. And this is another thing Andrew Huberman talks about. He's actually a big fan of Apigenin for the sleep-promoting effects, and he stacks it together with magnesium threonate, magnesium actually being a mineral that is important for overall testosterone synthesis as well. So taking some extra magnesium at night and some Apigenin, and then he also recommends L theanine. Taking all of these together would have an additive effect to the increases in testosterone you will see with tongkat ali and cistanche because you're also helping enhance sleep. But you also have these prolactin lowering effects from Apigenin. So that's very positive. But helping to enhance sleep is a good strategy. So as we go along in this podcast, we're actually putting together a bit of a stack. So we started with tongkat ali. Now we're adding cistanche to it. cistanche also increases growth hormone. And growth hormone can also help with sleep and recovery, so it's all starting to flow into each other now. So we have tongkat ali, we have cistanche. Now we have Apigenin, which you're taking at night. Now let's add some magnesium to that, because magnesium helps you sleep a little bit better. And magnesium is important for testosterone synthesis, too. And now let's add one more factor. Let's add zinc. Zinc is another important mineral for testosterone production. So we want some extra zinc. And zinc also for most people, helps you sleep better. Not everyone, as we found out with our sleep support formula, which contained zinc. And this zinc actually kept some people up. So be careful there, maybe beta test it once or twice and see how it impacts your sleep. And if it impacts your sleep positively, you could have a testosterone-increasing sleep stack, which would be Apigenin, Magnesium, any of our magnesiums. For me, for sleep, magnesium bisclycinate is actually one of my favorites, and then adding some Apigenin to that.

Erika

So this is really exciting and fascinating because I never thought about the fact that sleep supplements would have benefits for hormonal levels and just balance in general. But you can increase the effectiveness of your testosterone supplementation while you sleep with things that are just addressing other systems in the body. And I guess this is the part of stacking that's always so exciting and fascinating to me, is that these individual botanicals or these products, they don't just have one singular effect. They have a multitude of effects. And when you put them together, when they work synergistically, and when you take them at specific times of day, you can get even more benefits out of them that are going to help you during the daytime, during the nighttime for your workouts, maybe in your relationships and just in general.

Emiel

Yeah, and I would like to call this intelligence supplementation. Paying attention to what's happening, taking supplements at different times. And we're making blanket recommendations here for the average population. But you might find that Apigenin works so much better for you during the day, which actually is the case for me. I love taking Apigenin during the day. So I have a different sleep stack that I use, actually, just our sleep stack, which I helped formulate. So that's the one I use. And that may actually also help enhance testosterone levels because it contains Shilajit.

Erika

This is something I wanted to touch on because a couple of you in your Reddit questions were asking about testosterone supplementation outside of tongkat ali and cistanche and Fadogia. And Shilajit was one that I saw coming up quite often. And Shilajit, just in and of itself as a raw material, is pretty fascinating because they call it Rock Sweat, which is, like the coolest and strangest name I've ever heard. And from my research, it's organic material and fulvic acid. But I'm curious what kinds of benefits it has for testosterone. Emiel, you're definitely going to have to give me the lowdown on this one.

Emiel

Yeah. And the Rock Sweat name is very apt because you have to go quite high into the Himalayan mountains. And there's also, I think, the Russian Caucus Mountains. There's some Shilajit there, too, under a different name. But Shilajit, if you're looking kind of in Himalayas, you have to go up quite high. And then when you're walking around and there's no sunshine, you won't necessarily find any Shilajit. But when the sun is hitting the rocks and especially in the summer, when it's nice and hot, then the rock starts sweating and it starts sweating. This black tar-y ooze. And that ooze is what we call Shilajit. And the interesting thing is we don't really know what Shilajit is. It's likely just fossilized plants that have been pressed under immense pressure under these rocks and heat over many, many years, thousands of years, maybe even millions of years, and it just oozes out. And, yeah, it contains high levels of fulvic acid, of humic acid and dibenzo alpha pyrones. And all of these kind of work together to do a lot of things, one of which is to increase cellular energy. It helps enhance Coq10 levels. But then another thing it does is it acts on some of these similar testosterone production enzymes. And by working on those enzymes, it can help support overall testosterone synthesis. It doesn't necessarily help increase testosterone like tongkat ali or cistanche does, but it helps support testosterone synthesis. So it is another good one, actually, to add into the overall stack with cistanche and tongkat ali.

Erika

And if you were to add Shilajit along with this stack, what would be other benefits that you would experience from this, like, beyond just the specific benefit of increasing these enzymes that help with testosterone production? What, like perceptible mood or physical or cognitive benefits would you experience?

Emiel

Well, you may get some more of those classic testosterone-like effects, because hopefully if you are taking Shilajit in this context, then it would further help enhance testosterone production. But another thing that I personally really like about Shilajit is that it has a nice recovery benefit when you're exercising because it has a good oxidation and inflammation balancing effects. And furthermore, it helps enhance ATP synthesis because it helps enhance CoQ 10 levels. It helps the recycling of CoQ 10 and CoQ 10 is a very important compound for enhancing ATP synthesis. And the more ATP we have, the more stronger the stronger our muscles can contract, the more cellular energy we have. So in the context of a performance-enhancing stack, this would be beneficial. And actually, if we're talking about ATP and also going back to some of these androgens we should definitely talk about Creatine, because Creatine is one of the most highly studied, has a ton of high quality human clinical data, and it, similar to Shilajit, enhances cellular energy by enhancing ATP levels. This is a fantastic way of increasing strength. But another thing that Creatine does, it enhances dihydrotestosterone levels.

Erika

What's dihydrotestosterone?

Emiel

It's a different version, I guess, of testosterone with two hydroxyl groups. But what happens is that the binding affinity for the androgen receptors that it acts on, similar to testosterone, goes up significantly. So dihydrotestosterone is a lot more potent than testosterone in terms of anabolism-building muscle and things like that. Creatine doesn't cause an enormous rise in DHT, but it causes a measurable rise in DHT. And this has been replicated in many different studies. So mostly the benefits you're getting from Creatine are going to be the ATP synthesis effects. It's just going to give you more cellular energy to contract those muscles. And that's what helps enhance the strength and things like that.

Erika

Okay.

Emiel

But the DHT component of it then further enhances that anabolism effect that you're getting with tongkat ali boosting testosterone levels, and then you get a little bit of dihydrotestosterone in there as well. And actually, there's an enzyme called 5-Alpha reductase, which takes or it converts testosterone into dihydrotestosterone. So this is an enzyme that comes up from time to time as well, because a lot of the mushrooms that we have actually inhibit this 5-AR enzyme.

Erika

Which one in particular or which ones in particular?

Emiel

Lions Mane, for example, does this a lot of just culinary mushrooms do it like brown mushrooms that you eat from the store. Those are actually-

Erika

Shiitakes?

Emiel

Shiitake? I'm not sure if it's a 5-Alpha reductase inhibitor, but a lot of the different mushrooms are. And for some people, this is a bit of a cause for concern because they want some more of these DHT levels around. So they want more of this conversion to take place. So they don't want to inhibit five offer reductase. But that's how we produce most of our dihydrotestosterone. It's through this enzyme and on the flip side, dihydrotestosterone can act on androgen receptors by our hair follicles. And when they get stimulated, it actually stimulates some hair loss, so.

Erika

I was just going to say, we see this question comes up sometimes on Reddit and in emails about whether certain testosterone boosting products will actually prevent DHT from being produced. Or I'm getting that mixed up - testosterone boosting supplements will increase DHT production, which could cause some hair loss. Am I getting that right?

Emiel

Yeah. If you have more testosterone around, then there is more conversion happening to dihydrotestosterone because we need testosterone in that step. So the more testosterone is available technically, the more DHT we can have around. But honestly, the increases we're seeing with Tongat and cistanche are likely not enough to cause massive increases in DHT, which could then lend to balding.

Erika

Got you. How about with Creatine?

Emiel

With Creatine, it's the same thing. If you look at the IFBB pro, I think that's what it's called, the pro league bodybuilding, the Mr. Universe guys. They're all huge and they're all bald. And there's a good reason for that, which we can't really get into here. But it's related to DHT. We're not seeing those kind of DHT increases with things like Creatine. And if we're enhancing testosterone levels, we're not necessarily seeing them. So that's not something I would necessarily be worried about. But having that extra little bit of DHT production in there from Creatine together with something like tongkat ali could really help just dial in that last little bit of extra performance. And there's a lot of human data that shows that it's really effective. Plus it's an interesting nootropic. And we can get into Creatine at some point because,

Erika

Maybe on a future podcast.

Emiel

Yeah, it's always overlooked and it's one of the most highly researched compounds around. So it would be really cool to dive into that a little bit more because I just recently started taking Creatine again. I kind of forgotten about it for a while. And then I realized, hey, I should be taking Creatine again once we started working on this podcast, and I really do like the effects of it.

Erika

What do you find are the most standout effects of Creatine?

Emiel

For me, I seem to have a bit of an issue, maybe maintaining ATP levels consistently. So things that help enhance ADP production are really beneficial to me, which is part of the reason why I take CoQ-10 every day. When taking Creatine, I get a little bit more of those effects. I have a little bit more energy overall, and I seem to be less prone to getting headaches, which is something that CoQ-10 helps me with as well. And I think my headaches are related to ATP production. So taking Creatine really helps me there, and it helps me cognitively, but it also just helps me with overall physical energy. And a really interesting thing is, and this is something that's often taken out of context because people are mega-dosing Creatine and then cycling it. So when you do that and you take like 25 grams of Creatine a day at the start of the cycle, you start to maintain a lot of water in your cells. But this is a really positive thing, actually, that Creatine does. And in normal doses, it allows your cells to stay better hydrated, which for us living in the desert and especially with the summer approaching, Creatine is a really nice one that I take during the summer because it helps my cells retain more water.

Emiel

So I drink a little bit more water, and then my cells can retain some more of that water too, which might help with electrolyte balance and things like that, too.

Erika

I never even considered the benefit of Creatine just in terms of maintaining hydration, because when I was first introduced to Creatine, it was around the time that I was in college, and some guys I knew were super, super into Creatine. That was like the first supplement they were taking because they were really into weightlifting and going to the gym every day. And I remember them complaining about how they were putting on so much water weight with this Creatine. And, oh, it was such a big issue, even though it was really helping them with their workouts. And I never really understood why that was. But I remember that was like a big topic of conversation was the water weight related to Creatine. But at this point now, thinking about it, in terms of the summer coming up in this super hot desert where we live, that's not a bad idea to start supplementing Creatine for hydration purposes.

Emiel

Absolutely. And honestly, with a lot of these young guys, they want steroid like effects, and they think, "I'm young, I've got a lot of testosterone. I'm a protein synthesis machine." I'm just going to take some large doses of Creatine and get really significant effects really quickly, which is why Creatine is often cycled, which I think is kind of inappropriate, given what it actually does in the body. So people will take maybe 25 grams a day, maybe even twice a day for the first week, and then they will drop down to a maintenance dose of 5 grams a day. But if you just take 5 grams a day, you don't get this crazy initial bloating stage where a lot of water is being retained in your cells. And if you just regularly take 5 grams, you will just help promote overall cellular hydration, which if you live in a hot and dry climate, is a really good thing during the summer.

Erika

Good to know. So it sounds like we have a pretty well rounded idea of what to stack with tongkat ali, tongkat ali being our centerpiece, so to speak, and then cistanche being a really great option to stack with tongkat ali. Shilajit also sounds like a great addition to this sort of daily testosterone supplementation as well as Creatine. So that sounds like a really nice, well-rounded way of approaching testosterone supplementation to benefit mood and motivation and energy, and hopefully, give you a little bit more of an edge and a little bit more drive when it comes to your time in the gym, perhaps your time and your special time and your relationships. And generally speaking, I've found such great results from taking tongkat ali the past couple of days. So I'm curious what it would be like to just stick with a simple, simplified testosterone supplementation stack just for myself.

Emiel

Yeah. And I've noticed very similar effects too, over the last couple of years, experimenting with some of these testosterone enhancing stacks. They're really beneficial. I feel like I recover a lot quicker. I have a lot more physical capabilities. I just feel stronger overall, which is really nice.

Erika

Probably a result of building strength, but also building confidence, too.

Emiel

Absolutely. Yeah.

Erika

So they all go together hand in hand. I think this is a perfect segue to one of our fun segments that we use to break up the In Search of Insight podcast, which is: new product releases. So every month In Search of Insight, we go over new products that new Tropics Depot has released since the last podcast episode. And this month we have a handful of super exciting products. The first one we're going to start with is a product that I really love, the taste and the feel and the effects of it's a new solution that we have out. It is our Holy Basil Supercritical CO2 solution. Emiel, tell us a little bit about the inspiration for the solution and who should consider adding this to their daily stack?

Emiel

Well, I actually think you are the inspiration for this one, at least for me. A few years ago you had given me a cup of Tulsi tea and I really liked the taste of it. And you were really excited about the taste of it, which is why you let me try some of it. And then we both noticed some interesting effects too. So then a few years went by and we were looking for some Holy basil products, but all of it seemed somewhat uninteresting. And then we crossed paths with this super critical CO2 Holy basil extract. And for those unfamiliar with what supercritical CO2 extraction is, basically CO2 can exist in a few different forms or phases. A gaseous phase, which we're quite familiar with, and we're quite familiar with that gaseous phase dissolved inside of beverages, sparkling water, sodas, and things like that. That's gaseous CO2 in there. Co2 can also exist as a solid dry ice, if you've ever played around with that. And then under very specific conditions of pressure and temperature, it can exist as a sort of liquid. And that's what we're working with here. So we take this liquid and it has really good properties for extracting certain botanicals. So we take this liquid, liquid CO2, and we force it through Holy basil leaves. And then what comes out is this really strong terpene-rich extract. So two of the things that we standardized for in the Holy basil extract are eugenol, which is a terpene, and Caryophyllene, which is a terpene and is actually also found in one of our other products, Rephyll, which is a beta-caryophyllene product.

Erika

And if I remember correctly, eugenol is also the property within cloves that causes a numbing feeling in your mouth.

Emiel

Correct. And you'll notice a bit of a numbing feeling if you do it sublingually with the solution, which is actually one of the ways I like taking it. So basically the solution, we take this really potent supercritical CO2 extract and we dilute it a little bit with olive oil. It Mellows out the taste a little bit too in the solution and makes it a little bit easier to dose out because of its potency. But this is a really interesting one if you're looking for calming effects that also have pain management effects. So similar to rephyll, rephyll, one of the main effects is for pain and it's achieving this through its caryophyllene content. So caryophyllene actually is a CB2 cannabinoid receptor agonist. And that's where it produces some of its pain management effects through. And the caryophyllene in Holy basil extract does a very similar thing. But Caryophyllene also has a nice mood-enhancing effect. It is good for controlling inflammation and things like that. So that's a really nice component to have in there. But when you link it up with eugenol, it further enhances the pain management effects of Caryophyllene. But in addition to this, eugenol also has a really interesting effect on balancing the HPA axis, which is part of the mechanism that controls stress levels and the effects that we experience from stress. So eugenol has a very nice stress management effect. And together with the pain management and mood-elevating effects of Caryophyllene, it makes a really nice combination. And one of the nice things about it is if you do use it sublingually, it kicks in really quickly. And I recently actually two days ago, I recommended it to a colleague who was having some issues with nervousness. And she was a little bit on edge. She was trying out the Holy basil and was really helping calm her down. But then she also told me that she was having some back pain and the back pain started to ebb away, which was a surprise for her and something I didn't necessarily tell her about because we were mostly focusing on the calming effects. But then I realized, yeah, it is a very good pain management effect. And even though I didn't tell my colleague exactly that it had a pain management effect, she noticed this effect herself and it was quite prominent.

Erika

That's really exciting. So you mentioned early on that the inspiration for the Holy basil super critical CO2 solution was from that cup of Holy basil Tulsi tea that I had. Trader Joe's was supplying it for some period of time. I just love the taste so much. But now it's really cool to see this product come to life. And I really love the taste of it. I think it's one of my favorite solutions and one of my favorite Nootropics Depot products, just because it just has so much character to it in the flavor, but also in the calming effects. And I noticed those, too. So thanks for giving us a really comprehensive understanding of what it's doing and where it comes from and what its intentions are. Moving on to our next new product release. Since the last podcast episode, we have released L pyroglutamic acid powder. And this is an exciting one for a lot of reasons. But Emiel, give us just a couple of reasons why this product was added to our offerings and what it's doing in the body.

Emiel

One of the main reasons why we started carrying this, I actually can't really talk about. But you guys figured it out on Reddit already. I'll just say that L pyroglutamic acid contains a Pyrrolidone base structure. And for those who've been around nootropics for a long time, you'll know exactly what that means. And you'll know exactly why we came out with this product. And it does exactly what it's intended as a very nice nootropic effect. But it is a naturally occurring amino acid, which is really interesting. And it's usually in our body, and we actually need quite a bit of it, too. But if you take it as a supplement, then you can further enhance these nootropic activities of this already endogenously existing amino acid. And you can get nootropic effects that are very similar to one of the most popular class of nootropics, which, again, we cannot mention the name of. But you're all probably smart enough to figure it out for yourself.

Erika

Thank you for that. Very well navigated. So moving on to our next new product release. We've released Nobiletin capsules. And I'm not super familiar with Nobiletin and what its effects are and where it comes from. So will you give me just kind of a background on Nobiletin, what it is and what it's doing?

Emiel

Yeah. Noble Eaten is found in various citrus fruits. And actually ours is extracted from citrus Aurantium, which is a bitter Orange. And in fact, a lot of our flavonoid-type products are extracted from citrus aurantium. So another new product that we'll touch on in a second, Apigenin, is also extracted from citrus aurantium and hesperidin, which we've had for a while, is also extracted from citrus aurantium. And then Nobiletin is just one of those other very interesting flavonoids. To get more into its effects, one of the most interesting effects is that it is an AMPA receptor agonist, which again, if you have been around nootropics for a while, you probably, this probably rings a bit of a bell. And enhancing AMPA activity is a really good way to enhance long-term potentiation. So LTP basically, memory formation. So, again, Nobiletin is a very interesting natural nootropic. In addition to that, though, and this is where it gathered a lot of attention recently, is that it may help enhance sleep, which has confused some people, because the AMPA effects also cause stimulating effects. And in my experience, and in a lot of people's experience Nobiletin is in fact, stimulating. So seems kind of odd that it would enhance sleep. Right. But the interesting thing is it helps enhance circadian rhythm, so it gets our circadian rhythms into a better groove, basically, which helps us sleep better. And it means that you can take this earlier on in the day, and it will help enhance your overall circadian rhythm over time, which will then help enhance sleep quality. And some customers have actually tried this strategy for a while, and it does seem to actually enhance sleep quality. And it would work in a somewhat similar way to Melatonin, because that's one of the things Melatonin does, too. It helps control our circadian rhythms. And Nobiletin does somewhat similar things through some different mechanisms. So very interesting if you're looking for Nootropic long-term potentiation type effects, but also interesting if you're looking to help enhance sleep quality through a really novel and different pathway.

Erika

I was just going to ask. It sounds like a different pathway than the pathways for sleep support from our sleep support stack. From Natrium Health.

Emiel

Yes, absolutely. Those real sleep stacks are more designed to kind of slow brain activity a little bit by increasing GABA activation. So GABA is one of the main inhibitory neurotransmitters, and it basically decreases neurological activity a little bit, which is nice for getting to sleep. So that's why a lot of sleep products contain GABA-ergic compounds like lemon balm or Magnolia bark or oleamide. And you'll find all of those actually in sleep support. But sleep support is really designed to help get you to sleep and keep you asleep. But it's not necessarily designed to help optimize your circadian rhythm unless you put in the, you can order a sidecar of little melatonin capsules with sleep support, and then it gets that circadian rhythm effect there a little bit more. But you could, for example, take sleep support at night and then Nobiletin during the day, help enhance your circadian rhythms, and then put yourself to sleep with sleep support. If you have difficulties with that.

Erika

That's really cool. Sometimes I just get on this train where I'm thinking, I want to stack for everything. And so I was thinking, okay, what could we stack with Nobiletin to get the best sleep benefits and sleep support was my first thought. So I like the idea that if you really want to take a very targeted and specific approach to improving sleep quality and working with supporting your circadian rhythms. Nobiletin might be a nice thing to add to take during the day that will help you throughout the day and throughout the sleeping night.

Emiel

And another interesting thing about it is one of my design goals for sleep support was that not only would it help you get to sleep and stay asleep and enhance sleep quality, it would also have certain nootropics in there like bacopa and uridine, which while you sleep, are enhancing neuroplasticity and enhancing memory function. So sleep support is really like an overall nootropic stack, helping you sleep better. But then also enhancing neuroplasticity. And Nobiletin, through its activity as an AMPA agonist, also has quite significant nootropic activity. So actually taking Nobiletin during the day and then sleep support at night, even if that was the only thing in your stack, would make for a really good foundation of enhancing overall cognitive function.

Erika

That's amazing. I love that. I'm actually really excited to try that. I might have to wait and space out my different tests with the sort of full-spectrum testosterone stack and then the extra optimized sleep stack. But let's move on to our next new product. We released a powder version of NMN or nicotinamide mononucleotide. Emiel, tell us a little bit about this powder. And maybe you can also answer some questions related to the concerns that people bring to us about the bioavailability of NMN in powder form, because previously we've carried this in tablet form. And there's a really specific reason why we came out with the powder. But this big question of how bioavailable is NMN comes up all the time, and I think it's important to address as we talk about this new product.

Emiel

Yeah, let's talk about these tablets first, then. So they're not just tablets. They are enteric-coated tablets, which means that the coating will not dissolve in your stomach acid. And then once it has passed your stomach acid and it's in your intestinal fluid and floating around in your intestines, then the coating starts to dissolve and then you get NMN release in the intestines. We did this for a variety of reasons when we first came out with NMN. The first being it was kind of unclear whether or not NMN would be stable at room temperature as a powder. One of the reasons for this was that our suppliers were stressing that we needed to store this material at -20 degrees Celsius, and there was no way we could get around this. So we kind of went along with this for a little while. We found some data that might indicate, yeah, maybe enemy isn't that stable. So we went along with it. But as time went on, we got more and more suspicious of this actually being the case. We looked around a little bit more and we looked at some of our older stock, and we realized the stability issue really doesn't seem to be that big of a deal actually. So that's one of the reasons why we finally cracked and said, okay, well, we can do the powder because we are more confident in the fact that it will stay stable even in powder form and not in an enteric-coated tablet.

Erika

So we do carry the NMN tablets that are enteric-coated. But now the new product that we've introduced and released is NMN powder.

Emiel

Yeah. And going a little bit further with the tablets still. So we pressed the tablets because that would allow less oxygen to get in, so it would be more stable. And then we put an enteric coating around it, which would then prevent even more oxygen from getting in and interacting with the NMN. So this was kind of one of our stability steps. And then another step in this was that there are specific transporters in your intestines that can transport NMN into your serum. So we didn't want to release the enemy in the stomach. We wanted it to release in the intestines so it would have a more targeted way of being taken up. So that's one of our ways in which to increase bioavailability. One issue there, though, is that not everyone seems to be able to digest this enteric coating. So some people were actually pooping out entire NMN tablets, which is not good because you do want them to dissolve before you poop them out. And people were finding enteric coated tablets in their stool, which is kind of interesting. We haven't really figured out exactly why. We have a method, actually, of testing whether a capsule or tablet is truly enteric coating. So we have a machine that simulates stomach fluid, and it simulates the temperature and the movements in the stomach. And we do that for about 4 hours. And then we take those tablets out, look at their integrity, and see are they still fully intact? And if they are, then that means it's passed our first test and it means there's an actual real enteric coating there. And then we take the tablet and we put it in simulated intestinal fluid. And again, similar movements and temperature and PH levels and enzymes and things like that. And then we put the tablets in there and see if once it hits the simulated intestinal fluid that it will immediately dissolve. And our enteric coated tablets always adhere to this. This is part of our testing, so we know that they work. But some individuals don't seem to have this normal activity of their stomach acid and gastric or intestinal fluid to strip off the enteric coating and have it dissolved. There were quite a few people with this issue. So that's one of the reasons why we consider the capsules as well, because then these individuals could take a different form that would actually dissolve and give them some NMN, even though it's not entirely optimized.

Erika

So let's move on now to the powder. Why should people take the powder even with this concern of bioavailability?

Emiel

And this is something we've talked about a few times on Reddit now. We get the question often about how bioavailable is something which you can put a nice number on that and say oh, it's 20% bioavailable or whatever. But at the end of the day we can account for this bioavailability issue in a few different ways, one of which is an enteric coating as we've just discussed. Another way is just to dose it higher if the raw material cost allows for it. So some raw materials are just so expensive you can't really dose them high enough and then you have to figure out different ways to make them more bioavailable. For NMN, we're kind of in a sweet spot where it's not the cheapest material on the planet, but it's still cheap enough where you can take a higher dose. So basically our first solution was an enteric coating. Our second solution is just a higher dose of NMN powder and of the capsules. Because the same NMN powder is in the capsules, there's absolutely no difference between the capsules and the powder except for the dosage form. So when we're talking about the powder in the capsules, we can just talk about them in the same breath.

Erika

Sure.

Emiel

So the dosage on the NMN and enteric coated tablets is 125 milligrams and the dosage on the capsules in the powder is 250 mg. And putting something in a capsule or in a tablet costs us money, which means that we have to charge more money for these products. A powder, we don't have to do that. So powders are always going to be cheaper.

Erika

Makes sense.

Emiel

For people who have scales and who want to experiment with higher doses of NMN. The powder is perfect because it is the cheapest way you can get NMN from us, properly lab tested and everything. It's super high quality, but then you can choose your own dose and if you want to say take 500 milligrams with the enteric coated tablets, this would have been too expensive and really wouldn't have been necessary because you are getting so much better absorption with this enteric coating or, we don't have specific data for it, but theoretically it should give you much better absorption because it's releasing around specific NMN transporters which when it releases in the stomach you don't necessarily get the specificity and stomach acid might degrade some of the NMN before it can get into the intestines. But again, it's so much cheaper that taking a higher dose just works a lot better. And this is where the powder is for people who don't want to necessarily take an enteric coated tablet or can take an enteric coated tablet or just want to try out something different or higher doses. The NMN powder is perfect in addition to the capsules.

Erika

Cool. Thanks for that. I think it's really helpful for everybody to hear just the details and the process and the reason why we came out with this powder, especially because this has been a big question for us on Reddit and in emails. So hopefully that answered some of your questions and also got you thinking about potentially trying out NMN powder instead of tablets if perhaps you pass them quickly. So now we're going to move on to two of my favorite new releases of the last month, the first one being ginger extract capsules. I really love ginger extract capsules. I find that they really help with my morning jitters, just that I get naturally even without taking caffeine. I can be very chipper in the morning, but sometimes the chipperness turns into feelings of nausea. And I find that ginger capsules really helped me to maintain a sense of calm and feel a little more grounded, especially when I take them first thing in the morning.

Emiel

I have a very similar experience with them because sometimes my stomach is not entirely happy when I wake up. Whether that is some slight jitteryness that I experience in the morning.

Erika

Maybe you ate too many peppers the night before.

Emiel

Maybe I did some crazy culinary experiments the night before. Whatever it is, I like taking ginger pretty much as soon as I wake up because it helps. My stomach just feels a little bit better. Even though I don't necessarily have any stomach issues, my stomach just feels soothed when I take ginger. In addition, too, I do think it has some interesting cognitive and mood effects, and it's good for inflammation, and it also seems to be helping with some of my seasonal allergies. So that's something I'm very excited about.

Erika

Absolutely. And then last but very not least is Apigenin capsules and powder, which there's a lot of hype about right now on the internet. Andrew Huberman has talked about Apigenin, and a lot of other people in the Nootropics community are talking about Apigenin and its benefits. So Emiel, tell us what it is, where it comes from, and why we should all be really excited about this new product release.

Emiel

Yeah, Apigenin is one of the main active compounds in chamomile, so if you've ever had chamomile tea, and you like the relaxing effects, part of this is likely because of Apigenin. Of course, there's also some other terpenes in there which have calming effects, but Apigenin seems to be a bit of a star player there. We have taken Apigenin and purified it to a very high level, so pretty much just pure Apigenin. And we were going through a lot of different research. And Andrew Huberman, actually, he suggests 50 mg, which I think is a good dose as well, and a lot of different people seem to be doing 50 mg. But when we were crawling through the research, it seemed like higher doses were actually a lot more beneficial and have been studied in animal and some human trials as well. So we decided to just go with the slightly higher does well, slightly higher, four times higher. We went with 200 mg for our capsules. And when you take this 200 mg, you get fairly significant calming effects coupled with some mild muscle relaxation, which is really nice. But as we talked about a little bit earlier in the podcast, Apigenin is also a good dopamine D2 agonist. So it actually gives you a little bit of focus and a little bit more executive function. You're a little bit more focused and motivated in addition to having this strong, relaxing effect. So in a sense, it's somewhat similar to caffeine L-theanine capsules, where you have this stimulating component and then this calming component that are working really well hand in hand.

Erika

Except this is doing that same or similar effect, but just from one bioactive compound.

Emiel

Yes, absolutely. And I've been testing it out on myself, and I really like it. I've been taking it every week for the last two weeks or every day for the last two weeks. I think, Erika, you've been taking it pretty regularly, too.

Erika

I have. And I've been including it in my daily stack. So to be honest, I am feeling a lot more calm. But I do take a lot of different supplements on a daily basis.

Emiel

It doesn't make you tired.

Erika

No, definitely doesn't make me tired.

Emiel

And that's a really good thing.

Erika

I really like the addition. Yeah, I really like the addition with the other sort of stress management supplements that I take in my daily stack. If I were asked to give a really specific description of the effects in terms of the sensation or how it feels, I would want to take it just by itself, with no other supplements interacting, which is something that I'll probably do maybe on an off day coming up. But I really like the addition with my whole stack and with ginger, it's like a double punch in the face of a freak out or a nauseous or a jittery moment. And I think it's a really great addition for anyone who loves Panamax or anybody who likes caffeine. Although I like Camille was saying, this could be a funding product to try. Maybe you want to combine it with your stress management stack. Or perhaps you might want to try something new just for fun to see.

Emiel

And Interestingly enough, one of the reasons why Andrew Huberman recommends Apigenin is because of its sleep benefits. And even though we're calling it stimulating, it's not necessarily stimulating. It's more focus-enhancing. It's not necessarily a wakefulness-type effect. So you can actually take this before bed as well, and it will help enhance sleep quality. And one way in which I actually like taking Apigenin and one reason why I asked Erika earlier, does it make you tired? Is a lot of calming supplements also have sometimes it's desired and sometimes not, but it can make you tired. And I'm always a big fan of calming things that have a mood-enhancing component and that don't produce much lethargy. And Apigenin is one of those. And with those kind of compounds, I like to take it after work to relax instead of drinking a beer or something. After work, I'll just take some Apigenin and have this nice, relaxed yet uplifted feeling that allows me to really relax and read a book or watch a movie or play a game or something and just really relax and prepare myself for the next day and prepare myself for bed. Something like Apigenin is really nice.

Erika

This makes me think that I want to compare my favorite calming supplements, Sibelius Sage with Apigenin to see what the difference is, because I definitely don't feel particularly stimulated by Sage, although it's certainly a mood booster, for sure. But I'd be curious to just compare them side by side because I have a feeling that I might notice some interesting effects and differences between the two, because Sage is kind of my go-to when it comes to time to wind down or time to relax, time to let go, even though Apigenin sounds like it's offering some of these similar effects, maybe a little bit more stimulation. Not quite as intensely calming as Sibelius Sage.

Emiel

Yeah. For me, I might actually compare it or might even stack it. And that's something you can consider, too, stacking Apigenin and Sibelius Sage. And for me, I would want to compare the Apigenin versus the Kava, which is one of my other favorite after work relaxing, read a book type of supplements is kava. And I actually think that combining Apigenin with Kava would further round out the effects and might actually be really nice. But I'm actually curious to compare them, too. And actually, another report of one of our colleagues taking one of these things. Yesterday, actually, I gave one of my colleagues some apigenin, and she took it this morning, and she reported really nice effects right around 45 minutes. It kicked in and it gave her a nice, focused feeling without making her jittery, which is something she often has issues with. So she can't really take caffeine, even something like caffeine L-theanine might be a little bit too much for her at times. But Apigenin was one of those things that gave her a nice boost in focus and relaxation that helped her really get into her work.

Erika

That's exciting. So maybe for people who are extra sensitive to caffeine or for all of you out there who are tea drinkers, you're probably familiar with chamomile tea, but perhaps Apigenin is a good option for you rather than caffeine on a daily basis, or maybe alongside your manageable caffeine doses from tea, take some Apigenin and it could have some nice kind of lifting effects early on in your day.

Emiel

Absolutely.

Erika

Very cool. Well, I'm really excited about all of these new products that we've released over the last month. So if you're curious to check them out, you can visit our website and go to new product releases. We have a tab in our menu with all of these products featured. And now we are going to move on into the absolute best part of the podcast, which is answering your questions from Reddit.

Emiel

You got a lot this time.

Erika

Absolutely. Every single month before we release our new podcast episode, we tell you what the topic is and we ask you for your questions because we want to know what you're curious about when it comes to testosterone, testosterone supplementation, testosterone management, stacking advice, dosing, cycling, the whole lot. And boy, you really delivered a lot of questions. So thank you so much for your participation. We're going to continue asking for your questions in all future episodes of In Search of Insight. So don't stop them from coming. Let's jump right into it. Let's start with questions about stacking for testosterone support. Our first question comes from u/rsodirteetoo, very interesting username. And I'm going to paraphrase this question a little bit. So the question is, "What supplements should I stack with tongkat ali for maximum testosterone support, for example, Shilajit, cistanche, et cetera? And how much of these other supplements should I add along with my tongkat ali for a great testosterone supplementing support stack?"

Emiel

I guess we've already kind of answered this question throughout the podcast. So one of them is Shilajit, which we talked about in depth a little bit more. Another one being cistanche, of course. So my ideal Tongat stack would be Tongat. For me, the 2%. I like the 2% more. I know there's a lot of division there. Erika likes the 10% more. I know most people in the office like the 10% more. For some reason, I like the 2%. So for my ideal stack, it would be the Tongat 2%, it would be the cistanche, it would be Apigenin, Shilajit, maybe Shoden if I'm having some issues with stress because Shoden can help with stress management. But it may also help with testosterone synthesis. Similar to Shilajit helps enhance some testosterone synthesis by enhancing the enzymes that produce testosterone. Then on top of that, I would also add some Creatine, like we talked about. Get some of those DHT benefits, some more ATP synthesis benefits. And I think that would make a very good strength stack. So to kind of summarize, tongkat ali, cistanche, Creatine, Apigenin, Shoden, perhaps. And in terms of doses, just follow our dosing recommendation. We spend a lot of time figuring out exactly what to dose it at. So this is the best information you're going to get. Just stick with our doses. And if you feel like you want to take a different dose, then you have to look at different dosage levels that will work with you and do some research on it and try it out yourself and see what doses work best. But for the general population, we feel that our dosing recommendations are very applicable to most people.

Erika

Awesome. And then our next question comes from u/ghjkpiuyn. I really don't know how to pronounce that, so I'm just going to spell it for you. And their question is "Not exactly testosterone-related, but can you talk about supplements that would stack well with those two," similar to our earlier question, but they're saying, "for example, Epicatechin, which is part of your strength and muscle mass stack. And that's not something we've talked about yet in this podcast.

Emiel

Epicatechin is a myostatin inhibitor, myostatin being something that may limit muscle growth. So if you inhibit myostatin, you potentially get more muscle growth. And some really famous examples of this happening genetically or with certain animals that have their myostatin knocked down.

Erika

I think I know what you're about to say.

Emiel

Yeah, the Belgian blue cows.

Erika

Yes, the super buff cows that have the most amazing-looking muscles, bodybuilding cows.

Emiel

Super jacked cows. And then I think I've maybe seen a dog that had a myostatin deficiency that was really just ripped to shreds. And then I think there's a type of horse as well that has low myostatin activity. And they're also super shredded. So ideally we would see some of these effects in humans too. And a lot of people do seem to have success with Epicatechin. So Epicatechin would stack well as an anabolic aid. So something that would help speed up muscle protein synthesis and help you get bigger and stronger without necessarily interacting with testosterone. And because of this, it will probably be synergistic with testosterone enhancement strategies. So that's actually a really cool one.

Erika

Great idea, in a question form.

Emiel

Yeah, exactly. And something like Creatine is not exactly elevating testosterone. It's elevating DHT to a certain degree. Fairly small degree, I think. But then the ATP effects, the phosphor Creatine to ATP effects would really help with overall strength and endurance and things like that. So that would be another good one to take alongside Tongat. I think Apigenin is a great one, like we've talked about because of its prolactin-lowering effects. And it may help a little bit with recovery and things like that. Speaking of recovery, we'll have to go back to our first podcast ever. Tongkat ali would also stack really well with tart cherry. And actually, tongkat ali helps excrete some uric acid as well, which is one of the main reasons why tart cherry has such good benefits overall on muscle recoveries because it lowers uric acid levels. So tongkat ali is doing a similar thing and they might stack well because of that for enhanced recovery.

Erika

Super cool. And then another question we have about stacking with tongkat ali. This comes from u/ZennZen. And the question is "Any reason not to combine tongkat ali and cistanche? If so, what kind of cycle would be best? And also curious about claims regarding fat loss with tongkat ali?"

Emiel

I honestly don't really see a reason not to combine the two. I think they go really well together. One thing to consider is maybe how you approach it. So the way I do it is I take cistanche every day. And then when I add tongkat ali on top of that daily stack, I notice a very profound impact from the tongkat ali, something that I didn't necessarily notice when I was just taking tongkat ali by itself long term. So it seems like taking cistanche is kind of priming my system for the effects of tongkat ali. Which makes sense because one of the things cistanche does is it elevates luteinizing hormone levels and luteinizing hormone levels then also likely increase the density of Leydig cells, which means there are more leydig cells available for testosterone production, which means that when I add tongkat ali in there, which stimulates these Leydig cells to actually make more testosterone, then because there are more leydig cells around, I get a greater response when I'm taking cistanche regularly. And then when I need like a little bit of a nitrous boost, like in those old car racing games, then I take some tongkat ali and really push my performance to the next level.

Erika

Nice. I like that example you used.

Emiel

Oh yeah, and then fat loss.

Erika

Yes.

Emiel

So let's talk about that a little bit too. I don't think tongkat ali necessarily would help specifically with fat loss. I think there are some metabolic health benefits to it, but it's not going to be a really strong fat loss agent. In fact, not a whole lot of things are really strong fat loss agents. You have to lose that fat through diet and exercise. But one thing, when you are limiting your calories, then you are also at risk of not only losing fat but also muscle. So that is where tongkat ali comes in. So if you want to lose fat weight or just overall weight, but you want to maintain your muscle mass, having some extra testosterone around is really good for that. So you can maintain that muscle mass because of the extra testosterone while you're losing weight. So it's not necessarily going to help you lose weight, but it's going to help how you lose weight.

Erika

I like that, a little bit more nuanced.

Emiel

Yeah.

Erika

And now another question about another product that we haven't mentioned to stack with tongkat ali. This question comes from u/chris106. And the question is, "Is Cordyceps on that list, the list of what to stack with tongkat ali, especially if the 1:1 or the 10:1 extract would be best suited in combination with tongkat ali and/or cistanche.

Emiel

Yeah. Cordyceps would be another really good one. It seems to have some maybe minor testosterone elevating effects. It definitely does seem to have libido enhancing effects, which would go well with the libido enhancing effects of tongkat ali. So for that purpose, it would be a good stack. But Cordyceps, of course, helps enhance physical endurance and physical strength, too. So for that aspect, if we're again going a little bit loose from the testosterone thing and seeing other things that would stack well with Tongkat, something like Cordyceps would be perfect because it's going to help enhance your stamina and your endurance, whether that's in the gym or even in the bedroom, it might help too. So that I think would be a really good one. And then in terms of 1:1 versus the 10:1, I personally really prefer the 10:1 Cordyceps because it has a lot more of an endurance enhancing, almost stimulating, mood enhancing feeling. And it's very distinct, whereas the 1:1 is nice, but it isn't as distinct and it's better as kind of a daily thing to help elevate your overall energy levels and get all of the immune promoting effects from the mushrooms, which Cordyceps does as well. But if you really want to go more for those physical energy, endurance kind of benefits, go with the 10:1, ideally, get both of them in smaller sizes so you can compare and contrast. Maybe you can even stack them together. But if you were to just go with one, get the 10:1 to stack with the tongkat ali, because I think it will be a very interesting effect. And I think actually if you were to take the 10% tongkat ali with the Cordyceps 10%, you would get a very, almost like aggressive energy, which would be really good for in the gym.

Erika

Nice. So almost like a stack that could mimic perhaps a pre workout feeling, even though it's not taking that same exact approach.

Emiel

Definitely

Erika

Super cool, okay. And now one more question. In the realm of stacking, u/ArcticPlatypus asks, "It would be great to see research-based and anecdotally based discussion of cycling protocols for both tongkat ali and cistanche, and maybe Shilajit as well. Like, if five days on and two days off is good for Tongkat and how many testosterone boosting supplements are safe to take simultaneously. Also, it would be cool to see a discussion on the importance of specific vitamins and minerals in the production of testosterone, such as vitamin D, magnesium, zinc, and maybe boron." Really great question.

Emiel

Yeah. And the cycling thing is difficult. So the cycling thing comes from more of these risk taking bodybuilders that are taking substances that if you don't cycle off of them, might literally kill you. So to me, it seems like they are kind of riding the line of what's possible. And to make sure that they have a somewhat longer lifespan, these people will cycle on and off of these really strong compounds that help enhance muscle growth and things like that. But basically, there isn't a serious need to cycle off of these things. But this same concept has kind of bled into the supplement and bodybuilding industry for people not going that route and going more with supplements and natural supplements. Natural supplements. And like we talked about earlier with Creatine, this is also a popular thing to do with Creatine, take these massive doses and then drop your levels and then stop it after a while because you think taking these huge doses of creatine might not be safe, but it's getting the maximum amount of benefits in the shortest amount of time. So let's just blast it and then cycle off to save ourselves.

Erika

So what you're getting at is, I think at a point in conversation that we talked about at length in our January podcast, which is about bioassaying and mindfulness, we had a long conversation about cycling. But I'm going to let you take it away and discuss why it's valuable to take a normal, more manageable dose of testosterone supplements on a daily basis long term, rather than taking these mega doses expecting crazy, super intense results right away and give us a little bit of a backstory on that in terms of testosterone supplementation, because I know that the hormone conversation and concerns about changing hormones and hormones being affected can get kind of sensitive. So it makes sense that you're asking this question. Take it away.

Emiel

Yeah. And we want to do things subtly, and that's the name of the game here. And that's what we do with supplements. We are trying to promote health in a long term vision. We are looking far into the future. We don't want results in a week. We want results ten years from now that are still the same as the time we started taking it. And this is something with Creatine. If you were to take 5 grams of Creatine every day, you could take it for the rest of your life and you would have these Creatine benefits always, not in these haphazard, maybe dangerous cycles. So my advice would be start low and slow, keep it nice and steady, and with something like tongkat ali, it is quite potent, but at the same time, it's helping enhance testosterone production in a fairly natural way. So with that in mind, you could take tongkat ali long-term and have these benefits. Maybe at certain points, you will get higher prolactin levels, which we talked about at length in the podcast. And you could take something like apigenin to help knock those prolactin levels down. Or you could then cycle off of the product for a little while, wait for your prolactin levels to drop again, and then start it back up when you feel like starting it back up. So my advice would be, take it as long term as possible. But if you notice bad effects starting to pop up, maybe cycle off, or maybe take something like apigenin to help balance some of those effects out. But pay attention to what is happening in your body and do what seems most natural. If you're getting a lot of bad effects, you should probably stop it. And if you weren't getting bad effects for the first month or two, maybe it is because you've been taking it long term now and you just need a little bit of a break from it. So keep that in mind. Be mindful of what you're doing and go there with that mindset into determining if you need to cycle on or off or not. For me personally, I don't really cycle things. I just take it all the time. Every once in a while I'll skip a Sunday or maybe even a Saturday. If I really don't have a whole lot going on, and I kind of just want to reassess my baseline state in a controlled, relaxed environment, then I'll do that. But other than that, I focus on the long-term effects.

Erika

Thank you for that response. I think it's really helpful for people who are listening that are concerned about the potential for what kinds of long term effects testosterone supplementation can have. But I think that's a really great answer and it really drives home the point that we make in every single podcast, which is at the end of the day, we want to provide the highest quality supplements to help you live your life better and to optimize your health and to support your health. So that's what we did with the tongkat ali 2% and 10%. And take it slow, take it easy and pay attention to what happens, the benefits, and trust yourself, listen to your body and keep doing research, because that's a really important part of this whole process. So now we're going to move on.

Emiel

Actually, we missed a part of this question, I'm realizing that. So the second part of the question was "Also would be cool to see a discussion on the importance of specific vitamins and minerals in the production of testosterone, such as vitamin D, magnesium, zinc, maybe Boron." And yes, you need zinc for proper testosterone production, so that is a cofactor you need. A lot of people, especially athletes, are deficient in zinc, so taking zinc is always a good idea, especially in the context of tongkat ali supplementation. And overall trying to enhance your testosterone production. Magnesium is involved there too. So it's no surprise that this ZMA stack was really popular for a long time, which was zinc, magnesium, aspartate. So people would take that before sleep, it would help them sleep a little bit better with the idea that would be enhancing testosterone production while they sleep. Honestly, I don't have a whole lot of trust in ZMA doing this, especially now that we have things like tongkat ali, readily available at high quality, those are much better options. But with that in mind, there was a reason for this. And zinc and magnesium and vitamin D are definitely important for our overall testosterone production. And this is why we also always say, and not just us, a lot of people in the industry say, the most important thing is to make sure that you're sleeping well, you're eating well, you're resting well, and you've got your basics covered. So magnesium, a lot of us are deficient in magnesium. If you don't have enough magnesium, it will impact a lot of things negatively. Cognitive function, muscle function, testosterone production, same exact thing for zinc, same exact thing for vitamin D and vitamin K2. So getting those basics covered first, making sure that you're getting enough of these essential micronutrients consistently on a daily basis is really important and is important not just for testosterone production. So you want to have adequate levels of these around at all times for all purposes, including testosterone production.

Erika

So now we're going to move on to another category of questions, and this I'm particularly interested in the responses for, because these questions are about testosterone in women. So we're going to start with u/juantoconero's question, which is "It would be interesting to hear about how these supplements affect women and older people of both sexes and any possible benefits, side effects or risks to consider in these groups."

Emiel

Yeah. Contrary to popular belief, women also need testosterone. And testosterone wouldn't necessarily give women facial hair and Adam's apples and stuff like that. In fact, the facial hair thing, we talked earlier about DHT playing a role in baldness, but it also plays a role in facial hair growth. So DHT is maybe something we want to look out for. But testosterone, women needed for libido, for building muscle, also for confidence, and for overall mood and things like that. So very important. And actually, since Erika has been looking into this herself and has been trying out some testosterone supplements for a while now, I'm actually going to let you answer the rest of this question.

Erika

Okay. So just to give a general overview, I started taking cistanche, I want to say, about four months ago daily. And the one thing I really noticed about cistanche when I first started taking it was the mood-boosting and the calming effects of it. It honestly felt like one of the most effective calming supplements I've ever taken. Even alongside of my favorite calming supplements like Sibelius Sage or lemon balm, for example. I take the cistanche tablets, and I find that it's really important in my daily stack to take cistanche, because it just gives me this seriously calming and grounded feeling. But it doesn't affect my energy levels. It doesn't make me feel super stimulated or particularly up or down. It's just like this nice kind of across the board calming mood boosting effect. And then when I started taking tongkat ali a few days ago, I really noticed a huge effect from the tongkat ali 10%, primarily with confidence and motivation. So, generally speaking, I can be somewhat of a fickle and picky person, and I really pay attention to details. And I can be very particular about certain situations, whether it's in my social life or in my creative endeavors. And I have found that since starting to take the tongkat ali 10%, I'm really able to address issues that would normally make me frustrated or normally feel somewhat emotionally or cognitively challenging. And rather than being stopped by those feelings or those obstacles, it's like I bulldoze straight through them. And as soon as the obstacle pops itself up or I become aware of it, I make it my point to be swift and direct in addressing that obstacle, which has meant that for the past couple of days I feel great. I feel confident. I feel like though tongkat ali 10%, it's not necessarily having this effect where I feel like I can speak better or more eloquently. I feel more confident in what I'm saying and how I'm communicating and the fact that there feels like there's more of a connection between my thoughts and my body sensations on the inside and how I'm able to translate that and put that out into the world.

Emiel

And speaking of your body, so we're covering the psychological effects now. What have you noticed physically?

Erika

Physically, I would say I notice more muscle tone. I think this is likely due to having taken cistanche for a couple of months. I noticed that I'm building muscle even though I'm not working out in the gym. But other exercises or other activities that I'm doing in my day to day life really require a lot of focus on posture and specifically like core strength and upper body strength. And I found that by taking cistanche for this extended period of time that I've been able to build strength in my core and in my posture, which is really helping me to just avoid repetitive stress injuries. But also I've noticed that I just have this feeling of calm. And so I have less issues with like nausea, less issues with certain digestive discomforts that I might have on a day to day basis. And just generally I just feel better physically.

Emiel

Perfect. And I think this is a thing a lot of women can experience if they open their minds to some extra testosterone, which I think through years of stigmatism, it's kind of like testosterone is for men. Women can't touch it. Similar to how estrogen is for women. Men should stay far, far away from it. And that's another common myth. Men need estrogen just as much as women need estrogen. So we should consider for all sexes supplementing with something like tongkat ali.

Erika

Absolutely.

Emiel

Have you noticed any negatives for yourself?

Erika

No, really the only thing that I've started to think about is the long-term effects and what kinds of effects testosterone supplementation has on things like fertility and my menstrual cycle and just these other cycles that I experience as a woman. And I think if I can use my personal experience related to my menstrual cycle, I would say that after starting some testosterone supplementation, I experience less intense PMS symptoms, specifically for mood. I think the physical symptoms of PMS, cramping, are also alleviated somewhat, although this varies depending on other environmental factors. But I would say in general, it does make my menstrual cycle less extreme and less intense.

Emiel

Perfect. Another kind of data point that testosterone is important for women and might underlie some of the negatives during menstrual cycles and could maybe help that.

Erika

Absolutely. And then to answer the second part of this question, which is how tongkat ali might benefit older people of both sexes, we've heard a really great array of reports from our coworkers and from some family members of coworkers who are older and who have been taking tongkat ali and really, really loving it for the motivation effects. It's helping performance in the gym, it's helping mood and just in general, really amazing and astounding to see just how effective the tongkat ali 10% in particular is for so many people. And Emiel definitely likes the 2% more. But we find that a lot of people, a lot of our coworkers really do love the 10%. And I think for older folks, the 10% seems to be really effective because it's a very direct and a very specific effect from that extract.

Emiel

And like I said earlier in the podcast, too, I grew up in Malaysia and would drive around and see these billboards with really old men on them with these Canes and then like a sachet of tongkat ali infused coffee next to them. And I was never able to read the Bahasa signs. But I'm pretty sure it would say something like, hey, if you're old and frail, take some tongkat ali and revitalize yourself, because that's kind of the imaging that was in the billboards. But interesting that in one of the countries where tongkat ali originated in Malaysia, it also exists in Thailand and some other Southeast Asian countries. But it seems that it is maybe marketed more towards older populations, especially older populations who have issues with libido and overall vitality.

Erika

Yeah, absolutely. So this leads us perfectly into the next question, which is from u/shiny_milf, which they ask, "I'd love to hear if these supplements could be beneficial for women AFAB," which is assigned female at birth, for anyone who's wondering. "I feel like we are so neglected when it comes to supplements that can boost our libido, energy, et cetera." And I'm going to go out and say, yes, I hear you and I agree. However, there are so many supplements out there, so many supplements that I have taken and tried that I've found have been really beneficial for energy and also for libido. And I would say that even though I haven't noticed the libido-enhancing effect specifically from tongkat ali, I think over the last couple of months of taking cistanche, I've definitely noticed some of these benefits. And then the energy aspect of taking cistanche and tongkat ali is really prominent and really noticeable even upon like the first day of taking these products. So if you're curious and these are two areas that you're really looking to support in your life and in your health, libido and energy, definitely give tongkat ali a try and try out cistanche, too because you might like one or the other better, or perhaps even both.

Erika

So our last question related to testosterone in women comes from u/PennyLaneKitty, and the question is, "Would love to hear more details for women. Please address any data or experiences for women. What considerations should we have? Appreciate our hormones are pretty tricky and change as we age, but so many women in perimenopause stage are looking for energy, building muscle keeping libido, and seeking any edge that they can get to keep up with everything on their plates."

Emiel

And actually, one of the main things that women in menopause or perimenopause or postmenopausal women experience is decreases in testosterone levels. So this is definitely a good thing for menopausal women or postmenopausal women to think about as well. Helping to enhance testosterone levels a little bit.

Erika

Absolutely. And from everything that I had discussed in the previous question, I would say try out tongkat ali, see how it works for you. Take note of the benefits and in terms of what considerations you should have, you should have the same considerations as any other person taking Tangata Lee, which is, are you getting the benefits that you seek from it? Does the dose feel right for you? Does it feel right for you to be taking it on a daily basis? And do you have enough research for yourself and information to feel confident and comfortable taking this? Because this is a really important sort of system to go through as you're trying new supplements. And I think what you refer to seeking any edge to keep up with everything on your plate. In my experience, taking tongkat ali the past couple of days, I feel like this has a really significant benefit for exactly this. So I would highly recommend and encourage you to give it a try yourself. Now we're going to switch into questions about the mechanisms of action related to testosterone, how testosterone is synthesized, and how tongkat ali itself works. So the first question comes from u/Delightfooll, nice name. And the question is, "Can I increase testosterone by lowering cortisol? What supplements can you suggest for this specifically?"

Emiel

Not really. Cortisol definitely impacts muscle protein synthesis and metabolism and actually can cause some catabolism. So lowering cortisol is a good way to enhance overall muscle strength and muscle building and things like that. Interestingly enough, though, tongkat ali is great at lowering cortisol, so you are literally getting both. When you take down a leak, you're getting testosterone synthesis benefits and you're getting cortisol lowering benefits.

Erika

Cool. And our next question related to mechanisms is coming from u/blyatboy. And this question is, "Does Tonga or any of the other natural testosterone supplements present the risk of down regulation of their respective receptors? In Tongat's case, I presume it would be Leydig cell, LH receptor, but possibly other receptors involved in its MOA from long term or high dose.

Emiel

Mode of Action, by the way.

Erika

Thank you for that.

Emiel

Yeah. So anything can cause some level of down regulation. That's just how our body works. But again, we are looking at not insane increases here. So I wouldn't expect shut down or anything like that to happen. And over time, yes, maybe we'll get a little bit less effective. But at the same time, you are elevating those testosterone levels and you might not have the same benefit of it after a few months. But overall, it would help maintain those testosterone levels at a slightly higher level. Other than that, I think this is another reason why you should stay away from high doses like we talked about in the cycling questions, the higher the dose, the more there is going to be a need for cycling off of it because you're pushing the extremes. You're getting much larger effect sizes, which for short term benefits might be good. But for long term benefits, you actually want to prevent very drastic down regulation from happening. So this is another reason why we just suggest taking a normal low dose of tongkat ali and just taking it long term so you can maintain those testosterone levels and you're not see-sawing back and forth all the time.

Erika

Absolutely. All right. Our next question comes from u/xnxxnxxxxn, and the question is, "I have no real questions about testosterone, but rather estrogen. Some stuff supposedly affects estrogen, such as astoxanthin found in your krill oil, but lots of us take it separately. So my question would be how to balance estrogen and testosterone effectively, especially in men who lift who don't want gyno or testicle problems."

Emiel

Yes. And this is a good question. And some of this I'm not going to mention the exact name because it's a bit of a medical thing, but the enhanced breast tissue growth in men is likely not due to estrogen at all. Like we talked about earlier in the podcast.

Erika

It's due to prolactin.

Emiel

Yeah. So with that being said, though, helping to balance your estrogen levels is a good thing. And it seems like your question is hinting at lowering estrogen levels. But this is a bad thing because men need estrogen as well. For example, estrogen is really important for microvascularization in your brain. If you take away estrogen, this could cause issues. estrogen also plays a role in the optical system, your eyes, so it could impact eye health and optic nerve health. So we want estrogen to stay around. One of the ways in which tongkat ali does enhance testosterone is by blocking one of the estradiol receptors. It's not necessarily lowering estrogen levels, but it is basically overriding the system that would limit testosterone production by blocking one of these estradiol receptors. But when you enhance hormone, luteinizing hormone is also important for estrogen synthesis. So when we are looking at things that help enhance luteinizing hormone expression, like tongkat ali and cistanche and fadogia agrestis, which we talked about earlier, which is not a great idea to take that probably. But when you take these luteinizing hormone-increasing supplements, then you're also increasing estrogen production in a beneficial way. So one way to actually help enhance both and help balance them is actually by taking the supplements we're discussing in this podcast.

Erika

Awesome. All right. Our next question comes from u/amazeface, and the question is, what are the risks of interfering with the hormone system? This was always something I was wary of. Ultimately, my curiosity led me to try tongkat ali, and I'm glad I did. But I wonder if there's still some wisdom to that wariness of hormone-affecting substances. Certainly, children should probably stay away from them at a minimum. What about college student aged people? When is it safe? Besides that, I would also echo some other questions around cycling this substance. I took it for a few months without a break and ended up feeling run down, though maybe another nootropic contributed to that, so I can't pin it directly on Tongkat. I only take it like every three days now. I'd be curious if there's some good advice around this."

Emiel

Yeah. So the hormone system is a little bit trickier and not as well understood as other systems in the body. But another thing is the hormone system usually gets abused to no end. And this is something we don't necessarily see with a whole lot of other things other than when we're looking at drug abuse or something like that. But in some of these bodybuilding circles, the hormone stuff they're doing there is definitely really pushing the limits. And I think we base a lot of our public perception about hormones and that kind of stuff on things like birth control and some of this performance enhancing stuff. But we're not really in that area at all. And we're looking at more natural ways of just optimizing and enhancing testosterone synthesis. And by just elevating it a little bit to where it is at more normal levels. If your testosterone is low or if your testosterone is at a more normal level to kind of get you a little bit more testosterone, but it's not really getting massive, massive increases of levels of testosterone that your body would never see. We are more mimicking youthful levels of testosterone. And this kind of brings us to the children thing. And no children should be taking any supplements, to be honest, until the age of 18 or unless you have some very serious doctor supervision, which is also why it says that on our labels. But after the age of 18, you could potentially take something like tongkat ali, but again, at the age of 18 and below that, your testosterone levels are probably quite high and you are doing a lot of muscle protein synthesis. So is there really a need for it? Would it really do anything if your testosterone levels are already that high once you are past the age of 18? Maybe you're 22, 23, 24 or something in that age range and you're starting to get more stressed and your nutritional intake starts to degrade a little bit because you're in college and you're probably pounding beers all weekend long like I did, then taking something that helps enhance testosterone production is probably a good thing, especially as we start to get a little bit older. So that being said, you can try it if you're college aged, stay away from it as a kid. You don't want to take anything under 18 anyways and you probably really don't need it anyways.

Erika

Nice. I like that response. So moving nice and quickly onto our next question from u/nightwaif. "I'm interested in tongkat ali's ability to inhibit aromatase. I've seen people mention this a lot, but I wonder if there's any evidence to back that up or how strong the inhibition is. I haven't gotten blood work to support this, but I seem to get high estrogen sides when I use your 10% extract daily and I expected it to have the opposite effect." So Emiel, what say Ye?

Emiel

Again, we're not really talking about enormous increases in testosterone that you would never see in a normal human being. We're more optimizing overall testosterone. With that in mind, we're probably also not seeing a ton of testosterone being aromatized into estrogen and tongkat ali does seem to have some mild anti-aromatase activity which would help prevent some of this conversion of testosterone to estrogen. But like we've been touching on a lot, I think we are oftentimes misreading the negative effects we're getting or misattributing the negative effects we're getting with some of this hormone stuff to estrogen when it is really prolactin. So again, I think prolactin is the culprit here. So having something like apigenin which can lower prolactin levels might prevent some of those things from happening. And maybe some of the negative effects that you're experiencing is actually because of prolactin and not because of estrogen.

Erika

Good to know. Now another question from u/Delightfooll. "Echoing other comments, this is from your description of cistanche. Echinacosides support overall testosterone levels. Isn't free testosterone what matters, not overall levels? How do we finesse this, the role of aromatase inhibition? Does testosterone affect dopamine, motivation, mood, and if so, what's the general significance?"

Emiel

Yeah. So you have indeed bound testosterone to sex hormone binding globulin, SHBG, and then testosterone bound to albumin, and then you just have free testosterone. Free testosterone is what is interacting with the androgen receptors and is causing the effects that we want bound up testosterone isn't, but you need bound up testosterone to transport it around your body. So if you just have a bunch of free testosterone floating around, then it might not actually get to where it needs to. So we are actually concerned about elevating overall testosterone levels, not just free testosterone levels, because we want that testosterone to be able to get to where it wants to get. So enhancing overall testosterone while making sure that we don't have everything always bound up is the way to go. And this is kind of what tongkat ali seems to achieve. It seems to achieve a nice balance between bound and free testosterone.

Erika

Awesome. And now we're going to move on to a really interesting selection of questions about cholesterol and testosterone. So our first question comes from u/Hyrcane, and the question is, I would be interested in learning more about the relationship between cistanche and cholesterol intake as well as tongkat ali with iodine. I've read some people and u/MisterYouAreSoDumb talking about it on the subreddit.

Emiel

Yeah. So testosterone is synthesized at the end of the day from cholesterol, so you need cholesterol to help enhance testosterone synthesis. It doesn't necessarily mean eating more cholesterol-containing foods is going to help enhance testosterone synthesis.

Erika

That would be nice.

Emiel

It would be nice. And if anything, we usually have too much cholesterol floating around. And I would say we're probably never really in this situation where we just have such low cholesterol levels that we can't really make testosterone from it. So that's why when we're adding things like tongkat ali or cistanche in, we do get fairly good testosterone synthesis enhancing abilities from cholesterol without really messing with cholesterol too much. That being said, perhaps because more cholesterol is being turned into testosterone, potentially it could be seen as that is a cholesterol-lowering strategy, except we're not burning through grams of cholesterol to do this. We're burning through small amounts to produce relatively small amounts of testosterone because we're talking about testosterone in like 1020 30 milligram levels floating around. We're not talking about grams floating around, like we do see with some other endogenous compounds like glutathione and things like that, which are present in grams. But you won't see a huge drop in cholesterol levels, likely from enhancing testosterone synthesis. The iodine thing is interesting. I'm still not entirely sure why this helps, but it might have something to do with thyroid hormones and how this interacts with tongkat ali, so that's kind of, I think where we are looking at this, it does seem like taking some iodine with tongkat ali is nice. And actually, we could probably all take some more iodine because we are likely a little bit low in iodine, which is also why sometimes you see warnings on table salt that it says "This is not a good source of iodine." Or sometimes you see iodinized salt because it does seem like we are all a little bit low on iodine. So taking some extra iodine is not a bad idea, and especially if it seems to enhance the activity of tongkat ali.

Erika

Awesome. Our next question comes from a frequent question asker, u/solothesensei and this question is "If testosterone is ultimately made from cholesterol, then what part of the conversion process usually goes wrong that leads to low testosterone assuming adequate cholesterol intake? I know ND has a few products that help and would love to get a broad overview of how they fit into the picture, perhaps as cofactors or enzyme activators." Excellent question, as always.

Emiel

Yeah. So Cholesterol is being turned into testosterone by a bunch of different enzymes, actually, some CYP type enzymes, too, and tongkat ali and cistanche and even Shilajit, they help enhance what they call these steroidogenic enzymes. So these enzymes that are converting Cholesterol into testosterone. So maybe if something goes wrong here, we would see lower testosterone levels, and that definitely seems to be the case and especially as we age. So Shilajit specifically seems to enhance testosterone levels and aging individuals. And if we consider that these aging individuals have lower levels of these steroidogenic enzymes, then enhancing this enzyme activity with something like Shilajit, tongkat ali or cistanche is going to help there. That being said, when things go wrong, I think they might go wrong somewhere else, like tongkat ali blocks one of these estradiol receptors that kind of serves as a check. If it determines that there's too much testosterone floating around, then it will kind of shut off testosterone production. And I think this is more where the issue is. So the issue is probably much further upstream in the hypothalamus and the pituitary. And this is also where you see individuals who play extreme sports or in football, and they get certain head injuries. If they have injuries to their pituitary gland or the hypothalamus, then testosterone production can be impacted. So we want to enhance these things or prevent this from happening in athletes. So this is something Andrew Huberman talks about a lot on his podcast, too. And it's a really interesting topic that I think hasn't been researched enough yet. So we might figure out a lot better strategies of how to keep testosterone production and synthesis good in athletes and extreme sports, but also just aging individuals or individuals who have other sort of issues where they can't produce enough testosterone.

Erika

Nice way to flex on that question, Emiel. I'm impressed. All right, now we're going to go into another segment of questions, which is about side effects. And our first question comes from u/Savage545 which is "Will taking these supplements to increase testosterone, contribute to or speed up the process of hair loss or balding? If so, out of Tongkat, cistanche, Epicatechin, etc. Are some more prone to cause hair loss than others? Also, what is the ideal timing for taking these supplements for bodybuilding first thing in the morning, right before bed, pre workout, post workout, etc. With food or on an empty stomach? Lots of questions within that question. So we'll just go through them nice and efficiently for you.

Emiel

Yeah. Like we talked about a little bit earlier, DHT is really the thing that contributes to hair loss. So enhancing testosterone levels could in theory, enhance DHT levels, which then could in theory, enhance the process of hair loss. But that being said, with something like tongkat ali or cistanche, Epicatechin doesn't even really enhance testosterone levels so that's definitely not a concern there. And the level at which testosterone is being enhanced by things like tongkat ali and cistanche, I don't think you're going to get massive, massive increases in DHT, like some of these Mr. Universe type bodybuilders we see, which is why they're mainly all bald. We're likely not seeing that here, so I wouldn't really worry about that. It's another thing with creatine. Even though creatine enhances DHT levels, we don't see people suddenly losing their hair because of the extra little bit of DHT from creatine. There are some things you can do to help prevent some of this DHT from being formed, but at the end of the day, we need DHT. DHT also has an effect on our cognitive function and muscle growth, and it's an important compound to keep around. So that being said, I just really wouldn't worry that much about DHT in a supplementation setting.

Erika

Awesome. And now the second part of this question, which is "What's the ideal timing for taking these supplements for bodybuilding first thing in the morning, right before bed, pre-workout post-workout, et cetera, with food, or on an empty stomach?"

Emiel

In terms of timing. Really, honestly, take it whenever you want. We're more long term trying to optimize the synthesis of testosterone, and this is more of a long term thing. So whenever is most ideal for you, I will say, because tongkat ali does have a bit of a calming effect and it can knock down cortisol levels. This could be a really good thing to take post-workout, for example, because after your workouts, cortisol spikes. So you could help blunt some of this exercise-induced cortisol spike, which could be catabolic by taking some Tongkat. This is another reason why people like to take carbohydrates after a workout, because carbohydrates help blunt that cortisol response too. But taking something like tongkat ali after a workout might have the double benefit of knocking down that cortisol, enhancing anabolism and then also enhancing overall testosterone levels. Then in terms of with food or without food. If you can handle the tongkat ali on an empty stomach, which not everyone can, then just take it on an empty stomach because it will cause faster and more complete absorption, whereas taking it with food, you will have slower overall absorption. You won't reach as high of serum levels. But on the other hand, you will extend the effects a little bit because you're slowing down absorption, which also means you're slowing down excretion. So there are benefits to both. I always like taking my supplements on an empty stomach when I can, though.

Erika

Nice. All right. Our next question comes from u/12ealdeal, and the question is, why does tongkat ali make me feel sleepy, tired, unmotivated for a brief period after taking it?" And before you answer, Emiel, I do have to say, when I tried the 2%, after about 35 minutes or so, I had a period of 15 minutes where I felt really sleepy and really relaxed and then all of a sudden it kind of went away.

Emiel

Cortisol reduction.

Erika

Makes sense.

Emiel

Yeah. So tongkat ali does a really good job of knocking down cortisol. If you were to take it first thing in the morning, especially right around like ten or eleven, then your cortisol levels are usually the highest, which also helps you stay alert in those early hours of the day. So if you're knocking down cortisol levels there, you could certainly notice that kind of effect.

Erika

Awesome. And that leads into our next question from u/jcash2142 which is "It would be cool if you guys could talk about the negative reactions to Tongkat and any counters. It worked great for me in the past, increasing testosterone, muscle size, energy, but it also gave me insomnia. If I take it now, I end up feeling fatigued. I assume it's something to do with the anti-estrogen effects, but who knows?"

Emiel

It's likely, again, the cortisol. So I've looked into this a few times because a few different people have experienced this and I've kind of been at a loss. What exactly is going on? Because I've actually heard a similar thing from our marketing director yesterday. They've been taking the Tongkat 10% for about a month now, I think, and his sleep quality has really improved. So there seems to be two sides of the coin. And it does look like if your cortisol levels are really low, you might actually get this paradoxical issues with sleep. So perhaps your cortisol levels are a little bit too low, which would be worth checking into. It would be worth maybe taking cistanche instead, because cistanche doesn't have this much of an effect on cortisol levels. Or you could take something like ginseng because ginseng helps mimic cortisol. So it produces a very small controlled stress response, which is important because you actually do need some cortisol to stay motivated and alert and focused. So one thing you could do is maybe try taking Tongkat together with ginseng, maybe the ginseng leaf extract, because it's a little bit more stimulating than the other ones too. So this could help. And again, I really don't think it is necessarily related to estrogen. It's probably cortisol.

Erika

Awesome. And now moving on to another question. "I'd love to hear a discussion on possible supplements to stack with tongkat ali," and then quick interjection, we've done that at length, so you've probably got plenty of things to work with here, "in order to counter the reported anti-estrogenic effects. I've always taken five milligrams DHEA daily with it, which I'm not really sure is helping or not. It would be nice to know if this is a good strategy or if there are better ones out there." Emiel, you'd probably be the perfect person to ask.

Emiel

Yeah, because I actually take DHEA with it as well. And I also take pregnenolone, both in five-milligram doses. And I hope this is something we'll carry at some point in the future, too. And I do feel like it helps enhance the overall effectiveness of tongkat ali. Again, because one of the things that cholesterol turns into before it turns into testosterone is pregnenalone and DHEA. So they work as very efficient precursors. And taking those alongside things that help enhance overall testosterone production is a really good strategy. So, yeah, good intuition there and good intuition on sticking with the low five-milligram dose of DHEA, because most people way overdose DHEA. It's a similar problem that we see with melatonin, for example, where most over-the-counter products are dosed enormously high. You want those lower doses, they work better.

Erika

Awesome. And our last question in this realm of questions comes from u/eamonn123. And they ask pretty specific question, why would tongkat ali and cistanche cause brain fog? I noticed the 10% causes a lot more brain fog than the 2%.

Emiel

This may again, be a cortisol thing. Your cortisol may just be dropping a little bit too low and you're getting that unmotivated lethargy thing. So the fact that it's happening with cistanche, I don't really have an explanation for necessarily maybe elevated testosterone levels don't really work well for you. Or if it is cortisol-related, again, taking something like ginseng alongside with it might solve some of these problems.

Erika

Awesome. And now getting to the most exciting and controversial part of our podcast. We're going to talk about one question on Fadogia. And it comes from u/12ealdeal. And the question is, men in my social circle have been taking Fadogia and they all say their testicles have increased in size. Why is that? I'm skeptical of it. And after just preliminary digging around on Reddit and on the internet, it's on my not-yet list.

Emiel

And it's on my not yet list, too, because this testicle enlargement effect is being attributed to this effect on luteinizing hormone, which, as we talked about a little bit earlier, enhanced luteinizing hormone production will also enhance the density of leydig cells that may grow the testicles because of that. But in some of the studies I was looking at, the testicular increases or size increases may also be an indication of its potential testicular toxicity. So it seems to mess with some other enzymes in the testicles that might cause them to swell a little bit and get bigger. So, yeah, maybe your testicles are getting bigger and maybe this is what you want because we all want big balls, right? But at the end of the day, this might actually be a sign of toxicity. So another reason not to take Fadogia like we've talked about in the actual body of the podcast, there are some toxicity elements that have not been properly explained away yet by science. So it might have testicular toxicity, it might have liver toxicity, and it might have kidney toxicity. So before we know more, I'm going to keep this one on my not-yet list.

Erika

Awesome. And last but very not least, we have questions about other testosterone supplements. The first one coming from u/TheOptimizzzer who is asking great questions on a lot of our podcasts. And this one is "Also, are there any studies indicating that Shilajit actually increases testosterone? And, is washing down Shilajit with tap water actually concern at normal chlorine levels, or is that a myth?"

Emiel

So there is some evidence that Shilajit enhances steroidogenic enzyme activity, part of the thing that takes cholesterol and eventually turns it into testosterone. But this effect really seems to work the best in older individuals or individuals with impacted enzyme activity there. But in older individuals, there is actually human clinical data showing increases in testosterone, so there is some evidence for it. Whether or not this happens in young, healthy people is a bit of a question mark, but the evidence and the mechanisms are there for supporting testosterone synthesis, but not really at the same magnitude as something like Tongkat or cistanche.

Erika

And then for the remaining part of the question, "Is washing down Shilajit with tap water a concern on normal Chlorine levels?"

Emiel

Yes. So this is a bit of a question mark, too. And the data is there to show that chlorine interacting with Shilajit is potentially not good. So I would just say skip this and Shilajit tastes kind of gross anyway, so it's probably better to take it in a capsule or in an Oblate disk anyway. And then you would prevent this issue of potentially Shilajit interacting with Chlorine.

Erika

Good to know. All right, our next question comes from u/lewanay, and the question is, can you talk about the mechanism of Tribulus? Is there any synergistic effect with combining Tongat, cistanche and Tribulus?

Emiel

So Tribulus, a lot of people seem to think that it enhances testosterone levels, but I really don't think it actually enhances testosterone levels, but it might have an effect on mTOR, which will enhance muscle building and muscle protein synthesis. So I think that's where some of the strength benefits are coming from with Tribulus. And we're actually looking into some Tribulus extracts because we do think it is quite interesting, but we kind of need to set the record straight that it's likely not a testosterone enhancing thing, even though it's oftentimes promoted as that. That being said, because it is working through a different pathway, but it still seems to be enhancing overall muscular strength and endurance and things like that, recovery. It could be very good to stack alongside something like tongkat ali or tongkat ali and cistanche because of their potentially synergistic effects, since they are working through different mechanisms.

Erika

Awesome. Good to know. And another question about other testosterone supplements comes from u/cheddabob25. Love that name. "Would love your thoughts/research on ashwagandha for testosterone support, and also the combo of fenugreek and ginseng."

Emiel

Ashwagandha does seem to have some minor testosterone benefits, more so supporting testosterone levels not necessarily increasing testosterone beyond your normal baseline levels, but more maintaining it there and helping to enhance overall vitality through some research there. It seems to work well, so it is a good one. But again, if you're really looking to really optimize your testosterone levels, go with something like Tongkat or go with something like cistanche, or go with something like cistanche and then stack it with Shoden or Ashwagandha. I always say Shoden now because Shoden is just my all-time favorite. The other ones are really nice too by the way, but I really like Shoden. Anyways, if you take something like Ashwagandha alongside cistanche, you might have this nice stress-relieving effect, but also dropping cortisol levels in a similar way to tongkat ali, but maybe in a more controlled way too. So those could stack well together.

Erika

Awesome. And then the second part of the question about the combo of fenugreek and ginseng and we don't currently have a fenugreek extract, but I love fenugreek as an ingredient for food. I'm really curious what you think about this combination.

Emiel

There is some interesting research there that fenugreek may indeed help enhance testosterone synthesis. I haven't delved too deeply into it, so I still have to do this and I'll have to specifically do some research actually into the fenugreek and ginseng combo because this is one that's new to me. Ginseng is another one of those where it will probably help support overall testosterone levels, but it may not really boost testosterone levels to the levels that we're wanting to see and that we see with things like Tongkat. But it could again have a supportive role and ginseng would stack especially well with Tongkat because Tongkat is dropping cortisol levels, but then Ginseng is providing some of that more controlled stress response through its cortisol mimicking abilities, so having taken those together would probably make a really nice stack overall.

Erika

I love it. And our very last question comes from u/TheEternalTruth. What a great name to end with. And the question is "What about information on Turkesterone? This research chemical is all the rage now, especially since a few popular YouTubers brought it to the awareness of the fitness industry." Emiel thoughts on Turkesterone?

Emiel

So Turkesterone is not a research chemical, I'll just say that right away. It's actually something that is technically found in nature. I don't want to give away too much information yet, but we have been doing a lot of research into this and it's not looking all too great for Turkesterone, so it is something we're interested in. It is something that we don't necessarily think is realistically possible, and we'll talk more about this later when we are ready to present our research on this. But it is an interesting thing and I know actually Andrew Huberman has talked about it too, which is probably where some of the interest is coming from as well. But Turkesterone is also very similar to beta ecdysterone and that is something that's more realistically possible. And you may see from us in the future. In terms of your last question about SARMs or, I'm just reading it off the page here. Erika hasn't said it, but this is not something we will discuss or ever carry. They're not really allowed to be sold as supplements and they're a little sketchy, in my opinion.

Erika

So what an episode, right Emiel?

Emiel

Oh yeah.

Erika

We covered a ton of ground. Thanks to anyone who's still listening. Truly. Thank you. And thanks for your questions. And thanks for steering the In Search of Insight Podcast into these really interesting areas. We covered so much ground today, talking about testosterone and hormones in general, talking about tongkat ali and cistanche and fadogia agrestis and the way that we at Nootropics Depot approach testosterone supplementation. I'm really glad to have tried out Togkat Ali, the 10% and I'm excited at the effects that I've experienced over the last couple of days because I think when it comes to conversations about hormones, we can all be really sensitive and perhaps deterred by fear or misinformation to not dig a little bit deeper and find out for ourselves what's going to be beneficial for supporting testosterone and supporting these areas of our lives, like our workouts and intimacy in our lives and energy and motivation. But Nootropics Depot, we're all about pushing the boundaries. We want to research, we want to learn more. And that's really what drives the In Saerch of Insight podcast is our curiosity, your curiosity and your questions and the back and forth that we get. So, for anyone who's not aware who might be listening to this podcast, we have a really active subreddit where you can talk with us all the time, not just through questions in the podcast, but you can actually ask questions on our subreddit that's r/NootropicsDepot and get into conversations with other Nootropics geeks just like you every single day. So go and join our community on Reddit, r/NootropicsDepot and join the conversation and ask your questions and share your knowledge and research studies that you're finding. Because the more exchanges that we have, the more we all learn and the better able we will be to optimize our health and to push the nootropic supplement industry forward, which is our main goal and the thing that we're truly passionate about at Nootropics Depot. So thanks for participating. Thanks for coming on this very long podcast journey with us. Thank you, Emiel, for your wealth of knowledge and your answering of all these questions that we have and really guiding us along this super informative conversation.

Emiel

Of course, it's a lot of fun and it's a lot of fun to be able to talk about this at more length because this is what I really like doing and I don't often times have the opportunity to do so because this goes over a lot of people's heads. But you guys are very smart and I'm confident that you're understanding what we're putting out there.

Erika

Absolutely. And if you do have follow up questions or things you want to know about specifically from the podcast, write us a comment on YouTube, make a post on Reddit, interact with us on Instagram or Facebook. You can follow us on social media and as always you can listen to the In Search of Insight podcast on a host of your favorite streaming platforms so be sure to check it out, share it with your friends who might be interested and come back next month. That's going to be, the next month is going to be our 7th episode of In Search of Insight, for more information, new products that have been released and exciting conversations all within the world of supplements. So with that we will sign off and say thanks for listening and we'll see you next time. Bye!

Emiel

See ya.

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#005 | A Delicate Balance | The Science Behind Intelligent Supplement Stack Development | Natrium Health

Podcast Transcript

Erika

Hi, and welcome to In Search of Insight, Nootropics Depot's monthly podcast. I'm your host, Erika or u/NootropicsDepotGuru on Reddit. And standing across from me is our product specialist, Emiel.

Emiel

Hey, everyone. And I'm called u/Pretty-Chill on Reddit.

Erika

So this month we are getting into a very exciting topic, which is stacking and stack development with Natrium Health.

Emiel

Yes, and Natrium Health. For those of you who are unaware of that brand, it's our sister brand of Nootropics Depot. So if you've been on Nootropics Depot and you've seen some of these products on our site, it's not a different company. Well, it is a different company, but it is us. These products are made by us, they're tested by us, and we develop them. And the development process is what we'll be talking about today.

Erika

Before we get into that complex process of talking about stacks and stack development, I want to know a little more about the history of Natrium Health and where the sister company actually came from and why it was started.

Emiel

Natrium Health started as our outlet for natural products and mostly natural products in stack formulations, which is what we'll be talking about during this podcast. The important aspect of this was Nootropics Depot and Ceretropic, the company that we still had around at the time, we were just doing single ingredient things in bulk so that you could just experience a single ingredient and you can make your own stacks. And it was more geared towards people who really knew what they were doing and very advanced users of supplements and users that could very easily put together effective stacks. But stack development is very complex, and we got more and more requests if Nootropics Depot could do their own stacks. And we realized at the time, at least Nootropics Depot wasn't necessarily the right platform for this. And that's why we developed Natrium, so we could have more creativity with the products that we do, different branding. So you'll see, with Natrium Health, our labels are a little bit flashier, and we had a lot of fun with that. And the stack development product is more interesting and dynamic. So the whole purpose of it was to have a refreshing young and fun brand with products that are easy to use and easy to understand.

Erika

And that makes a lot of sense because some of my favorite stack products that Natrium Health puts out are just standbys that I take every single day in my daily stack. But I don't want to get too far into that right now because there's a big question, and it's something that you all ask us a lot on Reddit and in emails, which is, what is a stack and how do I create an effective stack? And what all goes into putting together a stack that works for me.

Emiel

So I would say a stack is at least two ingredients, if not more combined, taken at the same time with the intention to have synergistic effects. A very good, simple example of this is caffeine L-theanine where caffeine is the focal point, and we want to change something about caffeine specifically, we want to change the edginess, the stimulation of caffeine, the jitteriness. When we add L-theanine, we shave off that jitteryness that edge, and now we have a synergistic stack.

Erika

Okay, that makes sense. So stacking is a way for us to combine ingredients, not just because they both have benefits, but also for those ingredients to be interacting within our bodies as they're being metabolized and absorbed, right?

Emiel

Yes. And there are two different types of stacks in that sense. One where the focal point is one ingredient and we are trying to enhance and another where we are trying to just achieve a single effect. So if you look on Natrium, we actually have two different categories of stacks. We have essential stacks, which basically are stacks that are developed around one focal ingredient, trying to make it better. So, for example, Optimala is enhancing and optimizing alphalipoic acid. Panamax is optimizing Panax ginseng and Dynamax, which we'll talk about a little bit more in depth later, it's kind of broaching that gap between the essential stacks and the comprehensive stacks, because there's a lot going on. But really, at its essence, the Dynamax stack's focal point is caffeine. And we just took it to the extreme.

Erika

Because I don't have a strictly scientific background. In fact, science was not one of my favorite classes in high school. I didn't take science when I was in college. I'm really curious to know, Emiel, what were some of your challenges and some of the obstacles that you experienced when you first started formulating stacks for Natrium health?

Emiel

My biggest issue was that I am a scientist and a little bit too hardline of a scientist when I started. So I would read 50-100 studies a day, and I still read a lot of studies a day, not as much as back then, but I would just pour through the research all day, and I would pull out all of these interesting ingredients and conceptually on paper think these two ingredients will go great together. And I had a bit of a reality check when I made Sleep Support, the first formulation of it. I was making the beta testing capsules myself. So in a very controlled environment, I was measuring out all the powders and blending it together in the V blender and creating basically small batch runs of capsules. So I was very excited. This was one of the first ones we'd really done a comprehensive stack. The capsule came together perfectly. I distributed all of them. We went home, we took it, and we had the worst sleep of our night.

Erika

This is the beta testing group, right?

Emiel

This is the beta testing group. So it's just people around the office and willing friends and family who say, hey, what's that funny looking capsule? Yeah. Okay. Here, take it and tell us what you think.

Erika

Okay, so then what happened?

Emiel

It's very internal. So after that, everyone had a terrible night of sleep. We all fell asleep perfectly fine. 2 hours later, we all woke up in a puddle of sweat. Turns out I was a little bit blinded by the science because I was reading papers in very controlled environments. So a lot of these papers on sleep studies, they're not doing them necessarily on humans. They're doing them on laboratory animals, mostly rats and mice who are fed the exact same diet at the same time every single day. They have controlled amounts of light and dark periods.

Erika

So nothing similar to what a human being might experience on a daily basis?

Emiel

No, not even close. Sometimes I wish I was a rat and I had such a predictable schedule. But the reality is humans don't really have predictable schedules. All sorts of stuff happens all the time. You can't get to sleep because there's a cat outside meowing too loud. Or there's

Erika

Changes in your diet, perhaps?

Emiel

Changes in your diet, changes in your emotional wellbeing, maybe you broke up with a girlfriend or a boyfriend and you're so emotionally distraught you can't sleep anymore.

Erika

Okay, so how does this have anything to do with Sleep Support though?

Emiel

Well, to bring it back with animals, they live in such a controlled environment that you can just give them something and it will pretty much work and you observe them and they have a perfect night of sleep and maybe it's a little bit better. There are certain aspects of it that get measured and those things end up in studies. And if you just read those studies and never try those ingredients out on yourself, then you'll only know what it does in an animal model. And we really appreciate animal studies. In fact, most of what we know about supplements and isolated compounds and neurotransmitters and things like that are because of animal studies, but we want real world results. So if we just pour through the research, slap a bunch of ingredients together that according to separate research studies should go well together, then the end result could be something like the disastrous first version of Sleep Support. It actually took seven versions before we got it right.

Erika

That was going to be my next question, but I really didn't know that it was that intense and long of a process.

Emiel

Very long. And then when we did arrive at our 7th version and we put it out into the world, it was very well received until a few months later, a couple of people popped up that were saying they were having adverse effects to Sleep Support and it was keeping them up and we isolated it to the micro zinc. So the zinc content. So early versions of Sleep Support contain zinc and now they don't contain zinc anymore because more and more people start popping up with this problem. But if you look at all the research that's out there. Zinc should help with sleep, and there is no known pathway by which it should impede sleep. Which brings up a really interesting question, why is this happening? And I think I found out why it's happening, but that's not really a topic for conversation in this podcast. Maybe I can talk about it on Reddit at some point.

Erika

Yeah, absolutely. So once you got to that final version of Sleep Support, but then you're still getting feedback that it wasn't having the effect that you were hoping for, what happened then? So you removed the zinc and then how's the feedback been since then?

Emiel

Perfect. Yeah. All the problems that people were having with it disappeared after we took the zinc out. And it didn't really seem to make it a less effective product for people that did respond well to the zinc. So it was a pretty good trade off to take it out, but it was unexpected. And I think this is one of the things that sets Natrium apart. We look at the science, we formulate based on the science, we try it out, but then we're not so rigid that we don't deviate from this at all. We want real world results. And this is why I've oftentimes said stack development is sometimes more of an art than a science, because you need to know what these ingredients do when you put them together. And the only way to know that is by having experience with it, building up the skills, and then relying on those skills to bring it all together into a stack and then validate that stack again with science. So the science is always there. But you need to know how to be skeptical of the science, how to manipulate the science to your liking. Similar to cooking, if you cook from a recipe book, maybe the salt you're using has a slightly lower sodium concentration than the salt that the author was using, and maybe that's going to change the salinity in your end result, and then it's not good. But if you're tasting your food as you're cooking, you can compensate for that, and that's where the art comes in.

Erika

Yeah, absolutely. And this is kind of this tasting aspect or this idea of continuing to refine a stack is something that I am aware that Natrium health and the Natrium products go through a lot. You take a lot of time to reformulate products and take out or add ingredients that might optimize the stack itself to a point where it can be more effective for people. And then, like in the example from Sleep Support, we're also taking the feedback from you people who are taking these supplements into account and considering what kinds of additions or subtractions might make the stack useful for even more people. And that exchange that we have and your reviews and your interactions, and you sharing your experience, whether it's on Reddit or a product review or in an email that really has a significant impact on the way that our stacks are formulated, because we also rely on your experience, too. Just as consumers and people who are educated and curious about finding the best ways to optimize your daily stacks.

Emiel

Yeah, it's important to realize that a lot of the people behind Natrium Health and Nootropics Depot and Ceretropic at the time, we all use these products ourselves. We are all biohackers, too, and we want safe and effective products. So this is a very good position for us to be in because we get to develop products for you, and we get to develop products for ourselves, kind of while we're doing that. But that also means that our stacks have real world results with real human beings in mind, not lab animals in a study or just some random people who came into a clinical trial and tried, like, caffeine L-theanine in together and then had to go through some terribly boring, arduous task where you're sitting around memorizing words and doing it.

Erika

Playing with blocks, or filling out a survey.

Emiel

Yeah, I have a degree in psychology, so I've run a lot of these studies myself and running the studies, I didn't like it. Interpreting the studies, I didn't like it. And talking to a lot of the people in those studies, they didn't really like it either. And I think if you're trying to develop a product that's supposed to be taken just in normal everyday life in such a setting, you get very boring, homogeneous products. And if you look around at all of the stacks that are out there, they're all pretty similar. And when you compare those stacks to our stacks, our stacks can seem a little bit weird sometimes. Like, why did they decide to do that? For example, something in Sleep Support that a lot of people always are confused about is the fact that we put Shilajit in it and we put Shilajit in it because Shilajit seems to have glycine-mimetic effects and through this can enhance sleep, but wrongfully so, for whatever reason, a lot of people think Shilajit is a very strong stimulant. So they're always confused why we put it in there, but because we actually had years of trying out Shilajit ourselves, we noticed that, hey, if I take Shilajit close to bed, I sleep a little bit better. So based on that personal experience and then validating that with science, we decided it was a good ingredient to use in Sleep Support. Actually, Sleep Support was pretty polarizing because another ingredient in there that is for some reason wrongly assumed to be a stimulant is Uridine. I even went along with it for a while until I started seeing some reviews on our website pop up that people were having great success with it for sleep. And then when I was digging into the studies, I found that, yeah, there is actual evidence for Uridine enhancing sleep, but relying on that humanizing aspect of all of this makes it so that we have very effective stacks.

Erika

And as opposed to your kind of dry and controlled experience of putting together experiments and testing, whether it's different compounds or different ideas in your College days, the process of bioassaying and the process of researching for Natrium stacks is pretty fascinating and exciting because like you said, with stack development being a little bit more of an art than a science, there's always some creativity included in art or in things that you're creating. I think that's something that I really enjoy about Natrium Health stacks is they're creative and they're innovative, but above all, they're super effective. And having that element of creativity and flexibility to really trust in your own experience of a single ingredient or your own experience of a stack is such an important part of the development as a whole, because we really rely on the feedback from customers and our own personal experiences when it comes to putting together an effective stack. Whether that's a stack in one product, in one capsule, or combining different single ingredients in our daily lives to make stacks for ourselves.

Emiel

Absolutely. And one thing that this highlights is we don't like to play it safe. We come out with polarizing products that have real world effects. We don't design products just because they will sell. We could very easily do that. If we came out with a spirulina and Chlorella capsule with maybe some collagen in it, we would sell a lot of it, but it doesn't work. Chlorella basically doesn't do anything. Spirulina is very interesting. We'll probably do something with that in the future. But there are a lot of stacks out there that just combine ingredients for the main fact that they might have good search engine optimization results or they might just be searched for a lot. Or if you just slap those ingredients together, yeah, you'll sell it.

Erika

People recognize them, so they seem kind of familiar and stuff.

Emiel

Exactly. And that's not what we want, and especially not with Natrium. We want novel, innovative stacks that work, and that kind of push the boundaries, and that maybe make some people a little bit uncomfortable. Like if you're looking at sleep support, you might look at the formula and go, there's no way that's going to work. It has uridine, a stimulant and it has shilajit, a stimulant. But having stacks there that kind of push the boundaries and have real world results is what we like. And this is probably due also to the personalities of a lot of us. We like to live on the edge a little bit. We like to really push the boundaries. We like to push each other's buttons. We're always challenging each other and challenging each other to be better and to further push the boundaries and to discover things that no one's talking about and to try out combinations that no one's talking about and to find effects that no one's talking about. That's our bread and butter.

Erika

Absolutely.

Emiel

And that's why these stacks work.

Erika

And one of those products that I know for a fact is the result of that push is one of the most recently released Natrium health products, which is Dynamax Plus because there's an original Dynamax which is super effective. It's our optimized caffeine supplement. But then we recently just released Dynamax Plus, which is our optimized caffeine supplement to the max turned up to eleven. That was one of our hints that we gave you when we were asking what you thought the next Natrium release would be.

Emiel

And it really is because the Dynamax Plus is intense and we're really tiptoeing the line of what's possible with caffeine, really pushing the limits here a little bit, but still trying to make sure that we have a safe and balanced product. And part of this is also there are a lot of extremely high caffeine products out there. I've seen pre workouts that have close to 800 mg of caffeine in it per serving, which is just insanity. And we've seen a lot of energy drinks like Bang Energy and Rain Energy and I'm sure there's others on the market now that have at least 300 milligrams, maybe even more at this point of caffeine in there. So sometimes we see trends like this happening and we realize that it's undeniable. People want high caffeine products and a lot of people started requesting that we came out with a higher energy Dynamax formulation because they really like the overall character of effects, but they wanted a little bit more. So we have in the past suggested people just drink a cup of coffee and then take Dynamax Plus, but that's kind of inconvenient and at the end of the day you want an all in one product. Especially I imagine people that consume high amounts of caffeine probably have the need for a lot of energy in their day because maybe they do so much that they're short on time and they just want to open a bottle and take a pill and be great for 8 hours. And that's exactly what Dynamax Plus is. But because it is such a high caffeine stack and especially for myself, I'm a pretty low caffeine user, so developing Dynamax Plus was kind of an adventure because I was taking super high doses of caffeine and that's really intense. But if I had shied away from that and went, no, I'm not a high caffeine user, I can't beta test this stack, then it wouldn't have worked because we need my input and we need MisterYouAreSoDumb the owner of the company that's his name on Reddit, by the way, for anyone who sees him popping up. We both work together and we talk a lot about the effects we experience. And one thing with Dynamax Plus is that the character of Dynamax is very important. Dynamax, the original formulation has a very specific effect and to dial that up a little bit more proved to be quite hard, which is why beta testing was important. But it was also important that I wouldn't shy away from high caffeine experimentation just because I was apprehensive about it. And maybe it wouldn't work well for me. I kind of sometimes have to just push through that to make good products, and I think that's what sets us apart. We really put ourselves on the line with testing, and we take up valuable time in our day to day lives to track these and make notes with sleep support. It's an interesting beta testing phase because you need 8 hours to beta test it at night. Outside of work, you don't get to do it in a controlled environment. So there are some sacrifices that need to be made, like exposing myself to slightly higher doses of caffeine than I'm comfortable with. But doing it that way means that we have a very broad understanding of how these products work in people with low caffeine sensitivity, high caffeine sensitivity, people that don't sleep well, people that sleep well, having a pool to pull from and make it work as well as possible for everyone else, which at the end of the day, Dynamax Plus actually works quite well for me. It is very nicely balanced. And even though I'm a one small cup of coffee a day drinker, subjecting myself to 400 milligrams of caffeine ish I was surprised that within the context of Dynamax it worked well because I've tried other high caffeine products that weren't very beneficial for me. So being able to take those aspects and make it work for everyone is a big thing that we try and do here.

Erika

Absolutely. And like you're saying, the formulation process, going through the experience of taking these maybe higher doses of caffeine, these early iterations of stacks is something that we do ahead of time, and it's sort of one side of the coin. So we push ourselves to test and to bioassay these products before we release them, because we want to know exactly how they feel, what their effects are, things that we might want to change, or things that might need to be adjusted within the formulation ahead of time. But then for you all, for you who are taking supplements and working on putting together effective stacks for yourself, we advise you to take one ingredient at a time.

Emiel

Yes, and this is extremely important, and it's something over almost a decade worth of experience that I've been able to build up for myself is a very good, functioning catalog of ingredients in my mind that I know how they work for me. And because of that, I can make stacks.

Erika

And when you take one ingredient at a time, you can have a better experience and probably better results in determining what exactly that ingredient is doing within your body, how it feels, its overall effects, whether it has an acute effect or not. And then once you have that experience and that knowledge, once you start combining the supplements, you can better determine what might be working well effects that you like that you're getting from these combinations, and then also effects that you're not so into and which product and which ingredient might actually be the culprit for those less than desirable effects. And this system of isolating and taking things one by one and then slowly combining them is something that we've also discussed a little bit in a previous podcast about mindfulness and bioassaying and just being aware of what supplements are doing within your body and how you can determine their effects for yourself, especially if you're not someone who's reading scientific studies all the time, or if you're a person who's really attracted to the stacks that you can easily take that are convenient for your everyday life.

Emiel

Yeah. And the difficult thing here is, like Erika was saying, sometimes things have acute effects. And when something has an acute effect, and especially if it has a pronounced acute effect, it's easy to know what it's doing. When it gets tricky is those subtle ingredients, those subtle little changes. And it's for any musician here or audio engineer or mixing engineer within music. It's similar like that, too. When you have a lot of experience, you start noticing really small micro details and things like that, and that adds a lot to the experience. Similarly, in a stack, there's a lot of micro details and very small things that change here and there. That within the context of a stack can get amplified, similar to maybe if there's some distortion in a recorded track and then you re amp it, then maybe you're re amplifying that distortion and it gets louder in the mix and you don't want that. Similar here, maybe if there's something in your stack that only causes a very minor alteration and effects that you don't like within the context of multiple ingredients that could get amplified and take over.

Erika

And that's not something that you'd want, because of course, you want the combination of ingredients and products you're taking to work together as best as possible, because at the end of the day, it's about improving your life, improving your cognition and bettering yourself and coming from this biohacking perspective. So in addition to this really interesting kind of personal experience of taking stacks and formulating your own stack, I had a recent experience with a newly released Natrium health product, OmegaTAU, which when I took it, the effect and the feeling of it overall, I wouldn't say is an acute effect, even though it was very noticeable. But the way that OmegaTAU kind of changed the overall feeling of my daily stack was really profound. And yet it was hard to put a finger on exactly what it was changing and what it was doing. But that has meant that adding it to my daily stack feels like a really nice combination and a really nice addition because it's not changing anything else I'm taking in a dramatic way. And it's not taking away from the beneficial effects from these other products I'm taking. But it's actually adding another element, a very detailed and subtle element to my daily stack that I really love. And I find that the cognitive benefits, the ones that I can feel and perceive, just give me this calming feeling and this kind of awareness of stressors without reacting to the stressors, which I think is a really cool aspect of OmegaTAU.

Emiel

Yeah. And within OmegaTAU, one of the ingredients, the sesame extract, was one of those ingredients where when we really paid attention to what it was doing because it came out of science, and then we put it in and we beta tested it. And when we beta tested it, we discovered that it was adding one of those little micro details, something like it was gelling things together. It was like taking a slightly bland tomato soup and adding just a sprinkle of extra salt, which just makes it pop and come together. So this is something we do in stacking a lot, too. And we keep making these analogies. And the reason why we keep making these analogies is because it is very analogous to a lot of these different aspects. Making a stack is just like cooking. It's just like making a cocktail. It's like working as a barista and developing your new themed fall drink. And maybe you decide within your pumpkin spice latte this year you're going to add a little bit of cardamom because it just makes some of those other flavors pop a little bit more. And just experimenting and being subtle with things is very important because with the pumpkin spice latte, if you put too much cardamom in it, all you're going to taste is cardamom.

Erika

And then it's no longer pumpkin spice. And who wants that?

Emiel

Exactly. But if you do a little bit, maybe it makes other things pop while not drawing attention to itself. And that's what we try and do in stacking. We want it balanced, we want it synergistic.

Erika

And this is the essence of all the Natrium health products. It's really about combining the right amount of different ingredients that will work together synergistically that will be the most effective for the most amount of people. And of course, there's always going to be an outlier here or there. Not all of us respond the same way to different products because we're human beings, we're full of variabilities, and we're not living in these vacuum controlled environments. But at the end of the day, we take your feedback and your experiences into account. And we also try and work and finesse and these really subtle ways to combine ingredients to be as effective as possible and also push those boundaries, because that's just a part of our passion with Nootropics Depot and with Natrium health is really pushing the boundaries and moving the supplement industry and the nootropic industry forward the best way we know how.

Emiel

And one of these new innovative things that we'll be doing is creating some more video content. So over the next few months, you'll see some more video content from us pop up. Actually, the first video content because we haven't really done a whole lot here. And one of our first projects that we thought would be interesting and would link up with this podcast is an instructional guide on how to make your own stack. So selecting all of the different ingredients for the stack, making sure that they make sense together, then blending those ingredients together and encapsulating them. This can be a really difficult process. And you'll see in this video content that it is indeed a very difficult process that takes quite a bit of experience and knowledge to pull off correctly. But this is a perfect topic to choose to do a video on, because we need more of that kind of information out there to show how are these things done, maybe not even as a purely instructional video on how to go and do this yourself, but to give more insight into some of the challenges that we as a manufacturer might have with making stacks and getting it all together and testing it, and just to show how complex this can be. And I think video content does a great job of that. In addition to these podcasts, and we want things to be easy and accessible for all of you. And this is part of the reason why we do what we do here.

Erika

Absolutely. And I think having the instructional videos that will show you, as well as tell you some of the processes that we go through as a manufacturer will give you a little bit of a different view of Nootropics Depot and give you an opportunity to see the products in action and how you might be taking them and experiencing them in your own lives. Here at Nootropics Depot, we like to keep things fresh and shake it up. So we're going to talk to you about new products that have been released since our last podcast episode. In the last month, we have released a handful of exciting new products for Nootropics Depot, the first of which is Panax Ginseng leaf capsules. Emiel, can you tell us a little bit about those?

Emiel

Yeah. Panax Ginseng leaf extract is a really unique one because, well, obviously we're extracting the leaves, and this is unique because normally Panax Ginseng only the roots are used. And there's a lot of mysticism about this as well. And it's a whole big thing that we're not necessarily as clued into here. But anyways, the leaf extract is a really interesting part of the plant because it contains a much higher concentration of ginsenocides than the roots, which means that when we make extracts, we can actually standardize to a much, much higher ginsenocide level. So if you look at our root extract, it's usually between 7% to 10% ginsenocides. These new capsules are a little bit higher usually, but the current root powder that we've had, it's always between 7-10%. And the leaf extract is 40%. So it's significantly higher. Not only is it higher in those ginsenocides, the ratio of the ginsenocides is also different. And we'll talk about this a little bit more in a second. But all the different ginsenocides produce different effects. Some of them are stimulating, some of them are calming. And it seems like in the ginseng leaf extract there's an abundance of stimulating compounds, and there's a relative lack of calming compounds. So the leaf extract is probably the least balanced Panax Ginseng product around. And it's very stimulating. It's very zippy. It's very clear headed. And this is one of the reasons why I really love it. And I'll actually be picking up some Panax Ginseng leaf capsules to take alongside my Panamax. So some Panamax early in the day, and then later in the day, a capsule of the Panax Ginseng leaf as a quick pick me up.

Erika

Nice. And that leads us into another ginseng product that we've released in the last month, which is our Panax Ginseng root capsules.

Emiel

Yeah. And these are actually quite interesting because they're made with white Panax Ginseng root. And this is kind of the most natural way in which you can experience Panax Ginseng because it's the Panax Ginseng form that has the least amount of processing associated with it. So a more common, actually v product is red Panax Ginseng. And red Panax Ginseng is made by steaming the roots at a pretty high temperature. And when you steam the roots, various reactions occur, including a pretty simple one, the Mayard reaction, which is the same reaction that browns your food. When it happens in the ginseng root, you get a red color, which is why it's called red Panax Ginseng. But red Panax Ginseng has a different composition of ginsenosides because the heat actually changes the natural ginsenosides into different ginsenosides. So with the white Panax Ginseng root, which is in our capsules, you get to experience more of the route in its most natural state. And in its most natural state, it's not as stimulating, actually, and it's more calming. So the white panic shining root capsules are a nice calming option. And it's actually the root extract that we use in our Panamax. And using the white panics ginseng root together with the panic ginseng leaf made for a really nice balance. When we tried it with the red panic ginseng root and the panic ginseng leaf, it was a little bit too stimulating and we didn't have the balance that we were looking for. So this ties in nicely with the topic of conversation of this podcast is that we really try and finesse our formulations using different forms of the same botanical maybe different extract ratios, different processing ratios, different extraction methods, and we really get down into the nitty gritty there and use everything to make good stacks. But anyways, now you can try that one out as a standalone, and it's a pretty interesting one.

Erika

Yeah, absolutely. I like the idea of the different parts of the Panax Ginseng being useful, perhaps at different times of day or for different needs. And if you did decide you wanted to combine them, you could even adjust your dose for one or the other of the standalone ginseng products to get more of the effects that you're looking for.

Emiel

Absolutely.

Erika

Cool. Okay. So next, we're going to move on to another kind of exciting product that Emiel and I have both been really into recently. We are releasing or we have released Taurine capsules. Taurine is an endogenous compound. It's present in the human body. This is news to me, relatively new. And it's also really exciting because I've been taking Taurine powder recently, and I think having capsules available for any of our standalone products is really great for those of you who are a little bit scale averse or for those of you who just prefer the ease of taking capsules. So, Emiel, tell us a little bit about Taurine and why it's exciting that we have it in this new format.

Emiel

So Taurine is an amino acid. And the interesting thing about it is that it is one of few sulfur containing amino acids, and this is partially because it's actually derived from another amino acid called L-cysteine. And L-cysteine is one of the primary sulfur containing amino acids. Taurine is also sulfur containing amino acid. And while that might just sound like a little bit of jargon, that doesn't really tie into anything, the interesting thing is that it can act as a sulfur donor, and specifically, it can act as a hydrogen sulfide donor H2S.

Erika

And this is something we talked about in our last podcast episode about reduced glutathione and N-acetylcysteine talking about hydrogen sulfide donors in the context of L-cysteine. But now we're talking about it in the context of Taurine because Taurine is also coming from L-cysteine.

Emiel

Yeah. And I discovered that Taurine was also a really good hydrogen sulfide donor by doing research for the last podcast. And when we were talking about glutathione and N-acetylcysteine, this kept coming up. And then I realized, hey, Taurine is a really good hydrogen sulfide donor. And hydrogen sulfide has a lot of different benefits. It is actually an endogenous neurotransmitter. It's one of few gaseous neurotransmitters, the other one being nitric oxide. And as a gaseous neurotransmitter, it has lots of different functions throughout the brain, controlling neuroplasticity, long term potentiation, blood flow. It seems to upregulate GABA B receptors, which in the context of Taurine is pretty interesting because Taurine has GABAergic effects to begin with. So Taurine as a whole seems like a very attractive amino acid. And unfortunately, one I think that's often overlooked, and it was often overlooked by me. I don't know why it took me this long to get interested in Taurine, but now I've been playing around with Taurine a little bit, and I actually really like the effects. And while I was playing around with Taurine we also developed Dynamax Plus, and we wanted to enhance the energy levels of Dynamax Plus. And we found that L-theanine could smooth out the effects of caffeine a little bit too efficiently sometimes. So we dropped a dose of L-theanine and now a lot more stimulation of the caffeine was coming through. However, now there was a little bit of like an uncomfortable physical feeling with this high level of caffeine and a lower amount of L-theanine. And so we discovered that if we combine a small dose of Taurine with L-theanine the two together complement each other very nicely. And Taurine takes care of some of that physical uncomfortableness jitteriness from caffeine and smooths that out nicely.

Erika

So this is like an example of stack development, kind of in real time, making adjustments to the initial Dynamax formulation for this new product, Dynamax Plus, and adding and changing the dosages of certain individual compounds or products that are in there to make a better stack that works well with this high caffeine content.

Emiel

Yeah.

Erika

We just mentioned another one of the exciting new products that we've released, a Natrium Health release, which is Dynamax Plus. So we talked about it a little bit earlier in the podcast and we were mentioning some details about the formulation process. But Emiel, give us just a general understanding of what is Dynamax Plus. Who is it for and why is it the awesome new caffeine super supplement on the market?

Emiel

So I would say it is the super new awesome caffeine supplement for a select few people. Dynamax Plus really is for seasoned caffeine users. You've tried everything you want to push the limits a little bit more. You can try something like Dynamax Plus, but keep in mind it has a very high caffeine content. So if you are a little bit sensitive to caffeine, this is not a good one. But if you are interested in the effects, you can actually try out our original Dynamax, which has a much lower content of caffeine and higher content of L-theanine. And it's a little bit smoother. But Dynamax Plus is for people who always wanted to experience Dynamax with more power behind it. And this is what it is. So it's very stimulating, very long lasting. But even though it's very stimulating, it's also quite smooth and balanced. So that's what we went for with Dynamics Plus. One of the main aspects of this is that it kicks in very quickly. So within about 15 minutes you can start feeling Dynamine, which is very interesting because normally you have to wait quite a while for the stimulating effects to kick in from caffeine. But with Dynamine, it kicks in very quickly. So Dynamax plus also kicks in very quickly. But then it gets a little bit more interesting because after the methyliberine, you get some just normal caffeine. And that kicks in in around 30 minutes. But methylberine actually potentiates caffeine a little bit. So the two together work synergistically to create an overall more stimulating effect. But it's kind of a twostage thing. In the beginning, you get this very quick rise with Dynamine, and then it seems to level out. But then you start progressing from a higher plateau a little bit above your baseline. Your energy levels are up already. Your system is kind of primed in that sense. And then the real ride starts. It starts getting more and more stimulating. But then as it starts getting more stimulating, the L-theanine and the Taurine also come in and help smooth that out. And then at around the two hour Mark, we put in some delayed release caffeine. So at the two hour mark, it just releases a small bolus dose of caffeine. And I find that at around the two hour mark, because the Dynamine kicks in so quickly and it also wears off somewhat quickly, the effects start to dip a little bit at the two hour mark, even though it's still quite stimulating but I like to in beta testing, all of us like a little bit of a bump at the two hour mark to get you back up a little bit more. And then after that, there's some extended release caffeine in there, which releases a small amount of caffeine throughout the whole eight hour duration of the Dynamax experience, as we like to call it. And this actually doesn't really add to the stimulation all too much, but it cushions your ride down, so there's not as much of a crash. Even though there's quite a high caffeine content, it lets you down slowly.

Erika

That's probably exactly what we're looking for with a high caffeine supplement, especially because that come down period can be a little rough sometimes, depending on if you have some lack of sleep or you really need to stay focused. Maybe you're on the road or doing long cognitively challenging activities where you need that stimulation, you need that caffeine, but you also don't want to find yourself in a moment where you're going ah! Nothing's working in my brain anymore. Kind of coming down, being let down easy as you said.

Emiel

Yeah. And caffeine come down. It's no joke. And it gets worse and worse the higher in does you go. So we wanted to put something in there which would pad the landing, so to say, and it does a really good job at this.

Erika

Awesome. So now we're going to talk about another exciting Natrium health release in the last month. And that is OmegaTAU. So Emil set the stage for us. Give us a nice understanding of what is OmegaTAU, what's it doing, what are the cognitive benefits and what are some of the reasons why you think it's an exciting new product for Natrium health.

Emiel

Yeah, we have to do a bit of time traveling, actually, to get a good feel of what this one is. So this is based on a very well, not very old about a decade ago on a forum called Longecity, which is where a lot of the early Nootropic talk happened as well. It's still alive. I do like going on there every once in a while. It's an interesting forum to check out. But on that forum, there was a user called Mr. Happy, and he was going through a bunch of research, and he found some research that if you combine DHA, fish oil and choline, you could enhance brain membrane synthesis. And it's neuroprotective and it helps with memory.

Erika

So quick interruption. Can you give a little explanation, what is DHA and where does it come from?

Emiel

So DHA comes from fish oil. It's also found in algae. And we actually just released a really novel algae based DHA product as well.

Erika

That we're going to talk about a little bit later.

Emiel

We'll talk a little bit later about it. But the interesting thing is the algae powder that we came out with, it's DHA complex to lysine, and it's called Availom. And actually what's in OmegaTAU is also Availom, but the Availom fish oil version to stay a little bit more true to the original stack, which used fish oil. So anyways, on this forum on Longecity, this user found this combination and determined that this could be a very good stack to look into and was kind of a community driven approach. And I think the whole thread is still there. And it's probably hundreds of pages long at this point of people talking about the initial development of how people took the stack and where they sourced the ingredients. And back then, it was a lot harder to source a lot of these ingredients. So there was a lot of crowdsourcing happening there. Where can I find these things? And then a lot of experience reports. And we kind of wanted to pay homage to this period of nootropic exploration, too, because there were a lot of unknowns back then and a lot of the forum users kind of laid the foundation for what Nootropics are today. So OmegaTAU is our take on the Mr. Happy stack with a few small tweaks and innovations. So one thing we realized while we were developing our first formulations of the Mr. Happy stack, because the way it was traditionally taken is you basically had to source a bunch of different products and then take multiple capsules of different things.

Erika

So putting your own stack together.

Emiel

Putting your own stack together. And everyone was doing this, and it's great. And we wanted something. And a lot of people always talked about this. We wanted a all in one product, but it never happened. So we kind of wanted to make it happen and one of the challenges we had is first and foremost we thought we'll develop a soft gel, but dissolving all of those different ingredients that are in the Mr. Happy stack inside of an oil and then getting that oil inside of a soft gel and then determining if it's stable and then taking the risk on a large run because soft gels can be a little bit tricky. We decided this is not really a realistic option for a product like this. And then the idea was shelved for a few years because there wasn't really a good alternative to making this. Then Availom came out and that was kind of our answer because we had five times higher bioavailability than regular fish oil. And it's a powder, so we can actually encapsulate it in a regular capsule machine and we can do that ourselves and at other facilities that we've worked together with for years. So this really opened up the door for a Mr. Happy stack for us using only powders. So Avalon is an innovation we put in because it is a novel formulation of DHA. It's basically fish oil complexed with the amino acid Lysine. And through this complexation process, you have a much higher absorption rate. Another thing we did a little bit differently was a slightly lower dose of Alpha GPC because higher doses of choline seemed to cause some mood issues for people. I'm actually one of those people. So in the beta testing, this was also the thing for me that I was mindful of. I always wanted to make sure that the product works well for a large amount of people, not just certain types of people or certain groups of people. So with this lower dose of Alpha GPC, the people that didn't have any sensitivities to Alpha GPC still had really good effects and they didn't really want a higher dose. And the people with Alpha GPC sensitivity, like myself, also had no issues with it and had good effects. So this was one thing we slightly changed and then we put in some sesamin, which one of the main reasoning behind this was that it can help a little bit with the fish oil absorption even further and it helps with vitamin E recycling. And vitamin E is also part of the Mr. Happy stack. So this made sense. But Furthermore, sesamin has some really interesting neuroprotective effects and effects on oxidation and inflammation and neuroplasticity and metabolic health and things like this. So it made sense to have it in there and also because it is something like choline that is found in our diets. But I guess I haven't really given a good concise overview of what exactly is in OmegaTAU, so I should do that. So going from the top, it contains the Availom DHA fish oil, which we talked about. It contains Alpha GPC, it contains vitamin E, it contains sesamin, it contains Triacetyluridine as the uridine source, and it contains vitamin B nine or folate. And that's the complete formulation. And the main purpose, really, of it is as the way I like to see it, is it's like a nootropic vitamin almost. It's something you just take every day. And it kind of gives you all of the building blocks that you need for cognitive health. And this is a really nice way to look at it, too, because most people want some fish oil anyways. And here you are getting some fish oil and you are getting some extra things tacked on there, which are popular nootropic ingredients anyway. So it's a nice comprehensive all in one, one you can take long term every day. And something that actually works well together with other stacks because it gives you a good foundation. Just like good nutrition, good sleep, good overall work-life balance, and things like that can really add to cognitive function. Something like this can provide a good base on which you can build other cognitive function enhancing stacks.

Erika

Absolutely. I agree. And I've been taking OmegaTau for the past week or so. And I have to say it goes really nicely with the rest of my daily stack and the effect that I noticed the most, it's not really an acute effect I would say. If anything, it's sort of a peripheral effect, perhaps because when I take OmegaTAU, when I have a moment that I'm feeling a little overwhelmed or I'm thinking about my to do list for the day, if at any point I start to go, what's going on? Okay, the list is starting to pile up. You know, there's a lot going on, and I might be feeling a bit overstimulated by my environment. Omega Tau has this kind of nice soft touch that goes, that's okay, you got it. You've got it under control. And so in terms of maintaining this sense of mindfulness and groundedness with the different cognitive enhancing supplements I'm taking, Omega Tau sort of smooth that out in a really interesting way and in a way that's different than with other cognitive focus nootropics that I've experienced myself.

Emiel

Yeah. And if you look at the longevity thread, these are the kind of effects that you see a lot of people experiencing as well, which is very unique set of effects and uridine hits a lot of interesting neurotransmitter systems that can help with these calming effects. But then also the stack as a whole is also quite famous for enhancing dopaminergic sensitivity. So that might also be something you're experiencing.

Erika

Yeah. That certainly is probably part of what I'm experiencing. And you have the technical language to describe it. I only have these kind of layman terms to describe the experiences that I have when taking OmegaTAU. But it is really cool that even though I'm using different language than you are, we're kind of talking about the same thing.

Emiel

And at the end of the day, your experience is the experience that matters. The most because this is why we make products. We don't make products to have a check in the box for the science. To a certain degree, we do because we want to have it scientifically validated. But what we want is that we are producing real world results, and you need to describe real world results, usually with real world language. So a report like yours is very important, which is why I think Reddit has always been such an amazing platform. And longecity, too, because people actually talked about what they experienced, not just translating what they're reading about in research.

Erika

Absolutely. So you had mentioned Availom fish oil earlier and our next new product and our last new product that we're going to talk about today. It's been released since the previous podcast episode is an Availom product, but it's exciting. It's a vegan friendly Availom DHA algae powder. And I'm really curious to hear a little more detail about this product. And it's vegan. This is really exciting. And algae is such a fascinating plant, so many nutrients and so many compounds in there. And I know that you've got some exciting information about it to share.

Emiel

Yeah. I've always been really interested in algae, partially because it grows really efficiently. So I think you can harvest algae after like 24 hours. So it's really sustainable. It's quick to produce. And you don't have to go farm fish because I take fish oil and I really love fish oil. But it's something that sometimes on the back of my mind is we do have to go out and fish for this. And sometimes I don't know how I feel about that. So even for myself, even though I'm not vegan, having an option like Availom DHA algae around is nice because I have an alternative to get my DHA from something that is not a living being, which is always nice. I think fish oil is a great source of Omega three fatty acids, especially because it has a much higher amount of EPA, which you don't necessarily find as often in algae and algae extracts. So there are still some benefits with fish oil that you don't get with algae. However, there are clearly some advantages to algae, too. So there's two sides of the coin there. And I think even for people who aren't vegans or vegetarians, it's interesting to consider taking an algae source DHA at some point, too, just to try it out and see what you think. And maybe also a way to try out a more streamlined DHA, more selective because the algae doesn't contain a whole lot of EPA. So you are just getting pure DHA, which is kind of unique because with most fish oils, you're always getting EPA and DHA.

Erika

So what would you say is the main difference between fish oil supplement and an algae DHA supplement in terms of effects?

Emiel

For the most part, they'll actually be pretty similar, which is exactly what we want. We basically want all of the same effects that we get from fish oil, but we don't want it from fish, we want it from algae. However, there are some subtle differences. So there's not huge differences I've experienced between EPA and DHA. But what I found is that DHA, and not only I found the whole conclusion of the longecity thread with Mr. Happy Stack was basically that you need a high concentration of DHA. That's really what's important for the cognitive effects. EPA, on the other hand, has some interesting mood enhancing effects and things like that. But in my experience and in others experiences, it seems like having just DHA provides a slightly cleaner cognitive enhancement effect. The differences are subtle of course. A fish oil by itself is not going to have a crazy huge acute impact often, but it's more of a long term thing that we all need those Omega three fatty acids, and especially DHA and EPA, and they're fairly hard to get through our diet. So supplementing them is a good idea. But in terms of teasing out acute effects that you can really feel the differences between EPA and DHA probably subtle, but you have a bit of a cleaner cognitive enhancement thing going on with just DHA, which is what makes the algae extract, in addition to it being a more eco friendly solution to a DHA source, quite attractive.

Erika

Absolutely.

Emiel

Especially in the case of Availom. Because not only is this just any regular old algae extract, which there are quite a few of, this algae extract is complexed to Lysine, similar to the fish oil Availom. So the same bioavailability enhancement technology is there, and we see higher levels of absorption with Availom algae than we do with normal algae, which is great.

Erika

Yeah, definitely. So there's a handful of exciting new supplements released. We'll just go over them one more time. So it's the vegan algae DHA Availom powder. We have Taurine capsules. We have our two exciting new Natrium Health Stack products that we released, Dynamax Plus and OmegaTAU. And then we also have Panics Ginseng leaf extract in capsules. And we have Panax Ginseng root extract in capsules for you.

Emiel

Yeah. And this is a pretty big release, but we're on fire. We're coming out with another big release. This podcast is releasing on Tuesday, and if you're listening to it on the release day, in a couple of days on Thursday, we will have a release of a few new products. So we're going to have NMN powder now. A lot of you have indicated that you want some powder, because some people actually pass the entire enteric coated NMN tablet. So the enteric coated NMN really helps with stability and absorption. But not everyone can take it, and they are also a little bit more expensive. So having the powder available means you can take higher doses of nicotinamide mononucleotide, NMN. We also have the powder in capsules for a convenient option for those that don't react well to the enteric coated tablets, we'll have Sabroxy in 500 mg tablets. So for people who want a little bit more stimulation and I actually thought, man, that's a really crazy dose, but it's a dose that the manufacturer recommends. So we thought maybe we should offer some 500 milligram tablets. And a lot of people on Reddit indicated that they would want a higher dose tablet. So I decided to try it out. And I was a little bit nervous about it because I'm sensitive to stimulants, but I actually had really good effects with it. So even for those that think they might be a little bit sensitive to a higher dose, I would still recommend caution, but it could actually be an interesting dose to try sometimes.

Erika

Yeah, definitely a 500 mg dose of Sabroxy. You never know. It might work actually better for you than a lower dose.

Emiel

Yes. I actually found that in lower doses, Sabroxy is maybe like a little bit zippier in the stimulation, where with the higher dose it became more stimulating, but it also became maybe a little bit more fullbodied in a sense. Like there was more calming, there was more smoothing going on. So I was more stimulated, but in an interesting way. It was also a little bit smoother, even though it was more stimulating. So that was interesting to try out. And for those that need the higher dose of Sabroxy, this is a really good option. And we'll be releasing two new mystery products.

Erika

So we're not going to tell you what those are right now because we do want to keep them a mystery, but keep your eyes peeled.

Emiel

We can give you the hints, though, because we've released some hints if you check out our new product mystery release page. So we put up a timer and you can see when these new products are coming. And sometimes we'll tell you what they are if they are already existing products.

Erika

And this is going to be on our website.

Emiel

Yeah. So one of the products, the hint was this is a Nootropic amino acid. And then the other hint was this has a 2-oxo-pyrrolidone base structure. So for those in the know, you probably know exactly what that is and exactly what it could maybe replace. But we won't get into that. The second one, it's a super critical CO2 liquid extract. Very exciting. I think you'll really like this one. But that's the first hint. And the second hint is this botanical is often made into a tea. And I'll give you a bit of an additional hint here. It's made into a tea in Ayurveda and in Ayurveda this herb starts with a T. These are some really good hints.

Erika

So I'm excited to see what you all think these new mystery products might be. You can add your thoughts and your guesses onto the thread that we have going on our Subreddit that's r/NootropicsDepot and let us know what you think might be coming your way. And then stick around and either visit our website or you can sign up for our newsletter. You'll get notified when new products are dropped to figure out what these new mystery products might be. So that concludes our new product segment of the podcast. Now we're going to go into my personal favorite part of the podcast In Search of Insight, which is reading and answering your questions from Reddit. So these questions are specific to stacking, stack advice. They're specific to Natrium Health products. And we're going to get started with this first question from u/Mcgrufer, who asks, "How are the stacks or blends for Natrium products decided upon?"

Emiel

Yeah, I think we kind of answered that question with this whole podcast. It's a very involved and complex process. And we go through a lot of different research studies and personal experiences with ingredients and even looking through forums and seeing what people had been combining and looking at traditional Chinese practices and Ayurvedic practices and looking at historically what was done, but then also looking at new research and new botanicals. And we always try to go for botanicals that are kind of a little bit more unknown, a little bit more novel or maybe a very well known botanical, but properly standardized or standardized for unique ingredients, like what we do with our Tongkat Ali. So we always try and focus on unique ingredients like that for our stack compositions.

Erika

Absolutely. And in addition to that, I think another important part of the stack development process for Natrium health is also the feedback that we receive from you, our customers and our listeners and what you're interested in in terms of stacks and in terms of just general wellbeing, things that you want to be improving in your daily life, whether it's your waking life during the day as you're working or going about the things you have to do or at night time with your sleep schedule, your workouts, your recovery, and these things that we get a lot of feedback on. So Natrium Health stacks are put together from many different perspectives, but a lot of it is also from the requests that you make and also the ideas and the requests that we within Nootropics Depot have for fun and exciting and boundary pushing stack ideas.

Emiel

Absolutely.

Erika

So there's a follow up question that u/McGrufer asks, which is, "I know the Natrium products pride themselves on using natural ingredients, but would the Natrium team consider using other lab developed ingredients in any of their stacks in the future? Or is that strictly a Nootropics Depot area? Great question. Yeah.

Emiel

And it's strictly a Nootropics Depot area, which is why for Natrium, our slogan is "Science Powered by Nature." We're really going for the most cutting edge things we can achieve with natural compounds.

Erika

And this is a great follow up question to finish u/Mcgrufer's contribution, which is "Without giving too much away, what kinds of stacks is the Natrium Health team excited about developing next?"

Emiel

Yeah, I'm not sure if I can answer that, actually, but maybe if I don't go into the details, I can give some small things away. So actually today, as I'm recording this, I'm actually beta testing one of our new Natrium Health stacks, and I can't tell you what it is, but I'm very excited about it. And I'm also currently working on developing another one that we're about to start beta testing and also very excited about that one. And I also can't tell you what that one is. You'll just have to wait for it, but it will be fairly soon. Don't quote me on that.

Erika

More like soon tm. For those of you who know on Reddit. But all joking aside, we are always working on exciting new ideas and stacks and approaches for Nootropics Depot and for Natrium Health. And right now, there's a lot of exciting activity going on that's under wraps. We can't tell you about it, but we promise as soon as we can, we will. And you'll know, if you're signed up for a newsletter, if you're following us on Reddit, and if you're active in the chat. So if you want to know more, you can always hang out, ask us questions, and we'll give you as much information as we can. But for now, it's just bait.

Emiel

And one thing I can promise is that you've probably noticed we've had a very solid output of new products, and we have absolutely no plans of slowing down. And I look every day and an enormous list of products gives me a little bit of anxiety sometimes because there's a lot and you'll be seeing a lot of new products coming in over the next few months, which is very exciting, though. And there's some very interesting and cool products on there that I'm sure all of you will be very excited by.

Erika

Absolutely. Okay, so moving on to another question that we have about the stack design process. This one comes from u/Unusual_Invite_5668. And the question is "The main problem I have with blends," and this is in parentheses, "(I haven't tried any of the Natrium Health ones, though) is that one ingredient can make me feel off, and I have no idea which one it is. So I just have to discard the whole bottle. How do you ensure to the best of your ability that your blends don't cause this problem?" Well, my first request for you is why don't you give a Natrium Health product to try and let us know how it goes for you? But now I'll let Emiel actually answer the real question.

Emiel

Yeah. And I'll counter that and say we can't design a product specifically for you. And that's unfortunate. It would be great if we could figure out exactly what works for you and what works and doesn't work for you or gives you adverse effects or something. So we can specifically develop something that will work well for you. But maybe it will work terribly for myself or for Erika, and that doesn't really work either. So to the best of our ability, we design smart stacks with ingredients in there that complement each other and are producing similar types of effects. So that is what we do to ensure that we have stacks that work well for people. Another thing that we do is we do beta tested with multiple people. First is Alpha testing. The owner of Nootropics Depot and Natrium Health and myself, we are usually the first people to test things. Erika actually recently came on board this Alpha testing team too because she has a very keen sense of what's going on with Alpha testing. So she's a very valuable asset there, too. But this means that the whole product development isn't hinged on just one or two people. A lot of people try it out, and we oftentimes find that in a group of ten people, a few people have different reactions, and then we can kind of try and smooth it out. So everyone has a similar reaction. So earlier in the podcast, I was talking about the Alpha GPC dose in OmegaTAU and deciding what worked well for people that were sensitive to it and people that weren't sensitive to it and finding a nice middle ground there. So we do do some things to ensure that on average, for the average person taking these, it's going to be a very well designed stack will do what it does. It doesn't have a bunch of random, crazy ingredients thrown together. It's well thought out, science based stacks, so that's what we do to ensure that. But unfortunately, there's no way to ensure that a stack will work well for you. And this brings us to an interesting point, too, with creating your own stacks.

Erika

Yeah, that's what I was going to say. If a stack product doesn't work well for you, because there might be one or two ingredients in there you can't take out. Specifically, you feel like you have to throw the whole product away. Why not start with a couple of the ingredients or the botanicals or compounds that you know you're interested in and take those individually and find out the best dosage for you for that product by itself, and then start to create your own stack modeled after a product that you're interested in just so that you can get a feel for, what is it like to combine these things at certain dosages? What is it like to take them by themselves? And then you might actually be able to figure out for yourself if there's anything that's in that stack that you wouldn't have a desired effect from, and then you can do it independently, too.

Emiel

Yeah. So a big thing here is isolating. And what I was going to quickly interject with while you were giving a very good explanation of this was that sometimes you might already be very familiar with ingredients. You probably have some experience with caffeine. Like a lot of us have maybe years of experience with caffeine. We know exactly what it does. So building a stack around caffeine is much easier than, say, building a stack around some sort of novel peptide that came out of spinach that no one knows what it does and you've never taken it before. No one has ever taken it before, and there's no data on it. And you really have to go out there as an explorer and determine what it does and then see how it can integrate with other things. But this is a hypothetical situation, but more realistically, we are at one point always new to an ingredient and we need to discover what it is. Similar in cosmetics, you don't just go and smear your face full of a new cosmetic thing. You do a little patch test and you see maybe do I have some breakout there or a rash? Am I sensitive to this product? Do the same with supplements to try each one out individually.

Erika

Take it slow.

Emiel

Take it slow, take some good notes, see what everyone does, then combine a few, see what changes do I lose something like with caffeine and L-theanine? You lose some stimulation, but you gain some smoothness. So keep track of what's changing in a stack, and then you can figure out what works well for you. Annoyingly, though. Sometimes, even though you are familiar with certain ingredients in isolation and they work well for you when you combine them, they don't work well for you anymore because there are interactions that happen. So this is not as common, but it's also something to keep in mind. Maybe you started with three ingredients that work wonderfully separately and then you combine them and now you're having bad effects. So I could imagine a scenario aware you take Gotukola by itself, it works great. You take Shoden Ashwagandha by itself, it works great. And you take some Bacopa by itself and it works great. Now you combine all three and you're hopelessly tired and lethargic and unmotivated all day. That can happen because all three interact in a way where they increase each other's effects on stress reduction and calming effects and things like that to the point where you get lethargic and demotivated. So this is something to keep in mind too. And this is why stacking is hard. And this is obviously something that we keep in mind when we are developing stacks that the combinations that we make make sense and aren't contradictory or producing unpleasant effects.

Erika

That was a great answer and really comprehensive too. So we're going to move on to another question related to the stack development process. And this one is from u/Zidatris, who's a regular listener and a regular asker of great questions. This one's kind of fun and I'll just go for it. So the question is, "Do you ever get some inspiration from big name stacks such as Neurohacker, Mind Lab Pro, Alpha Brain, et cetera. And there's an edit "Out of pure curiosity, really."

Emiel

Yeah. And I don't want to shoot those other brands down too hard, but I feel thoroughly uninspired by a lot of those combinations.

Erika

The simple answer is no.

Emiel

No, I do look at them because I'm curious and I want to stay aware of what the competition is doing and what else is out there. And if someone else came out a big brand, stack came out, and it made a lot of sense, then I would be very interested in picking it up. But as it stands, I've tried a few of these, and I've looked at a few of them, and they've never really excited me. They've never really had the intended effects that I necessarily wanted, which is why I started making just my own stacks at home. And then now I have the opportunity to create stacks together with a whole team of people where we're all chipping in ideas and research and testing it, and it's very collaborative, and we get to make these stacks, and we actually get to make them real products that all of you get to take. It's super exciting. But I wish I could take more inspiration from other companies, and I wish there was more creativity around. But I will say that while not a big name stack company or brand, I take a lot of inspiration from Ayurvedic practices and from traditional Chinese practices, because they spend thousands of years developing these systems and learning about different botanicals and plants and how to combine them and how to extract them and how to get the best effects out of them. And obviously, they are oftentimes linked up with spirituality and things like that. And this is where certain products, especially something like Panax Ginseng, actually takes on a life of its own, where it has its own spirit and there's some mysticism about it, and we don't have that here. And there's no place for it in, like, Nootropics Depot Products or Nitrium Health Products, because we're focusing on the science. But what I find really fascinating is that there's a big culture around it, and there's a lot of history around it. And if you look at these formulations and you look at the science behind them, somehow they got it very right. So now we guide a lot of our stack development and formulation with science, but back then, they just had to rely on experience. And clearly relying on experience and being an experienced person in this creates good stacks that lasts the test of time.

Erika

Absolutely. And that's something that I think is really amazing about Natrium Health. But nootropics people in general is that we're really focused on following the science and providing the absolute highest quality ingredients and products that are out there on the market. But we're also taking inspiration from Ayurveda and from traditional Chinese practices. We're taking inspiration from the challenges we experience in our own life and the challenges we hear our customers experience. And so there's a lot of different ways that we do get inspired to create stacks and products. And it's not only from research studies, it's also from cultures and from different places and people throughout the world. And I think that's something that's really cool to learn about as I've gotten a little bit more aware of the stack development process.

Emiel

And I would say if we dig into that a little bit deeper to everything we know about plants and that plants can have these effects in humans that are highly beneficial. The only reason we know these things is because over thousands of years, humans have taken massive risks, just trying out random herbs and plants at different doses and running their own bioassay and clinical trials, basically trying to figure out what's a good dose will this plant kill me? Will this plan heal me? What does this plan do for certain things? If one thing happens to me, what plan do I use to correct that? Or what plant can I use for preventative and a lot of Pharmaceuticals too today, it stems from that all to modifying those structures and creating manmade structures with more selective and highly specific effects. But there's a large history and culture behind all of this, and we can validate it with science now. But it's amazing that there's just thousands of years of human history showing that these plants can have very interesting effects. And specifically, what parts of the plant to use, how to extract them, how to use them, how to dose them, et cetera, et cetera.

Erika

And then how to combine them, with other botanicals, which is the whole point of this podcast. So excellent question from u/Zidatris. Loaded in more ways than one. Now we're going to move on to another question that we got from a regular listener and question asker u/Hormesis, who asks, "Would you ever consider editing existing formulas to improve them, or are they designed to be static in parentheses (I mean, aside from fixing, "bugs" like removing zinc from sleep support)"?

Emiel

Yeah, they're designed to be mostly static, so they should stand the test of time. We don't design stacks on the fly and have you guys be the beta testers like a lot of companies do. A lot of tech companies do this. A lot of supplement companies, I'm sure do this as well. We don't want you to be the beta testers. We take care of that. That's our job. The product has to be perfect when it leaves our facility and ends up in your hands. So if we went back and edited formulations, it would also mean that maybe we weren't as diligent as we could have been in the beta testing phase to make a stack that even 50 years from now may still be relevant. I would love to see a product like Panamax or Dynamax stand that test of time and see it still be available 10-20 years from now. That being said, our output certainly will never become static or boring or homogenous. We will always get new ingredients, and when we get new ingredients, we get new ideas for new stacks. And it would seem tempting to maybe take some of these new ingredients and revamp existing stacks, but then maybe we'll break a stack for a lot of loyal followers of that stack. So instead, what we want to do is when we get new products like that, we want to take our inspiration and creativity and just make new products with them, interesting products with different effects and different effect profiles and maybe more novel formulations.

Erika

The main idea is innovation, and that's really what I think Emiel is trying to get at. So we're going to move on to one more question that we got in this stack development process category, and this one comes from u/eamonn123 and the question is "How to know whether a stack is safe to take? Best way to research or things to look out for?" Great question.

Emiel

Yeah, I would say our stacks are safe. We wouldn't assign a dangerous stack. So I would say just go with one of our stacks. The thing to really look out for, even if a stack looks like it's properly formulated, you never know if it's properly tested. And this brings up an interesting thing with stacks is that they are very hard to test, because instead of just having a single ingredient that you test, you now have 8-10 ingredients, maybe in a single capsule, and you have to figure out a way to separate all of those different things and test if they're in there in the correct ratios, and we test each raw ingredient before that. So the testing costs become really high, and a lot of competitors who make stacks skip this process because it is too arduous. This is also why it takes quite a long time to come out with Natrium Stacks because it is such a lengthy process.

Erika

And Natrium Health stacks are tested, and they are held to an extremely high standard. And we provide Certificates of Analysis. And we really go to great lengths to make sure that everything that goes into a stack is safe and it's effective and it's working synergistically with the other ingredients that are there.

Emiel

Yes. And nothing leaves the shelf before I try it and the owner tries it. So with that in mind, we wouldn't make a product that would put us in harm's way, because at the end of the day, I'm the most important person for myself because I need to keep myself alive. I wouldn't design a product and then test it out on myself and inadvertently hurt myself. I want these products to be safe because I take them, my family members take them, my friends take them, and all of you take them. And we actually care about all of you. So we don't just want to make a quick buck. We actually want to ensure that you are getting safe, effective products that are enhancing your quality of life. Absolutely. I don't know what the philosophy is for other stack manufacturers out there, and we don't know what their testing is like. So I can't really say what to look out for necessarily, with other stacks outside of ours.

Erika

Yeah, absolutely.

Emiel

There are good stacks out there, probably. But you don't know. And there's not as much transparency usually.

Erika

Yeah, definitely. And I think that is something that really sets Natrium Health and Nootropics Depot apart is our transparency. It's something we really pride ourselves on and something that's really important to both companies. Nootropics Depot, and Natrium Health.

Emiel

Yeah. Honestly, it's the most important thing. It's what made us start the company to begin with. We wanted to see better testing in the industry because testing in this industry is very lackluster and it's very disheartening. And we could talk about it all day.

Erika

That's probably for a future podcast.

Emiel

Future podcast. But the state of the industry is pretty bad, and we've always been trying to change it. And Natrium was one of those things, too, where we want natural products naturally formulated, but also rigorously scientifically tested.

Erika

Yeah, definitely. So now there's some more follow up questions from u/eamonn123 and the first question is "General rules of thumb when stacking?" And we've answered this in many different ways over the course of the podcast, but we'll just reiterate it in a really short way now. To start, general rules of thumb. When stacking, if you're taking a couple of different individual ingredients and you're planning on putting them together, just take them separately first before you combine them, and then Emiel other general rules of thumb for stacking?

Emiel

Yeah. So I would say that's kind of your base, what Erika was saying. You need to get to know your ingredients well, if you don't know your ingredients well, it's hopeless. You're not going to make a good stack. You need to know what each ingredient does. You need to read up on them. You need to research, become intimately familiar with whatever you're trying to stack once you get there, there are some general rules of thumb, and this already leads into that first portion of research. The one general rule of thumb is combine ingredients that are synergistic. So if you're just combining ingredients because you think one ingredient looks cool and other ingredients look cool and you just want them in one thing. Yeah. It's just you're taking two ingredients. But if you want a stack, usually you want that the, how does the saying that the sum of its part is the greater than the equal or the whole?

Erika

Yes. So it goes "Greater than the sum of its parts."

Emiel

Yeah. Thanks for saving me there. Sometimes my English as a second language kind of trips me up.

Erika

Yeah. For those of you who don't know, Emiel speaks Dutch. So if there's any Dutch listeners out there or Dutch folks on Reddit send Emiel message, he might want to have a conversation with you about nootropics in Dutch.

Emiel

Yeah. We kunnen gewoon in Nederlands praten over nootropics en supplementen. Ik heb een beetje raar accent maar, we can do that.

Erika

Awesome. So we're going to move on to another follow up question from u/eamonn123 which is a little bit more specific to a mechanism kind of question. "Can you combine dopamine releasers and DRIs together, or do they have interfering mechanisms?"

Emiel

You could, and I've actually tried it recently with Sabroxy and a very exciting plant based dopamine releasing compound. The two together works quite well. But then we are talking about fairly mild. I mean, Sabroxy is not necessarily a mild dopamine reuptake inhibitor, but this other dopamine releaser was somewhat mild compared to some of the other stuff out there that's a dopamine releasing agent. So I think generally combining a reuptake inhibitor with a releaser is not necessarily a good idea, but it can be done in more subtle ways, it seems. So combining Sabroxy with this mild dopamine releasing agent actually worked quite well and rounded out the effects a little bit.

Erika

Nice. And one other question, or there's actually a few more questions, but this one's another mechanism question, "Nootropics that affect liver enzymes like the CYP2D6 enzyme, would these affect absorption of other nootropics?"

Emiel

Yeah. This is an interesting thing because the liver enzymes definitely apply to natural compounds and supplements, too. And you can have different interactions with liver enzymes and absorption. And it can get pretty complex, especially if a plant contains multiple different compounds that each have an effect on these cytochrome p-450 enzymes. So sometimes it can actually be beneficial, too. If we're looking at curcumin and piperine, for example, one of the reasons why piperine helps curcumin absorb better is because piperine is a pretty broad inhibitor of the cytochrome P-450 enzymes. And because curcumin is metabolized by some of the cytochrome P-450 enzymes, it enhances the absorption and how long the curcumin can stay in circulation. So sometimes it's a good thing. And sometimes certain compounds can actually induce certain cytochrome P-450 enzymes, which would mean that other compounds get metabolized a little bit quicker. So there are definitely some interactions out there. It's interesting to look at it. And another interesting thing that not a whole lot of people talk about, because the cytochrome P-450 enzyme system oftentimes gets oversimplified. But something a lot of people aren't aware of is that the cytochrome P-450 enzymes are actually under diurnal control, meaning that they respond to circadian rhythm. So I believe they are lower in the evening and higher in the morning, which means that depending on certain times of day, when you take certain things, you might have different interactions there with the cytochrome P-450 enzymes. So I think unfortunately at a certain point it gets a little bit hopelessly complex and it may be something that we don't have to concern ourselves with all too much, but being aware of it and being aware of the potential interactions that could happen is always good, especially when we can use it in our favor.

Erika

Definitely. So now we're going to move on to a new category of questions, which is stack suggestions or requests that we got on the Reddit thread asking what questions you had about stacks and stack development and stacks in general. And so the first one comes from u/Pentarriaza. Really cool username. The question is, "Will Nootropics Depot/Natrium Health consider releasing a digestive health stack? Maybe something along the lines of an optimized Psyllium Husk powder or capsules with ingredients focused on digestive support with pre and postbiotics, and perhaps ingredients with glucose/cholesterol management attributes? Someone who knows more than me can maybe comment below with some suggestions." So thanks for stimulating the conversation and thanks for asking this really interesting question. Emiel, how about a prebiotic probiotic postbiotic stack?

Emiel

Very interesting and definitely something we will do at a certain point and something I have a few ideas floating around with, and a few other people around the office have had a few ideas and I think we can come up with something really interesting.

Erika

Yeah, definitely. So while this might not go under the soonTM category, it is certainly something we're thinking about often.

Emiel

Yes.

Erika

Now we're quickly moving into another category of questions about stacks, which is questions about absorption and dosing of stacks. So this question comes from u/Lamanchin93, another regular listener and asker of great questions. And their question is "On the topic of combining supplements, I often wonder if I'm introducing negative interactions by taking my big morning stack, including over 20 Nootropics Depot products. Should I spread out my dosing over a couple of hours or is taking a large variety of products at one time fine?" Really good question. We get this all the time.

Emiel

Yeah. And I would experiment with a little bit and do some research on all the different things that you are combining. I personally take about 18 different things all at once in the morning. So I do take a large stack and I don't space it out because I like how all of the different ingredients interact together and have synergies together. And if I spread it out, I don't necessarily get that. There are some ingredients in my stack that I could separate out, like vitamin D and magnesium. It's not super critical when I take those, but it's just convenient to take them all before I leave the house. If I have to leave the house or if I'm just around the house, it's still convenient to just take them all and not have to remember to take another stack later in the day because I'm a pretty busy person so I can lose track of taking a second dose. So for me, if I don't get them all in at the same time, I'm liable to forget part of my stack. And I've had this happen a lot when I did try and separate it out. I have experimented, though, and taking certain smaller ones before I have some breakfast to give me some nice mental clarity and things like that and then taking the rest of the stack later, and I did this for a while, but currently I've been really, really busy, so I've just been taking it all at once.

Erika

Yes. So the short answer for Emiel is that yes, you can take the product all at once, and that should be fine. But do your research. And if you are feeling some negative or less than desirable effects, when you do combine all of those products at once, take it a little slow and maybe back off and you can take a couple at a time together and see what combinations work best for you. And I'm a little bit different than Emiel because I can be really sensitive sometimes when I take lots of capsules at one time, especially if I haven't had enough to eat. And so I like to take a handful of more of the cognitive benefit supplements early in the morning, which really helps to jumpstart my day. And then I'll wait a little while until I've had some breakfast and had a little bit of time for my stomach to settle and maybe digest some of that a bit. And then I'll take the rest of my supplements in the afternoon. So I'm still getting the benefits that I want, like earlier in the day. But I do like to break it up into two smaller groups. And that's just my preference. Our next question about absorption and dosing of stacks is coming from u/Mrfilip and the question is, "One of my stacking conundrums is based on timing. I've been a Tau user for nearly twelve years, and I have always stacked it with an oil MCT, omegas, et cetera. But I always felt that I needed to take the oil first. I assume, but I don't know that each supplement has different uptake times, and therefore to be efficiently synergistic based on its half life the timing of each supplement should be important. What's the science behind this?"

Emiel

Yeah, it gets pretty complex there too, with a lot of different ingredients that have different pharmacokinetic profiles and things like that. But one thing I will say is that you don't have to take oil with triacetyl uridine. You'll be fine just taking it on an empty stomach. Oils can sometimes enhance absorption. It could enhance absorption for not just fat soluble compounds but also water soluble compounds. And there is a lot of research we're doing in this area yet, and I'm not necessarily ready to share some of that data yet that we found. But there are some interesting things happening with lipids and absorption that can affect a lot of different supplements. So there might be some merit to taking an oil source beforehand. So it's already in your digestive tract before you take the supplements. And that would apply globally to all sorts of different supplements. If somehow the oil is having an absorption enhancing effect, but only if the oil is in the intestines, which is what our theory revolves around, then it would mean taking the oil maybe half an hour before you take the supplement or even an hour before even if you eat a fatty meal an hour before taking your supplements or something like that, then potentially you'll have some better absorption.

Emiel

But then maybe you'll also have some interactions with what's in your food with supplement absorption. So it gets pretty complex there. But if that works well for you, keep doing what works well for you, because that's what matters.

Erika

Definitely. And if you're really interested in learning more about the absorption process in general, we have a really informative blog on our website. It's called "When Should I Take My Supplements?" And it talks about-

Emiel

We can link that in the product description.

Erika

Yeah, definitely.

Emiel

Or the podcast description.

Erika

Yeah, definitely. And that blog talks about absorption, absorption times, it talks about some of the nitty gritty science of digestion. And I think you'll benefit a lot from checking this out if you feel like it, because it has some really good info in there that's specific to your question and that you can apply to all the different supplements you might be taking on a daily basis. So we have one final question. This one comes from u/TheOptimizzzer. Thanks so much for listening and for asking your thoughtful questions. So the question is "How digestive enzymes could impact the bioavailability of my stack if taken at or around the same time?"

Emiel

This is a very interesting question, because digestive enzymes, what do they actually do? And one of the main things they do is they break down carbohydrates and proteins, things that we consume through our diet. And that's why they're called digestive enzymes, because they help digest our food. But can a digestive enzyme break down a compound like caffeine or something like that? I don't think so. Maybe it could degrade some of the betaglucans or something like that in some of the mushroom products because those are polysaccharides, they're starches. I could conceivably imagine that there might be some sort of digestive enzyme interaction that could break some of those bonds, but it's hard to predict exactly what it would be doing because all of the different digestive enzymes have different effects and some act on proteins and some act on carbohydrates. And most supplements are not going to be proteins. I don't know, actually, if anything, at least that we sell that is a protein or contains any sort of active protein fraction. The one thing I could maybe see happening with some of the digestive enzymes is that peptide based products could be sensitive. So things like glutathione, which is a peptide, and L carnisine, which is a peptide. Potentially in the presence of protein digesting enzymes, those enzymes may be able to break some of the peptide bonds too, because that's maybe how they're breaking down some of these proteins. And if that's the case, then taking those sort of digestive enzymes together with specific products like glutathione or L carnisine could maybe impact absorption.

Erika

A follow up question from u/TheOptimizzzer is "The differences in taking stacks with or without fish oil and or MCT oil. And if this should be thought of differently than taking stacks with meals?

Emiel

It goes back to my first part of the answer is that it probably doesn't make a crazy huge difference, especially like one small fish oil capsule. It's not a whole lot of oil. It would be pretty... 1 gram of fish oil interacting with a few milligrams of an active compound coming together miraculously somewhere in your digestive tract is a little bit far fetched, maybe. So I wouldn't imagine that taking something like just a single capsule of fish oil would necessarily aid absorption. I would imagine taking 1020 grams of something like MCT oil. And especially maybe with a phospholipid like a phospholipid, like if you took some of our Smart PS, maybe with a larger amount of MCT oil, because Smart PS contains these phosphatidylcholine type things and phosphatidylserine, which is how they make liposomes too. But they act as emulsifiers. And in the presence of fats, they can cause some of that emulsification to happen during absorption. And that really helps. So maybe if you're playing around with higher amounts of fat like that and some of these phospholipids, then together, if you preloaded, like half an hour before you take it, and then you take your supplement or your stack, then potentially some things will work better. But again, maybe not everything or compound in that stack absorbed in intestines, maybe some of it absorbs in the stomach. And then maybe the fat thing doesn't matter as much. So it's hard to know what in a stack, how it would interact. But my advice would be just try it out, because I have actually noticed some pretty interesting interactions. I made an extract once of a plant, and when taken by itself, this extract, it worked fine. But then one day I had some Zing Zang Bloody Mary mix laying around that I needed to get rid of. So I thought, oh, I would just mix my extract in there because the taste will complement each other. And then when I drank my Virgin Bloody Mary mix, the effects were better. So I don't know what it is. Maybe there's something in Zing Zang. Maybe there's a specific emulsifier that they use to make it so it doesn't separate. And maybe that emulsifier also helped emulsify some of the compounds. So who knows, maybe take a shot of Zing Zang and then half an hour later, take your stack and maybe that will work. Who knows?

Erika

Yeah, exactly. And to get back to the second part of the question, if taking a stack with MCT oil, if that should be thought of in the same way or in a different way as taking a stack along with a meal, what would you say? The meal is going to be different because it will probably contain fats, proteins, carbohydrates, maybe different flavonoids. Like maybe you were eating some cabbage and you're getting some cabbage flavonoids, or maybe you were eating red cabbage. We're just on the cabbage train here. But maybe you're eating some red cabbage and you're getting huge amounts of anthocyanins. Then maybe those anthocyanins can bind to open binding sites, maybe the open binding site of something like magnesium. Maybe those anthocyanins could bind there and effect absorption. So I would say with a meal, it becomes more complicated because there are so many more different interactions that could happen. And I would say using just a simple oil just to test out oil content, maybe of a meal, or does just oil in general, enhance absorption? It's more streamlined to do it with an oil rather than eating a meal. Like eating a piece of salmon is going to be much different than taking a capsule of fish oil that gives you the same amount of Omega three as a piece of salmon. But in the salmon, there's going to be some interesting bioactive compounds, maybe some proteins and sugars and things like that.

Erika

Potentially even more interactions that might not have a strictly beneficial effect, but might just kind of complicate the process. Perhaps.

Emiel

Or maybe it's positive, like if we think about, for example, milk. There's a lot of proteins in there, and I've read some research that certain bioactive compounds can bind to those proteins in milk and then kind of get micro encapsulated in these whey proteins. And when that happens, they absorb better. And this is maybe why KSM 66 decides to use milk in their extraction process. But I haven't been able to completely confirm this. But maybe they're working with that. But that also means that within taking supplements and eating food with it, certain foods might be able to enhance absorption. For example, those phospholipids we were talking about earlier than help us emulsifiers and might help with absorption. Egg yolks are full of them. So if you ate breakfast with lots of eggs, then, yeah, maybe things will absorb better. Maybe if you just ate some scrambled eggs for breakfast with some MCT oil over it and you ate that, maybe you would have insane absorption. It would actually be something interesting to try out.

Erika

Awesome. And now our very last question or follow up question from TheOptimizzzer is "Which stacks or categories of supplements are best taken with fat/food or meals? And are the absorption differences significant?"

Emiel

Yeah, so I think at this point we've kind of exhausted this question because we've answered it through some different parts of the question already. So I think if I were to answer this part, it would just become a little bit redundant. But just keep in mind, it's hard to know exactly how something will interact. Your stomach might be a little bit warmer one day and might churn a little bit harder, might have more acid in there, and the PH is different that can affect absorption. And then you throw food in there and maybe you ate something really spicy and that's causing some different excretions of stomach acids or maybe the opposite. And how that interacts with supplement absorption is it's hard to predict, which is why my advice actually always is, if you can handle it, take it on an empty stomach, because that's the most controlled, variable free way of taking things and everything pretty much absorbs well on an empty stomach, and usually it absorbs faster. So if you can handle it, just try it on an empty stomach. Maybe try and add something simple like the MCT oil you're mentioning, and then see if that enhances absorption or if it doesn't do anything and it's just easier to take on an empty stomach.

Erika

That's a really great way to conclude this month's episode of In Search of Insight. So thanks so much to all of you for your insightful questions and for participating in that question and answer thread that we have going on Reddit.

Emiel

Yeah, always very interesting. And I like the places that can take us.

Erika

Absolutely. You ask us questions that we wouldn't think of ourselves, and we really love interacting with you on Reddit, and we love reading your questions and answering them on the In Search of Insight podcast. So if you want to have your question featured in a future episode, join us on our subreddit that's r/NootropicsDepot and keep your eye out for our podcast Q&A thread that we post two weeks before the release date of the podcast so you can ask your question and perhaps have it featured on a future episode. To conclude, thank you so much for listening and for your participation in In Search of Insight. You can listen to this podcast on a variety of streaming platforms, and we are now available to listen on Audible as well. Another handy feature that you might notice if you're listening on YouTube is that there are chapters for our podcast. You can scroll along the play bar of the video and see what categories and subjects we talk about. And if you wanted to go back to a really interesting section, you could just hop back. Or you can also hop ahead and get the exact information you need.

Emiel

Yeah, these podcasts can get pretty long. And if you don't want to listen to everything we have to say-

Erika

We totally understand.

Emiel

I completely respect that because it is quite a bit but use that functionality on YouTube to kind of get to the things that you want to know specifically about because Erika does a great job of splitting this up and they're very accurate.

Erika

And we try to make them as user friendly as possible, so if you ever have suggestions for different segments, different information that you'd like to hear in our podcast or different functions that would be really helpful to you for understanding the information we're providing, please let us know on Reddit or leave us a comment on YouTube. Another thing to mention is we have transcripts available for all of our podcasts and those are going to be available to read on the landing page for our podcast on our website that's nootropicsdepot.com/podcast. So to conclude this really nice, long, super informative episode we just wanted to say thank you and good luck in your stacking adventures and your stacking research and keep asking us questions, keep asking yourselves questions and we're excited to be releasing more podcast episodes on topics that you're interested in releasing more stacks and continuing to push the boundaries with Nootropics Depot and with Natrium Health in these really interesting and exciting ways. So, at long last, thanks for listening and we'll see you next time. Bye bye.

Emiel

Thank you. See you next time.

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#004 | Is Glutathione Really a Master Antioxidant? Immunologists Claim it’s the Most Underrated of Them All

Podcast Transcript

Erika

Hi and welcome to In Search of Insight, Nootropics Depot's monthly podcast. I'm your host, Erika and standing across from me is our product specialist, Emiel.

Emiel

Hey everyone!

Erika

You may know us by our other names. My name on Reddit is u/NootropicsDepotGuru, and Emiel is u/Pretty-Chill. So if you are familiar with the In Search of Insight Podcast, if you follow us on Reddit, that's r/NootropicsDepot, you already know the topic of today's podcast. We are talking about glutathione, all things glutathione. But before we get into the podcast details, we just wanted to say thanks so much for listening to last month's episode on mindfulness and bioassaying.

Emiel

Yeah, that was a really good episode, and we got a lot of good responses, a lot of good questions, and we were able to talk about a lot of different topics that we normally wouldn't talk about.

Erika

Absolutely. Thanks so much for asking so many interesting questions, both about mindfulness, about supplementation in general, and about your personal experiences with cycling supplements, talking about caffeine and just ways that supplements can help you optimize your physical and mental health in this new year. So if you haven't heard that podcast episode, we highly recommend checking it out. It's going to be available on our YouTube channel, as well as all of our other streaming platforms, which include Spotify, SoundCloud, Google Podcast, and Apple podcast as well. So now that we're about to jump into today's topic, we also wanted to remind you that if you ever have a question for us in general about supplements or about Nootropics Depot, you can make a post on Reddit. Our subreddit is r/NootropicsDepot. You can post your questions there and on our subreddit, we also announce the next month's podcast topic ahead of time so that you can ask questions that we include in each podcast episode.

Emiel

And they really help steer the direction of the podcast. So we're very appreciative of those questions, and they oftentimes allow me to research some different areas that I wouldn't have come up with myself.

Erika

Absolutely. So keep asking us questions, keep interacting and keeping the conversation going on our subreddit. And now is our perfect segue into this month's topic for the In Search of Insight podcast. We are talking about all things glutathione, so we're going to be talking about glutathione synthesis, pathways, glutathione effects, and synergistic compounds that you can combine with glutathione, as well as different ways to increase glutathione within the body through supplementation. So together throughout the podcast today, we're going to develop a working understanding of what glutathione is and what it's doing in the body. So the first question I have for you, Emiel, is what is glutathione?

Emiel

That's an important starting point. So for this episode, actually, we're going to have some visual aides up on the screen if you're following along on YouTube. So if you are looking at the screen right now and you kind of know a little bit about peptides, then you might realize that you're looking at a tripeptide. Glutathione is a tripeptide, which means that it is composed of three different amino acids. Those amino acids are cysteine, glutamate and glycine. So when those all get together, you have glutathione. So with that in mind, let's actually take a look, maybe at the synthesis pathway. So that's the next image that will flash up on the screen. So let's take a look at that. At the start of this process, you see that you have glutamate and cysteine, and there's an enzyme that joins these together with the first peptide link. So this enzyme is called gamma glutamylcysteine synthase, and that produces it's a dipeptide at this point, then a dipeptide that is composed of glutamate and cysteine. Then there's another enzyme called glutathione synthetase, which is what produces the link between glycine and then gamma glutamylcysteine that we generated in the previous step. And once all of those are bound together, then we have glutathione, and this is how glutathione is produced. So clearly, it is very important to have a lot of L-cysteine around, glutamate around and glycine around, because without those amino acids, you can't actually synthesize glutathione. So those are essential for the glutathione process here. And we'll touch on that a little bit later.

Erika

I'm also seeing ATP and ADP in the beginning of this process, and we discussed the functions of ATP a little bit in our very first podcast episode of In Search of Insight. That's the Tart Cherry episode. So, the more that I learn and the more that I look at these visual aides, the more I can see how it's all connected. So let's dive a little bit deeper into how to increase glutathione levels in the body now that we understand how glutathione is actually made, coming together these three separate parts to create this tripeptide.

Emiel

So once we have this tripeptide, it gets in every cell of the body pretty much and in very high concentration. So in millimolar concentrations, which that might not seem like a lot, but inside of cells, that is an extremely large concentration. And pretty much in every cell of the body, we see this concentration of glutathione. This clearly indicates that glutathione is very, very important to the overall functioning of our body. And every process similar to ATP, like Erika was talking about, ATP is necessary for pretty much every single process in the body. Glutathione is at a similar level where wherever there is oxidation happening in the body, we need some amount of glutathione. And this is especially important in areas of the body that experience a lot of oxidation, like the lungs, the liver and the brain. So this is where we see really high stores of glutathione, and it's important to keep those stores up.

Erika

In addition to these areas in the body, I also imagine that glutathione is highly present in skin, because our skin experiences a lot of oxidation when exposed to sunlight and UVB rays specifically?

Emiel

Absolutely. Glutathione is also a very important mediator of skin health. And part of this is through its oxidation regulating effect. So Besides its antioxidant effect, which we've established is one of the main things that's going on. And actually, to put this into perspective, let's talk about this antioxidant effect a little bit more, because antioxidant is such a general word and it can really encompass a lot of different processes. It can encompass a lot of different enzymes. But we are specifically concerned about glutathione here. So let's look at some of the enzymes that are involved with glutathione and its antioxidant effect. Up on your screen now, if you're listening to this on YouTube, then you'll see an image where we're looking at one of the primary ways in which glutathione gets rid of hydrogen peroxide. If you look at the left hand corner, we see something marked as GPX. And this stands for glutathione peroxidase. Glutathione peroxidase, by using reduced glutathione, then can reduce hydrogen peroxide into basically water, which is safe and doesn't have an oxidative effect. So this is one of the ways in which glutathione has a direct antioxidant effect. It basically is fuel for glutathione peroxidase to then break down hydrogen peroxide. And because hydrogen peroxide is one of the main and oxidative compounds in our body, this is a great effect and makes sense why there is so much glutathione in all of our cells. That being said, since glutathione is not the only antioxidant, it doesn't really make sense that this somewhat simple and minor antioxidant effect overall is why glutathione is present in every single cell.

Erika

So if the antioxidant effect of glutathione on hydrogen peroxide is relatively minor compared to its overall...

Emiel

Well, its not relatively minor. So hydrogen peroxide, being one of the main oxidative compounds throughout our body, produces an enormous amount of oxidative stress. So it's important for glutathione to be present. But there are other things that can take care of hydrogen peroxide. So that indicates to me there should probably be another mechanism by which glutathione is so important for overall bodily function.

Erika

Okay, that makes sense. So then what is the other function of glutathione in terms of oxidation, or what are the other multiple ways that glutathione handles oxidation within the body?

Emiel

For this, we kind of have to go back to the start and remember what glutathione is actually made of. So it's made of glycine, glutamate and cysteine. And as some of you might already know, glutamate is also a very important excitatory neurotransmitter. And there is a theory that because there are such large concentrations of glutathione, pretty much every cell of the body, that glutathione might be a biological pool for glutamate. So basically, when we need some extra glutamate, then there's an enzyme, there's an enzyme called gamma glutamyl transferase, which actually can liberate a glutamate from glutathione. And to visualize this, we're flashing up another image on the screen now. If you look on the left hand side, you see where this enzyme, gamma glutamyl transferase, comes in and cleaves off a glutamate from glutathione. So then we have free glutamate, and then we have cysteinyl-glycine that goes off into other processes, which also has some interesting effects that we can maybe talk about later. But the most important thing here is that when we need some glutamate to drive glutamatergic processes, then we can pull glutamate from glutathione. And because glutathione is already present in pretty much every cell neuron and all of that, it means we basically have a very accessible pool of glutamate pretty much available to us at any point that we need it.

Erika

So I'm curious, what does glutaminergic that's the word you use? Glutaminergic. Glutaminergic processes would be just as an example.

Emiel

For example, memory. So one of the ways by which memory works is LTP, long term potentiation. And long term potentiation, it's a pretty complex process, but the gist of it is basically that glutamate binds to NMDA receptors, and this enhanced NMDA functionality is what causes neuroplasticity specific to encoding memories. And this process is called long term potentiation.

Erika

Oh, that's super important. Okay, so glutamate for memory and long term potentiation, are there any other really big, important kind of systems that glutamate is a part of? I'm just super curious about this part of glutathione.

Emiel

It's pretty much a part of everything. So overall cellular function, neurological function, it constantly needs glutamate, but the right amount of glutamate, because if we have too much glutamate, then we actually have issues with things like excitotoxicity, where cells get activated to such a large degree that they actually end up damaging themselves. Much like, if I were to turn up my speaker system too loud and I end up blowing out a cone, a similar thing can happen to your cells, which is why we actually have glutamate that's always been contrasted by GABA, which is the main inhibitory neurotransmitter.

Erika

That was going to be my next question is, does extra excitatory compounds within the cell, does that cause oxidation? But now that you brought up GABA and the fact that GABA is balancing out glutamate, so the excitatory versus the inhibitory neurotransmitters, there's a bit of a balance there.

Emiel

Yeah, and like you're saying, enhanced cellular activity because of something like glutamate would indeed cause oxidation. And that is part of the mechanism by which glutamate can have an excitotoxic effect. That's one of the main drivers.

Erika

Okay, so glutamate having an excited toxic effect, then we're kind of going back and linking to glutathione because glutathione is an antioxidant.

Emiel

Glutathione is an antioxidant. But more Interestingly, glutamate is important for glutathione synthesis, which means that a glutamate will get used up and locked away, and it can't perform its actions like glutamate because it's now part of glutathione. So this storage pool works both ways. It can both deliver glutamate when it's necessary and it can take away glutamate when there's too much glutamate.

Erika

So glutathione giveth and glutathione taketh away.

Emiel

Absolutely. And this seems to be one of the most important functions of glutathione is it seems to form synaptic transmissions of glutamate, and it really seems to be somewhat of a master regulator of that process, both providing and taking away glutamate at specific points in time when that is necessary.

Erika

That's fascinating. And now I feel like I have a much better understanding of Glutathione's function in the body, and the fact that it's in every single cell makes it seem like a really important compound to have in the human body, right?

Emiel

Absolutely. Yeah. You definitely want large amounts of glutathione, especially because there's a lot of environmental factors and things that we do, like drinking alcohol that decrease glutathione levels. It's important to top those glutathione levels up. And especially if you drink alcohol, it is a very good thing to keep in mind because glutathione synthesis is slowed down by ethanol. So this is one of the reasons why glutathione and alcohol and hangovers and that whole conversation often happened together. It's all because of glutathione here.

Erika

Oh, that makes sense. So if my glutathione levels are low or if I like to have my nice glasses and bottles of wine here and there, I would obviously want to increase my levels of glutathione in my body, right?

Emiel

Absolutely.

Erika

So how would I do that? What's the best way to increase glutathione levels in the body?

Emiel

The easiest way is literally just to take glutathione, specifically reduced glutathione. So we haven't really talked about the two different forms of glutathione. So you have reduced glutathione, which is oftentimes abbreviated as GSH, and then you also have oxidized glutathione, which is oftentimes abbreviated to GSSG. And GSSG is basically just two glutathione molecules bound together through a sulfur bridge. And oxidized glutathione, so GSSG actually has some of the opposite effects of reduced glutathione. So one of the main points in enhancing reduced glutathione status is also that you balance the ratio of reduced glutathione to oxidize glutathione.

Erika

And would oxidize glutathione be like glutathione that's already been used to manage or work on an oxidative stress event or within a cell that's experiencing oxidation?

Emiel

Yes, actually. So this is probably something we should have touched on with the glutathione peroxidase segment. When glutathione performs its antioxidant function, it actually produces GSSG.

Erika

Okay. So it changes from glutathione reduced glutathione to the oxidated glutathione.

Emiel

Correct. And this is actually a way in which you can look at how much oxidation is happening in someone's body. Basically, if you look at the GSH to GSSG ratio and GSSG is much higher than GSH, then that probably means there were major oxidative stress events and we needed to burn through a lot of GSH. And through this process, we generated a bunch of GSSG.

Erika

How would you determine the amount of GSSG? I'm curious. What would you use as your marker?

Emiel

You use GSSG as your marker.

Erika

Okay.

Emiel

So from blood.

Erika

Oh, I see. Okay, got you. So you're just measuring for that specific compound within the blood.

Emiel

Well, you're measuring for GSSG and you're measuring for GSH. So reduced glutathione and oxidized glutathione. And then you basically look at the ratio between reduced glutathione and oxidized glutathione. So if we have more oxidized glutathione than reduced glutathione, it means we are probably in a state of oxidation.

Erika

That makes sense.

Emiel

The interesting thing is when GSSG is generated, we can actually go backwards to and regenerate more reduced glutathione. So this is happening through an enzyme called glutathione reductase, and we'll touch on that a little bit later. But there's basically always a cycle going on where reduced glutathione is being turned into oxidized glutathione. And through this process, it is having an antioxidant effect. And then we need to get rid of the oxidized glutathione. And this is also one of the reasons why we actually want to top up our reduced glutathione stores.

Erika

And this brings us back into what we're talking about with increasing levels of glutathione in the body.

Emiel

Yes. So you can literally just take reduced glutathione. You can take it orally. There's been a lot of debate about whether or not reduced glutathione will actually enhance your glutathione status. And it will. But not all of it absorbs as reduced glutathione.

Erika

For those of you who are frequenters on Reddit or who are reading our blog or on Nootropics Depot's website, a lot, you may be familiar with some of the bioavailability issues or concerns with glutathione. So I think this is a really interesting part of our conversation.

Emiel

Absolutely. So while reduced glutathione, if let's say you take 500 milligrams or 1000 milligrams, only a small portion will absorb as reduced glutathione, but some of it will. And some of it will absorb straight into the bloodstream as intact reduced glutathione, which means that within the bloodstream it can already have an antioxidant effect, which is great. But because reduced glutathione is a peptide, it is sensitive to hydrolysis because those peptide bonds are not very strong. So those peptide bonds can easily be broken, whether that is in your stomach or once it is in circulation already, it can get broken down.

Erika

I'll ask the question that some of you might be wondering, which is, can you remind me, what is hydrolysis?

Emiel

Great question. So as the name hydrolysis might indicate already, what do you think is one of the main drivers of this process, hydrogen or water? Yeah. So basically, during hydrolysis, one molecule of H2O goes in and breaks the peptide bond. So that's basically what's happening.

Erika

Oh, that makes sense. Why hydrolysis would be causing that break of the peptide within your stomach. Because when you're drinking water or just the water that's naturally present in your stomach interacts with the glutathione peptide, then it's going to cause this hydrolysis break.

Emiel

Yes. And hydrolysis reactions are oftentimes also PH dependent. So because of the low PH of your stomach, this can speed up the hydrolysis of peptide bonds.

Erika

Okay. I like the direction that we're going in.

Emiel

So some of the glutathione will be absorbed as straight up reduced glutathione. Some of it in the stomach or in the intestines will break into its specific amino acids. So when we take a large amount of reduced glutathione, we then might get a bunch of L-cysteine that breaks off, a bunch of glutamate that breaks off, and a bunch of glycine that breaks off. And because L-cysteine and glycine and glutamate are all needed for reduced glutathione synthesis, it means that they can recombine in the body and create glutathione.

Erika

So the fact that glutathione isn't maybe as bioavailable like to be absorbed into the bloodstream as some other compounds isn't necessarily a concern actually, because if you're supplementing with glutathione and some of it is being absorbed into the bloodstream, but then others of it are being broken into the three different amino acids that actually help synthesize glutathione within the body, you are getting benefits from the glutathione that's not being absorbed into the bloodstream. It's just not happening immediately.

Emiel

Correct. And some of it is happening immediately because not all of the glutathione will be hydrolyzed, which is one of the reasons why taking a higher dose is beneficial, because it's much easier to hydrolyze ten milligrams of reduced glutathione than it is to hydrolyze 1000 milligrams of reduced glutathione. It will take a little bit longer, which also means that potentially more intact reduced glutathione can actually absorb.

Erika

Okay, so here's a curveball that I know might be a total tangent, but that's okay. So now I want to know because I'm thinking about the fact that I take powders and capsules. Is there a benefit to taking glutathione in powder form because it might be absorbed faster and then. Oh, wait. Actually it's the opposite way. So is there a benefit to taking glutathione in a capsule or a tablet form because it might actually be absorbed slower in the stomach or broken down slower and the powder is absorbed faster, so there will be more hydrolysis. Am I totally off the map right now?

Emiel

A little bit. If we did an enteric coating on glutathione, then you might bypass the stomach and then you might have different absorption parameters. But a capsule dissolves very quickly. If you ever want to test this out, just throw a capsule in some acidic water and it will break down pretty quick, especially in our stomach where we have a lot of agitation and it's warm and it's very acidic. Those capsules will break down very quickly and then instantly release all of its content into the stomach. And then you just have glutathione there.

Erika

Okay, so the bioavailability question, it's not so relevant to capsules versus powder. It's more just relevant to glutathione supplements in general.

Emiel

Well, actually now I'm thinking we just released some glutathione tablets, not capsules, because tablets are usually quite hard pressed, they take a little bit longer than a capsule to completely disintegrate. So that actually might slow down the dissolution of glutathione into the stomach. And potentially that could have a positive effect. I'm not entirely sure. We'll have to do some more research. So one other method that is employed, and I couldn't really see myself doing it because glutathione is actually a little bit sour. But you could potentially take it sublingually too. So putting it in your mouth, maybe a smaller concentration, 50 milligrams or something, because we actually can't absorb a whole lot of material sublingually, but we might be able to get a small amount of absorption of glutathione to happen sublingually. There actually is a study where they tried 100 mg sublingual glutathione on participants, and it did seem to work. So this is a route we could go down.

Erika

Okay, so we have the powder that we can drink, like combined with water. We have the tablets that you can take with any kind of liquid when you're swallowing the tablets. And then you have the potential benefits of the sublingual dosing, which may or may not result in better absorption.

Emiel

Yes. And for sublingual use, the powder formulation would obviously be the easiest. So you just measure out your dose on one of our scales or another accurate scale and then just put it under your tongue and probably leave it there for five to ten minutes. However, because glutathione is a little bit acidic, I personally wouldn't necessarily try this because I have tried sublingual using acidic compound sublingually, and it can make the sublingual membrane a little bit raw for me. And I don't like that feeling.

Erika

Okay, gotcha.

Emiel

So with that in mind, the way I circumvent some of these problems and I take reduce glutathione every day. I just take a higher dose. I take 1000 milligrams a day. I have a feeling that a significant portion of that is being absorbed as reduced glutathione into my bloodstream. And then I just have all of the precursors for reduced glutathione synthesis. And this brings us to another really important topic that we're going to have to discuss at some point in this podcast is that N-acetylcysteine is one of the most popular ways in which to enhance glutathione levels. And part of the way in which N-acetylcysteine does this is by acting as a pro drug for L-cysteine, which as we are all now somewhat intimately familiar with L-cysteine is one of the major components, it's one third of glutathione, so we need quite a lot of it. In fact, L-cysteine is one of the rate limiting steps in glutathione synthesis. So if we go back to that initial image and maybe we can flash it up on the screen again. So we have a bit of a visual guide here. But as you can see, first step in glutathione synthesis is combining glutamate and cysteine to make glutamylcysteine. And then later step in that process is where glycine combines. But in this first step, L-cysteine is the rate limiting amino acid for glutathione synthesis because we always have an abundance of glutamate, so we don't have to worry about that. L-cysteine is the rate limiting amino acid here. So one of the main ways in which we can enhance glutathione reduced glutathione synthesis is by increasing L-cysteine stores. And this is where an acetylcysteine comes in because it acts as a really good pro drug for L-cysteine, which can then deliver cysteine for glutathione synthesis. However, there is something a lot more interesting going on here. So there was a study in which they radiolabeled N-acetylcysteine. Radio labeling is a process in which you attach a radioactive isotope to a compound, and then during fluorescence studies, it will glow selectively. And you can see if we gave someone N-acetylcysteine, where in their body did it go? This particular study was a very elegant study because of its simplicity and how well it was executed. So basically what they did, they radio labeled this N-acetylcysteine. And they thought if the N-acetylcysteine is radio labeled, didn't think they knew, if the N-acetylcysteine is radio labeled, then the L-cysteine that N-acetylcysteine would produce through its pro drug action would also be radio labeled, which then also means that the radiolabeled L-cysteine, which then goes into glutathione synthesis, would make radio labeled glutathione. So you could pick this up on a fluorescent study.

Erika

Makes sense.

Emiel

Makes sense. But this is like the most perfect research setup that you can imagine because you can trace how things are happening. The interesting thing that they found, though, is that most of the glutathione that they saw appear after administering a large amount of N-acetylcysteine was not radiolabelled, which means that N-acetylcysteine probably is not really acting as a prodrug for L-cysteine, which is really fascinating because this has been the status quo for however long N-acetylcysteine has been around.

Erika

Okay, so if it's not actually acting as the pro drug like we introduced, then what is N-acetylcysteine doing that causes more L-cysteine to be created within the body so that more glutathione can be created?

Emiel

Yeah, so an acetylcysteine has a really unique mechanism of action. It can actually thin mucus, and this is one of its main uses it's to thin mucus out so it can be expelled easier. One of the main ways N-acetylcysteine does this is by breaking disulfide bonds of proteins. And mucus is made up of a matrix of glycoproteins. And usually that glycoprotein matrix is pretty loose. But if we get more and more disulfide bonds, then the glycoprotein matrix becomes stiffer and stiffer. And then that basically means we have less and less viscous mucus.

Erika

So to translate that into layperson's terms, your mucus goes from being nice and liquid-y and fluid to being hard, clumpy and crusty.

Emiel

Correct. Hopefully not crusty within your body.

Erika

Oh, sure.

Emiel

When its outside of your body and it crusts up, yes. But inside of your body, those glycoprotein matrixes become tighter and tighter, and then the mucus becomes less viscous, which makes it a lot harder to transport the mucus. So we want very viscous mucus so we can transport it. Now, this is where things get interesting during this disulfide bond breaking, a lot of these proteins contain thiols like L-cysteine. So a really big store of L-cysteine is within proteins and mucus membranes and things like that. And when N-acetylcysteine goes in, it breaks those disulfide bonds and basically liberates massive quantities of L-cysteine. Okay.

Erika

So L-cysteine is actually important to have within our mucus because it's doing things within the body and glutathione is coming in and saying, L-cysteine, be free to go, do the other things that you need to

Emiel

Sort of, yeah. So that seems to be what's going on. So not just mucus, but other different proteins. And actually in our bloodstream, we have a lot of albumin. Albumin is one of the most expressed proteins in our body and specifically within our bloodstream, we have an albumin called CIS 34 albumin, which is a cysteine-rich albumin, which means that when N-acetylcysteine gets into the bloodstream and it interacts with this CIS 34 albumin, then it can liberate quite large concentrations of L-cysteine from that albumin, and then that L-cysteine can go into glutathione synthesis. So N-acetylcysteine doesn't seem to be acting as a pro drug for L-cysteine. It seems to work as a liberator of L-cysteine from protein sources, which is fascinating.

Erika

Okay, gotcha. So I was a little confused there by bringing glutathione back into the conversation. But the point is that by supplementing N-acetylcysteine, you are allowing more of that liberation of those proteins to happen, which then in turn would allow cysteine to become a part of that tripeptide of glutathione eventually as that synthesis is happening.

Emiel

Well, because L-cysteine is the rate limiting step or compound in glutathione synthesis, it basically means that without an adequate concentration of L-cysteine, we cannot make glutathione. And because it is rate limiting, it means you can increase the rate of glutathione synthesis by increasing L-cysteine levels. So that is one of the main uses for N-acetylcysteine. And it was always thought that N-acetylcysteine is such a great inducer of glutathione synthesis because it itself is acting as a pro drug for L-cysteine. And the way it does this and this really does work. And a small concentration of the L-cysteine comes from this. There's an enzyme called acylase 1 which basically deacetylates N-acetylcysteine, and then we have L-cysteine, and then that L-cysteine can go into glutathione synthesis. But this study then found that that doesn't seem to be the main pathway. The main pathway seems to be that N-acetylcysteine is, through its disulfide breaking bond activity, liberating massive quantities of L-cysteine from stores of L-cysteine, which happened to be proteins that N-acetylcysteine can break.

Erika

Okay. That makes so much sense then why N-acetylcysteine has been a really popular topic of conversation because of recent current world events that we're not allowed to say specifically on this podcast. But you're all very smart and understand what's going on in the world at large. So let's keep the conversation going and talking about N-acetylcysteine and what is happening further down the line in this process. Now that we understand the ways that it's working, not directly to increase glutathione synthesis, but indirectly by liberating these proteins that are required for the synthesis of glutathione.

Emiel

Yes. So liberating L-cysteine from the protein.

Erika

Okay.

Emiel

With disulfide bond breaking.

Erika

Okay. That was the one piece that I was missing. So L-cysteine is being liberated from proteins.

Emiel

Yes. Because what are proteins?

Erika

Amino acids?

Emiel

And if we go up the line a little bit more amino acids turn into.

Erika

You got me there.

Emiel

When two amino acids link together.

Erika

Oh, peptides. Got it. Okay, cool. Gotcha, gotcha.

Emiel

And when multiple peptides link together.

Erika

We have dipeptides, triptides, quadro-peptides.

Emiel

Not entirely. So the di/tri/quattro.

Erika

I see. So when peptides come together, they make proteins.

Emiel

Yes. And the di/tri and that thing, it's really simple. It just indicates how many amino acids are in the peptide.

Erika

Okay.

Emiel

So a dipeptide would be produced of how many amino acids? Two! And a tripeptide, three, which is what we're talking about now.

Erika

Got you.

Emiel

The whole topic of conversation here is a tripeptide.

Erika

Right.

Emiel

But longer peptide chains, they can chain together and they can fold. And then we get proteins.

Erika

Okay. That makes sense.

Emiel

And then when proteins degrade, then we can liberate peptides again. And when those peptides degrade, we can liberate amino acids again. And actually on this topic, since this is actually pretty relevant here, protein is one of our main sources of amino acids, and protein is one of our main sources of L-cysteine. So what do you think enhanced protein consumption would do?

Erika

That would enhance glutathione levels in the body, right?

Emiel

Yes. Because it is providing that essential L-cysteine. It's also providing that essential glutamate and glycine.

Erika

Oh, cool.

Emiel

So protein is very important for overall glutathione synthesis as well.

Erika

Okay. So now I'm thinking just to connect it to all of you who are listening, for people who are eating a vegetarian or a vegan diet, they may want to consider increasing their glutathione levels.

Emiel

Yeah. So if you are a vegetarian or vegan and you know that your protein consumption is maybe a little bit low, then there is a good possibility that your glutathione synthesis is a little bit lower. So it would probably be quite beneficial to take some reduced glutathione, for example.

Erika

Besides being a liberator for L-cysteine, are there any other effects of N-acetylcysteine in the body?

Emiel

Yeah. So N-acetylcysteine has a lot of different effects throughout the body. But let's keep the focus more on glutathione. So one really interesting aspect of N-acetylcysteine and just L-cysteine in general and also glutathione itself. So for anyone that already is taking glutathione and has taken it as a powder. One thing you might notice is that it is slightly sulfurous, and this is due to the L-cysteine content. And in the context of N-acetylcysteine, that L-cysteine, part of it is being turned into glutathione, but part of it is actually being turned into hydrogen sulfide, which you might know as the smell of sewers, rotten eggs, things like that. Seems highly unpleasant. But Interestingly enough, hydrogen sulfide is what we call a gaso-transmitter. So a gaseous neurotransmitter. And there's a few of those, well, not a whole lot. There are three of those that we currently know of. One of them is nitric oxide. One of them is carbon monoxide, and the last one is hydrogen sulfide. So it acts like a neurotransmitter. But one of the interesting things about hydrogen sulfide is it also helps transport L-cysteine, and specifically, it helps transport L-cysteine to where glutathione synthesis happens. And after glutathione is produced, hydrogen sulfide actually helps partition glutathione into the mitochondria of the cell, which is kind of where we want glutathione to be anyways.

Erika

Hydrogen sulfide is a super important part in the process of this glutathione synthesis, and then glutathione being used in the cells.

Emiel

It's not necessarily a really important aspect of general glutathione function throughout the body, but in the context of N-acetylcysteine, it's very important, since N-acetylcysteine is generating quite large concentrations of hydrogen sulfide in addition to generating high amounts of L-cysteine. So this is maybe one of the reasons why N-acetylcysteine is so effective at enhancing glutathione status. It's because it itself is acting as a pro drug for L-cysteine. It is liberating through its disulfide breaking bond activity, L-cysteine from proteins, and it is getting that generated L-cysteine to where it needs to be for glutathione synthesis. And as the cherry on top, it transports glutathione to where it needs to be to the mitochondria. So this is a really interesting aspect of N-acetylcysteine, in my opinion. And hydrogen sulfide is a big player here, but it's not the only thing that can be a hydrogen sulfide donor. And we have a few other things that we can rely on for that as well.

Erika

What are those things?

Emiel

So one of those things actually might be taurine. So taurine is actually produced from L-cysteine and is one of the only other amino acids that has a sulfur group. And taurine itself seems to be able to enhance or not enhance, but act as a hydrogen sulfide donor. So by taking taurine, we might actually see enhancement in glutathione synthesis and utilization.

Erika

Oh, that's fascinating. Is taurine also an endogenous compound in the body, or is that only something that we have to take from outside sources?

Emiel

No, taurine is also an endogenous amino acid, and it actually works as a neurotransmitter as well.

Erika

Oh, wow, that's fascinating. So glutathione, taurine and cysteine are all endogenous, which means that they're all present in our bodies at all times.

Emiel

Yes.

Erika

Okay, cool.

Emiel

And we can obviously get them from exogenous sources, too, and then we can enhance their activity and get more of those benefits from those compounds.

Erika

Awesome.

Emiel

Another thing to consider here is actually if we talk about garlic. So a lot of people want to supplement garlic because of its health benefits. And indeed, garlic has a lot of health benefits. And part of these health benefits are that it enhances glutathione synthesis and glutathione status generally. I was always curious how this works, though, and I recently found out that allicin gets broken down into a few different compounds. One of them is diallyl trisulfide and diallyl trisulfide. When it interacts with reduced glutathione, very rapidly generates hydrogen sulfide. So this is likely one of the ways in which it is enhancing glutathione synthesis and then actually getting a lot of the neurological benefits of hydrogen sulfide because it does have some very important neurological functions, like enhancing LTP, similarly to perhaps glutathione, glutamate and that link.

Erika

Okay, so long term potentiation.

Emiel

Yeah.

Erika

Gotcha, remembering that.

Emiel

And hydrogen sulfide seems to be an important player here, too. And it seems that reduced glutathione is also an important player in generating hydrogen sulfide. So getting more or higher reduced glutathione status and then eating potentially just garlic in our diet could be generating hydrogen sulfide within our body, which helps enhance glutathione synthesis and then also acts as a neurotransmitter.

Erika

Wow. This is incredible. Ok. So now we have a couple of different compounds and foods and ideas of things that could be combined synergistically with glutathione that would help increase glutathione levels in the body.

Emiel

Yeah. And there's a few other things that can actually do this. So there's a few different enzymes that we can influence, and there's a few different herbs and different supplements that can affect glutathione status. One of these actually is glycine. So glycine is, again, a third of glutathione. So enhancing glycine levels could also enhance glutathione synthesis. And in fact, a recent study indicated that not only is L-cysteine a rate limiting step in glutathione synthesis, so is glycine, which if we and we'll flash it up again, if we look at the first image we looked at, you can see that after we have made glutamylcysteine, the next step is attaching glycine to glutamylcysteine. And this is further upstream in the process, too. Further downstream in the process. So we can imagine that glycine definitely is a rate limiting step here, too. And there is research now backing that up. This means that supplementing with glycine is also a good strategy for enhancing glutathione synthesis. And let's not stop there, because we have a really good glycine source, magnesium glycinate, which actually contains a very large quantity of glycine. But magnesium also seems to be important for glutathione synthesis. So there was a recent study where they looked at people who were or not people, animals who were deficient in magnesium. And in these magnesium deficient animals, they found a two fold decrease in glutathione status. So clearly magnesium is an important player here. So taking magnesium glycinate would then, one give you more magnesium, which should already enhance glutathione status. And two, it provides glycine, which should enhance glutathione synthesis. So it's kind of a nice two-pronged effect that we can get by taking magnesium glycinate. So this would be a great way to enhance glutathione synthesis, especially when taken alongside reduced glutathione.

Erika

Okay, cool. So we've got magnesium glycinate alongside glutathione. You briefly mentioned taurine, which could be something interesting to consider supplementing alongside glutathione.

Emiel

For a hydrogen sulfide donor.

Erika

Right. We talked about garlic as a potential complementary food to eat or include in your diet to help the processes of glutathione in the body. What other compounds, supplements or food might we want to combine with glutathione to increase levels of glutathione in the body?

Emiel

I like this food idea, so let's keep going there. So we already have identified garlic as a potential donor for hydrogen sulfide, which can enhance glutathione synthesis. Another thing that we could look at actually is broccoli or broccoli sprouts is even better, especially if we put a little bit of apparently dehydrated mustard seed powder.

Erika

So it's funny that some of these kind of stinky foods are working in a way to produce hydrogen sulfide because garlic maybe causes a little bit more smell than you'd like. But that's probably the hydrogen sulfide, right?

Emiel

Partially. And part of the other thing is with garlic, you just smell those sulfuric garlic compounds. So diallyl trisulfide, for example, very quickly turns into hydrogen sulfide. But on the other hand, diallyl disulfide doesn't. But those definitely have a smell to it, which you could probably excrete through your skin and that you can smell.

Erika

Yeah. And some people don't like the taste of broccoli, but more so because of the smell of broccoli rather than the taste. So I'm just thinking in terms of foods and food experiences. It's interesting that these kind of strong tastes and smelling foods like garlic or broccoli are a part of what might help increase glutathione production within the body.

Emiel

Yeah. And in the brassicas. So specifically here, of course, broccoli and broccoli sprouts, there is a sulfur containing compound called sulforaphane, which a lot of you are probably quite familiar with because there is a lot of hype surrounding this compound and for relatively good reason, actually. So one of the interesting things about sulforaphane is that it acts on a pathway called NRF. Two, through this pathway, it can actually increase the synthesis of glutathione and it can help regenerate GSSG. So oxidized glutathione back into reduced glutathione by enhancing the enzyme glutathione reductase, which is what drives that reaction. So if you really want a comprehensive food idea for enhancing glutathione synthesis and status, you could combine garlic with broccoli or broccoli sprouts, and then within broccoli sulforaphane exists as a different compound, and you need an enzyme to help break that down. And that enzyme apparently is highly present in dehydrated mustard powder. So put some dehydrated mustard powder on your broccoli and Cook it with some garlic, and you might have a pretty good food source for glutathione production.

Erika

Interesting. And then because we're talking about brassicas, there's also other foods that might include some of these similar compounds, like Brussels sprouts or even is cabbage a part of the Brassicas family as well?

Emiel

Yeah.

Erika

Okay, cool. So like red cabbage, which also has large amounts of anthocyanins, which is something that we talked about in our very first podcast episode, that Tart Cherry podcast. So that red color from cabbage has anthocyanins, but because it's part of the brassica family also has some of these beneficial compounds for glutathione production.

Emiel

Yeah, this wouldn't surprise me, but I didn't look that far into the brassica family. So I'm not entirely sure if every single brassica family will contain these beneficial companies.

Erika

You'll have to tell us on Reddit. For anyone who's a real brassica fanboy, let us know if you've done any research on red cabbage or Napa cabbage, broccoli or Brussels sprouts and any of the other vegetables in the brassicas family that we might be leaving out.

Emiel

Yes, this would be really interesting to look into. But back on the NRF two topic, another thing that acts on NRF two in a pretty significant way is Alpha lipoic acid. And it has been shown, in fact, that Alpha lipoic acid also helps enhance both glutathione synthesis and helps enhance glutathione reductase activity, which then helps generate reduced glutathione from oxidized glutathione. So Alpha lipoic acid would be another good thing to lean on for enhancing synthesis of glutathione and would be a good thing to take alongside reduced glutathione.

Erika

Now we're developing quite a robust dietary and supplemental stack idea for what you can pair alongside glutathione to help increase that glutathione synthesis within the body. But I'm curious, are there any other compounds or foods that can also have beneficial effects for this reason?

Emiel

Yeah, there are actually quite a few. So another really interesting one that I found is silymarin from milk thistle. So we've been talking all this time about enhancing glutathione synthesis and making L-cysteine more bioavailable or available for this synthesis process. But what we haven't even touched on is how can we actually increase L-cysteine synthesis? And this is also possible. And silymarin from milk thistle specifically appears to enhance L-cysteine synthesis, which then makes more L-cysteine available for glutathione synthesis. And this might be one of the reasons why milk thistle is particularly hepato-protective because it is causing localized synthesis of L-cysteine. So where we want that L-cysteine to be already so that when it is converted into glutathione, it's already where it needs to be. And we can have this very comprehensive oxidation regulating effect in the liver because silymarin likely is increasing L-cysteine synthesis.

Erika

Wow. So for those of you who are taking notes, add milk thistle to your list of things that might complement and work well alongside Glutathione.

Emiel

Yeah, that would be a really good one. Another good one. And we haven't actually touched on this aspect of Glution yet. So glutathione definitely is the master antioxidant that takes care of hydrogen peroxide. That's a very important effect and why it's in pretty much every cell. Another important effect of glutathione is that it is one of the main ways in which the body detoxifies itself. So the way it does this is actually by attaching glutathione to xenobiotics. Xenobiotics just being exogenous things that are coming in that are normally not present in our body that can have toxic effects. So we want to get those out. And one of the ways this is done is by attaching glutathione to these xenobiotics. For this to happen, though, we need an enzyme called Glutathione S transferase. And actually, as a visual aid, we will flash up an image of this happening now. So through this enzyme, Glutathione S transferase, we can attach glutathione to the xenobiotic, and then we have a glutathione S conjugate with the offending xenobiotic, and then it's neutralized. So we call this detoxification. And there are certain plants that can actually enhance this glutathione s transferase activity. And one of those plants is Ginkgo, and specifically within Ginkgo, bilobalide, one of the compounds that we specifically standardized for in our Ginkgo extract is the thing that enhances glucose activity, meaning that by taking something like Ginkgo biloba, you can enhance the activity of reduced glutathione and make it more effective at what it does, which is a really interesting effect.

Erika

Absolutely. What other supplements or compounds would be complementary alongside glutathione?

Emiel

One other one would be curcumin. So curcumin actually enhances the activity of glutathione peroxidase. And as we talked about earlier, glutathione peroxidase is the enzyme that uses reduced glutathione as a fuel to then break down hydrogen peroxide. So that's one of the most important functions of glutathione. So enhancing glutathione peroxidase activity is very important to overall glutathione effectiveness within the body. So taking something like curcumin would be a very interesting strategy of helping to enhance this. And this might actually be where some not most, but some of curcumin's antioxidant effects are coming from.

Erika

So I'm guessing that other antioxidant type supplements or foods would pair well with glutathione, right. Because we know that glutathione is doing a lot of work on oxidative stress events within the body, so it would only make sense to me, logically, that other antioxidant type foods or compounds would also help in that process.

Emiel

Yeah. And maybe for a somewhat unexpected reason. So if we are utilizing other things, exogenous things from plants that we're consuming or from foods that we are consuming that are combating hydrogen peroxide levels, then we need to actually burn through less reduced glutathione to reduce those levels, which also means we are generating less oxidized glutathione. This is really good.

Erika

Absolutely. So are we nearing the end of the helpful compounds or foods that might assist in glutathione production and glutathione activity. Or is there still more?

Emiel

No, I think that's it okay. There definitely are more. But we could keep on going and going. So maybe this is another thing we can talk about on Reddit. If any of you are curious, we can get a list of different things that we can get together to enhance glutathione activity, synthesis, standards, all of those interesting things.

Erika

Absolutely. This is also probably the perfect time to introduce a new segment that we're going to be having in all future episodes of the In Search of Insight Podcast. So cue jingle! New Product Releases. This is a really exciting segment of the podcast because we're going to talk about the new products that have been released since the last podcast has been out. Our most recent podcast episode was released in January 2022, talking all about mindfulness and bioassaying. And since that podcast has been released, Nootropics Depot has also released a handful of new products, the first of which is reduced glutathione tablets specifically relevant to this podcast that we're recording now.

Emiel

And very convenient because up until this point, we only had the powder. And powders don't always work all too well, especially when traveling.

Erika

Absolutely. Sometimes it's annoying to get your scale out and weigh your powder for your specific dose. So we wanted to make it a little bit easier for you to supplement glutathione in your day to day life. And that is why glutathione tablets might be a good choice for those of you who may be a little bit powder averse. The next new product that we have released in the last month is a sesame extract in capsule form. Emiel, can you tell us a little bit more about the sesame extract?

Emiel

Yeah. So sesame is very high in a compound called sesamin, and actually is also working on nRF2. So that goes back to the Alpha lipoic acid thing we were talking about and the brassica sulforaphane connection. So you might get something similar with sesame or sesamin specifically. Sesamin is also really interesting for enhancing cognitive health. It's quite neuroprotective and also has good liver protective effects and seems to really enhance metabolic health. So good to add to pretty much any stack.

Erika

Awesome. So the sesame extract comes in capsule. So again, for those of you who might be a little bit powder averse, this is really convenient. The next product that we've released is Cyracos 300 milligram capsules. Emiel, a little bit of background on Cyracos and why the 300 milligram capsule release is exciting at this point.

Emiel

Cyracos is a patented extract of lemon balm. So we have two different lemon balms on the site. One of them is just our generic and then this Cyracos one is much higher in rosmarinic acid and some of the other bioactives. However, in higher doses, something interesting happens with lemon balm. Instead of being calming and sleep inducing and things like that it can actually be a little bit stimulating. I first discovered this effect when I went on a plane ride somewhere and I thought, hey, if I take a large dose of lemon balm, I will surely sleep. So I took 3 grams of lemon balm, which by the way is a little bit high.

Erika

That's a megadose, what we would call a megadose.

Emiel

This was back in the day when I was a little bit less risk averse and these megadoses seemed like a good idea. The interesting thing I found though with this high dose of lemon balm, which was really inconvenient is I could not sleep. I was up and awake and I felt really good, but I was really hoping to sleep on this flight and that didn't happen. A similar thing happens with Cyracos. So Cyracos just generally is going to be more uplifting and less calming than our generic lemon balm just because of the higher content of rosmarinic acid and other bioactives. So especially in the 600 mg dose, some people were not getting the desired effects and they were getting those desired effects with lower doses. So based on this, we decided to offer a 300 mg dose that is geared more towards relaxation and the 600 mg dose can be more geared towards uplifting mood effects.

Erika

So now you have two options for your Cyracos supplements. One that is going to have these potentially stimulating and uplifting, and then one that's half the dose 300 milligrams that you can take when you're looking for those more typical and traditional effects from a lemon balm supplement.

Emiel

And I would say for people that are new to lemon balm or not necessarily lemon balm, but new to Cyracos and they want to try both a 300 and a 600 mg milligram dose, a very easy way to do this would be to get the 300 milligram capsules, try it at 300 mg, and then double your dose to 600 mg. With the 600 mg capsules, it's kind of hard to split them into two. So this is a better set up potentially to test out Cyracos for the first time.

Erika

And different dosage options for Cyracos.

Emiel

Absolutely.

Erika

Super cool. So this is probably one of my most sought after and exciting personal supplement releases that Nootropics Depot has done in the last couple of months and it is Sibelius Sage capsules. I'm so excited about Sibelius Sage capsules, primarily because I take Sibelius Sage every single day as a part of my daily powder stack. But I really do love the convenience of capsules. And I also like the option to take sage early in the day and then later in the day. And for me, reaching for a capsule is just a little bit faster and a little bit easier than measuring out the powder. And that means that I get the benefits that I really, really enjoy from Sibelius Sage with even more ease.

Emiel

Nice. And what are your favorite effects with Sibelius Sage?

Erika

Sibelius Sage has this really amazing calming effect. It makes me feel like I have a little bit more physical energy and just generally gives me a sense of calm and groundedness. So rather than energy coming from like a mental stimulation place, Sibelius age makes me feel like I have the physical energy to maybe do some yard work or wash the dishes. Things that might feel a little bit annoying or just a little bit like exhausting in my day to day Sibelius Sage makes me feel like I can tackle those physical tasks with a lot of ease. And because it gives me that sense of calm as well, I feel less stressed and maybe a little bit less annoyed at those kind of daily household chores or those things on my to do list that I might put off or procrastinate on.

Emiel

Yes. So a good thing to have conveniently available to dose whenever you need it.

Erika

Absolutely. Because it already helps my motivation and just kind of my sense of what do I need to do today? And can I be in this present moment to go through these different tasks? So having it available easily and quickly in capsule form makes that process even more enjoyable for me. Now, our last release that we've made since our most recent podcast episode is Baikal Skullcap Extract Tablets and Powder. And Emiel, I'm sure you have some interesting and exciting things to say about this new extract that we've released.

Emiel

Yes, this was a really interesting one to develop because we had a lot of freedom in what bioactives we could use. So during the beta testing program that we have internally. It's not external at this point. We just do it internally within other people in the office or with some friends and family. During this beta testing phase, we found that the formulation that we went with gave a really nice blend of effects. So nice and calming, but also focus enhancing, which was really interesting and only happened in this iteration of the baikal skullcap extract. But it was interesting going through and trying different combinations of the bioactives in there. And those main bioactives in this current formulation are baicalin, baicalein and apigenin. We also played around with wogonin and norwogonin a little bit and some other different flavonoids and flavones that are normally found in baikal skullcap. And the interesting thing is that every single iteration was completely different and this was our favorite and it was the favorite amongst a lot of different testers. So this is why this baikal skullcap extract is really interesting and exciting because as far as we know, baikal skullcap has never really been done with this level of specificity, but it's very beneficial to do it with this level of specificity because we can tease out very specific effects and we're very happy with the effect profile that we found. And similar to Erika with Sibelius Sage, I have similar effects actually with the baikal skullcap. So it helps calm me down while keeping me elevated and focused. So it's really good for me to do research work and writing work.

Erika

So to give you just a little recap of those new supplements that have been released, we have the reduced glutathione tablets, we have sesame capsules, we have Cyracos 300 mg capsules, we have Sibelius Sage capsules. And we have baikal skullcap cap extract tablets and powder. So every month in this segment, we're going to talk about the new products that are being released and have been released since the last podcast. And there's another really exciting announcement that we're making today in this podcast, which is that we have some new Natrium stacks about to release very, very soon, which for those of you who are signed up to our newsletter, you would have gotten an email giving you some hints as to what these Natrium stacks might be for you to guess. So I'll give you the hints now. The first hint for these new natural products is that we have made a novel take on a legendary stack. What might that be? You can start thinking about these questions and let us know if you have an idea of what it is on Reddit. Also, this would be Aquaman's favorite stack. So those two hints are for the first Natrium stack that we're releasing. So hint number one, a novel take on a legendary stack. And then number two, this would be Aquaman's favorite stack. Now for the second Natrium product that we are going to be releasing, the first clue is this one goes to eleven. And the second clue is smooth stimulation. So now you have those hints in mind for these new Natrium stacks that we're going to be releasing very soon. We're curious to hear what your thoughts might be, what your predictions might be for what these products are. So let us know what you're thinking on Reddit. Feel free to add your guess in that thread, and if you want, you can tag u/PrettyChill or nu/NootropicsDepotGuru and we'll chat with you on Reddit. We always love the interaction and the conversation that comes from interacting with you on Reddit. That's r/NootropicsDepot. So that concludes our new product release segment of the podcast. We're going to jump into my personal favorite part of the podcast, which is answering your questions, the questions that you submit in our monthly Q&A post on Reddit about this month's podcast topic. So the questions got really deep this month. You went into some really interesting directions and curiosities that have really helped us to do our research on glutathione and N-acetylcysteine. So I'm going to ask the questions. Emiel is going to talk about the research that will help answer these questions, and we will go through all of your curiosities that you have posted on Reddit. The first question that we're going to discuss today is by u/CW1008. And this question is about mucus and membrane thinning. So the question is, "Does reduce glutathione have the same membrane thinning effects of NAC? I had to stop taking NAC as this was a major side effect, making it painful to even swallow." Yikes!

Emiel

So that goes back to the disulfide breaking bond action of N-acetylcysteine so it can definitely sin the mucus membranes a little bit by breaking those disulfide bonds while reduced glucose to much lower degree. It could, but I don't think this is a concern at all with reduced glutathione.

Erika

That's really good to know. So now moving on to our next question. In a similar topic, this question was asked by u/ttyyllgabbagol. Sorry for butchering your username, but I'm really not sure how to pronounce it all in one go. So that's going to be it for today. So this person asks, "Is there any concern about stomach issues due to the thinning of mucus?" Great question.

Emiel

And again, this could be a concern, especially if you have some issues there already and if you are taking very high amounts of N-acetylcysteine because of that disulfide breaking bond effect. So there really is no way around that. And it seems to be very integral to the glutathione synthesis effects of N-acetylcysteine. That being said, N-acetylcysteine also appears to have some gastroprotective effects, and specifically hydrogen sulfide seems to have some gastroprotective effects. So you might want to take this with a grain of salt, but it is good to be aware of.

Erika

Absolutely. So now moving on to questions that focus on the mechanisms of action and the subjective effects of these two areas that we're talking about. u/Zidatris, who is a regular listener and asking awesome questions, thanks so much for your participation asked, "Would taking NAC with something like, say, caffeine for the increase in dopamine be counterproductive or actually favorable?"

Emiel

If NAC itself actually enhanced dopamine levels, then this would be favorable, but that doesn't seem to be entirely the case. What does seem to be happening is that the hydrogen sulfide, by acting as a neurotransmitter, can influence dopamine synthesis and dopamine release. It might even be a monoamine oxidase B inhibitor, but this is not totally confirmed yet. So with this in mind, the hydrogen sulfide portion of it would probably go well with caffeine because it would enhance the effectiveness of caffeine because one of the ways by which caffeine works is by blocking adenosine receptors. But by blocking adenosine receptors, you basically open more activity for the dopaminergic receptors because a lot of adenosine receptors form heterodimers with dopamine receptors. And basically when the adenosine receptors are turned on, the adenosine receptor limits the activity of the dopaminergic neurons. So when you block adenosine, then the opposite happens and we get more dopaminergic activity. So if that's what's going on here a little bit too. And actually hydrogen sulfide seems to also block adenosine A2A receptor, although this is a little bit of a debatable topic still because there isn't a very strong link, but there seems to be a link there. So with that in mind, they probably would make a good pairing.

Erika

Good to know. So now moving on to another question from u/Cupiddelocke7. They ask, "Does NAC help with racing thoughts?"

Emiel

Potentially. I mean, again, this would likely be going through the hydrogen sulfide pathway, although now that I'm thinking about it, since glutathione has an effect on how glutamate works in the body and acting as both a reserve for injecting glutamate where it is needed, but also taking away glutamate where it is not needed and might be causing more cellular activation that we don't want. Maybe if the racing thoughts are related to excess glutamatergic activity, then maybe the glutathione portion of things could take care of that. Another interesting thing is of course the hydrogen sulfide link because hydrogen sulfide works as a neurotransmitter, a gaseous neurotransmitter. And actually I found an interesting study that was showing that hydrogen sulfide might even upregulate GABA B receptors. So with this in mind, it might have a calming effect and it might be beneficial for this topic.

Erika

Amazing. Another question that we got from u/tuck3rs that's with a three as the E, is "Thoughts on longer term NAC and diminished pleasure from activities of life. It seems to modulate glutaminergic, neurotropic and dopaminergic systems that have a little bit too much after prolonged use. Would reduce glutathione carry the same effect or is it limited to the benefits of solely glutathione?"

Emiel

So as we've been talking about, those glutamate effects seem to actually be related to glutathione itself, so those effects would extend to reduce glutathione as well. But since we already have a lot of reduced glutathione in our bodies and we're just kind of enhancing this activity, I'm not entirely sure if this is where the link lies. So it might not be due to glutamatergic functioning, it might be due to some of the other effects, maybe of hydrogen sulfide, but it's hard to know and there doesn't seem to be any research on this. In fact, there seems to be a lot of research on the opposite end where it is enhancing pleasure.

Erika

So to be determined.

Emiel

To be determined.

Erika

Nice. u/tuck3rs also asks, "Does reduce glutathione work as well as NAC for alleviating alcohol induced damage? What about for reducing cravings?"

Emiel

So as far as I know, NAC shouldn't have an effect on cravings, it should just be enhancing the protective effects against alcohol through glutathione synthesis. Again, there might be a link with hydrogen sulfide here where hydrogen sulfide might be diminishing some of these cravings, but I personally have not delved into the research that deep yet for that. That might be where a link exists in terms of glutathione versus N-acetylcysteine for the alcohol mediated effects. As we talked about earlier, ethanol decreases the synthesis of reduced glutathione, and this is one of the ways in which alcohol can have negative health outcomes. So with that in mind, reduced glutathione and NAC will both help enhance glutathione status. So they should both be beneficial.

Erika

Awesome. And that kind of leads us into our next question, which was asked by u/schwiftshop, which is "What's the deal with NAC and alcohol?"

Emiel

Yeah, exactly that - it helps enhance glutathione synthesis. And because glutathione is depleted by alcohol and because alcohol causes a lot of oxidation throughout the body, it's a good thing to have.

Erika

Awesome. So now we're going to move on to questions about prolonged use, antioxidant effects and related systems in the body. So the first question was asked by u/Arjan. The first of a couple of questions in series is "Could NAC supplementation cause breakdown of the blood brain barrier in humans? A few years ago, there was a lot of talk about this possibility," based on this paper that they linked in the question on Reddit.

Emiel

Yeah, it's just a single study. It doesn't seem to have been replicated since. And it obviously got a lot of hype. I'm not totally sure if this really is a thing, especially because NAC itself doesn't cross the blood brain barrier. That being said, it could definitely still get to the blood brain barrier and do something there. And given its sulfide-bond breaking activity, potentially it could cause some issues there. But I honestly don't think that there is a serious concern there for actually breaking down the blood brain barrier. But something to keep in mind about N-acetylcysteine and related compounds that might have an effect on the blood brain barrier. But again, the blood brain barrier is incredibly complex and has a lot of protective features to not allow things in. So I would be surprised that a naturally occurring compound, which is normally also naturally present in our body and we get from our diet as well, wouldn't necessarily be breaking down the blood brain barrier. But stranger things have happened. So until we see more research, this is always a possibility. And I guess this is kind of how science works. There's a lot of unknowns, and until we have more research to prove this, more than just a single study that was highly hyped and never seemed to really go anywhere from there. No repeat studies. Something to keep in mind that maybe this is not the best designed study and maybe they were just adding enormous amounts of NAC straight to blood brain barrier tissue, and then maybe the low PH of NAC in such a high concentration could cause the damage, not NAC itself.

Erika

Really interesting. And a great question. So another segment of u/Arjan's question is, "Can antioxidant supplementation like with NAC, actually cause reductive stress and thereby indirectly increase oxidative stress as laid out here," in another study that was linked.

Emiel

This is always a concern with antioxidants, especially exogenous antioxidants that don't normally exist endogenously, and even endogenous antioxidants like vitamin C, vitamin C in very high doses. And just normally too vitamin C, when it produces its antioxidant effects similar to glutathione, then produces another compound that is a prooxidant. But there's other protective mechanisms that then take this prooxidative compound and take care of it. So similar to GSH, reduced glutathione turning into GSSG, oxidized glutathione, and then glutathione reductase taking that GSSG and regenerating reduced glutathione from that. A similar thing happens with vitamin C and other antioxidant molecules. However, once we start saturating these enzymes that convert those things back to the antioxidant compounds, then we might run into a situation where we have an overabundance of prooxidants with no antioxidants to balance them out. And this could be a direct result of taking too many antioxidants. But as far as I'm aware, you would really have to be going hard on a lot of different antioxidants. And I think this is another interesting aspect of glutathione is that because it's so tightly regulated and because it is present in every cell of the body, and because we need such large amounts of it, I see very little risk of prooxidant activity when taking reduced glutathione at normal levels, like 500 mg to 1000 mg a day.

Erika

Awesome. Good to know. u/Chocobo_Eater asks "NAC sometimes comes with molybdenum and selenium in the same capsule because it's thought to deplete those minerals. Does glutathione also deplete these minerals or anything else?"

Emiel

NAC actually doesn't deplete those minerals at all. But that being said, both neck and glutathione are both metal chelators and they can chelate metals, and this is part of their beneficial effects. That being said, the reason why selenium is oftentimes included with NAC and even sometimes glutathione supplements is because selenium is an important cofactor for the various glutathione enzymes. So increasing your selenium status would indeed be an interesting thing for further enhancing glutathione status and synthesis and function. But it's not necessary. And I don't think that NAC or reduced glutathione actually deplete them. It's just that they are beneficial cofactors. And I actually had never heard about this, so I looked it up and I found the page for Natural Factors, I think, who make this product. They also seem to be the only people who make this product, but I might be missing a few, but in their description, they even say molybdenum and selenium are both important cofactors for the function of glutathione, and that's why they're included.

Erika

Really cool. Good to know. So this is why we love you all asking us questions, because sometimes it leads us down pathways that we never would have found without your questions. So continuing, we have a question from u/TheOptimizzzer, which is, "Are there any situations where it may be beneficial to take both N-acetylcysteine and reduce glutathione at the same time? Can they be synergistic?" And the resounding answer is yes.

Emiel

And of course, this is because we would have multiple sources of cell cysteine and we would have that hydrogen sulfide donor activity, which is then helping to shuttle L-cysteine around and further enhancing glutathione synthesis. So one way maybe to do it would be to rely on NAC for the initial increases in glutathione, because NAC does produce quicker effects overall and then relying on reduced glutathione for long term supplementation to top those levels up.

Erika

Awesome. u/TheOptimizzzer also asks, "Other than cost, is there any advantage of NAC over consistent glutathione dosing?"

Emiel

Yes. So cost is definitely an issue with reduced glutathione. It's quite expensive, especially in the doses that we need to take, and NAC is cheaper and more effective overall at enhancing glutathione synthesis. So that would be definitely a major plus for N-acetylcysteine. That being said, N-acetylcysteine also has a bunch of different effects, like the sulfide breaking bond activity, which definitely has a lot of effects that maybe you're not looking for. So that would be a plus for reduced glutathione, because reduced glutathione doesn't have those effects. Another effect that N-acetylcysteine has is the fact that it is an H2S hydrogen sulfide donor. And maybe you don't respond all too well to hydrogen sulfide donors and you don't want this, then reduced glutathione again would win because it is a more direct way. Maybe not the most efficient way, but it's a more direct way of enhancing glutathione synthesis. But with that in mind, if you combine glutathione with some of the reduced glutathione with some of the other supplements we talked about, like curcumin or gingko or even taurine or milk Thistle, then you can enhance the effectiveness of orally taken reduced glutathione. So there may be some scenarios where reduced glutathione by itself actually provides a better base to go off for glutathione synthesis because it has less intrinsic effects and different things that it does. It's just a more straight cut way to enhancing glutathione status. So it would probably combine better with some of these other supplements that help the function and biosynthesis of glutathione.

Erika

Another question from u/TheOptimizzzer was "What's the deal with NAC and histamine? Is this an actual thing? And if so, is glutathione a better option for folks who might be worried about histamine?"

Emiel

This was the first time I've heard about this, but NAC indeed does seem to release histamine, and this can be a problem with higher doses of NAC. So with that in mind, I looked does reduce glutathione do the same, and it doesn't. So if you are worried about the histamine effects, which don't really seem to be all too pronounced for most people, but for some people it seems to be much more pronounced, then reduced glutathione would be the better option.

Erika

Awesome. And finally from u/TheOptimizzzer, "Is glutathione likely to be easier on the digestive system? Could this be related to histamine?"

Emiel

Well, so I think there we have to go back to NAC and it's sulfide bond breaking activity in the stomach and maybe attaching itself to the stomach lining and then breaking some of those bonds in the mucosal lining of the stomach. And reduced glutathione doesn't appear to do this. They are both quite acidic, though. So if you are just sensitive to acidity, then both will probably have the same effect. But if the sulfide bond breaking effect is where the problem lies, then reduced glutathione would not have this issue.

Erika

Amazing. Now moving on to a question from another one of our regular listeners and questioners, u/Hormesis. Thanks so much for your participation and your thoughtful questions. Hormesis question is, "What effect does glutathione have on the methylation cycle? Any particular benefits or pitfalls that people should be aware of?"

Emiel

There definitely seems to be a link here, but it might actually be working in the opposite direction. So some of the compounds that are produced during methylation cycle homocysteine, cysteine donor as well. So part of the output from the methylation cycle might also help enhance the synthesis of glutathione. So it might kind of be working in the opposite direction where the methylation cycle, working properly is an important factor for glutathione synthesis. That being said, it goes a little bit deeper too. So GSSG, the oxidized version of glutathione, appears to inhibit an enzyme called S adenosyl methionine synthase. So this is the enzyme that produces S. Adenosyl methionine, which is one of the most important methylation factors. So with that in mind, having enhanced levels of GSSG and having this GSSG not turning back into reduced glutathione could be something that is not good for the methylation cycle. So this is further evidence that we want to enhance the ratio between reduced glutathione and oxidized glutathione, always wanting to keep the oxidized glutathione higher, always wanting to keep the reduced glutathione higher than the oxidized glutathione. So this is that effect of balancing the ratio and this is where it comes into play. Another thing that seems to be a bit of a link between glutathione and the methylation cycle is that glutathione can actually protect vitamin B twelve. And because vitamin B twelve is also a major player in the methylation cycle, this is another area where having more reduced glutathione around can then keep more vitamin B 12 around and through this action can have a beneficial effect potentially on the methylation cycle.

Erika

Wow. Very comprehensive answer. Excellent questions were asked in that category. And now we're going to move on to another really interesting category of questions that were asked on Reddit, which is questions about muscle growth. So the first question comes from the u/TheGermanGuy21, which is, "Does reduced glutathione have the effect that it reduces muscle growth the same way NAC does?"

Emiel

This is kind of a difficult one to answer. So taking antioxidants is definitely not good for muscle growth if you take it too close to exercise. But because taking reduced glutathione, it takes a while to build up those levels and we're just building up reserves and we want those reserves around. I don't think we necessarily want to apply the same logic here because we always want to keep it around. And it's the same with NAC, although that being said, NAC seems to much quicker enhance glutathione synthesis and then enhance oxidative status there. So with that in mind, NAC may, due to its just rapid rise in glutathione synthesis, might not be the best thing to take right before exercise. But you could definitely take reduced glutathione at any time because that's going to take a lot longer to enhance those glutathione levels. But with that in mind, if you do go back to our previous podcast about actually our first podcast about Tart Cherry, we go quite in depth about taking antioxidants close to exercise. And indeed, the oxidative stress response that exercise produces is very critical for muscle growth. So inhibiting this process is not great, but I don't think this is necessarily a concern with increasing glutathione levels over time, globally through your whole body. It just gives you more protective effects.

Erika

Cool. That's really good to know. And a great question. u/TheGermanGuy21 also asks, "Does reduced glutathione have the same craving reducing effects as NAC?" Which is similar to a question we got earlier.

Emiel

Yeah. And again, I'm not entirely sure what pathway this goes through. It might be a glutamatergic thing too, in which case both NAC and reduced glutathione would have the same effect. But if it is going through the hydrogen sulfide effect, which seems a little bit more likely to me based on what it's doing in the brain, then only NAC would have that effect, but maybe both because of its glutamatergic effect will have that effect, but we're not entirely sure.

Erika

Cool. And then our last question about muscle growth in general comes from a user who asked a question earlier, which is u/ttyyllgabbagol. And their question is "Another question I've been wondering is, would NAC affect muscle growth and or muscle recovery in any meaningful way?"

Emiel

And the answer to that kind of goes back to what we were talking about earlier is that when we exercise, we get a lot of oxidative stress, and then that oxidative stress helps enhance muscle growth. But then after a while, that oxidative stress then turns into muscle soreness. And we call that delayed onset muscle soreness

Erika

Or DOMS.

Emiel

DOMS, which is a very fun word to say. So taking NAC maybe like 2 hours after exercise and then allowing those glutathione levels to build up would potentially be a good way to help enhance recovery. But I think there are some better options for that. Like Tart Cherry has a more comprehensive effect there and has a more direct oxidation regulating effect, where N-acetylcysteine definitely has that oxidation regulating effect. But because it's working through glutathione, which is always there, I'm not sure how impactful it will be for this specific purpose, even though it definitely will have an effect. But I'm sure other things other oxidation regulating compounds would have a more comprehensive effect.

Erika

Awesome. That concludes the question and answer portion of today's podcast. We really went in depth talking about glutathione synthesis, glutathione processes within the body, the relationship between NAC and glutathione, and all of the different compounds, foods and other supplements that can work really well synergistically alongside glutathione to have just this general antioxidant balancing effect in the body. So we're so glad that we got to research these topics because sometimes with this really technical, dense information, it can be tough to start to parse out and get a general understanding of what these compounds even are. Where do they come from? How are they working within our bodies and where do they come from outside of our bodies? But today we wanted to give you a really comprehensive understanding and working theory of what is glutathione doing. Why is it so important and why might you consider supplementing glutathione in your day to day life and in your diet and all the different things that glutathione is doing to help keep you moving and going in your daily life? Yeah.

Emiel

And I guess my concluding remark based on that is because we have such high concentrations of glutathione all throughout our body and we all have it already. It's kind of one of those things that pretty much everyone could probably benefit from taking a little bit, especially the older we get, the less glutathione we have. So as we're aging, it might be an important thing to add on.

Erika

Absolutely. So that concludes the main discussion for today. We're so glad that you are enjoying and getting good information out of the In Search of Insight podcast. We release a new podcast episode every single month and every month on Reddit. Before the new podcast is released, we announce the topic and invite you to ask us questions about the topic so that you can help direct our research and we can answer your questions about compounds, supplements, science, neuroscience, and Nootropics in general. We really love having this back and forth with you online, and specifically on our subreddit. That's r/NootropicsDepot, so if you have a specific question for one of us, my Reddit username is u/NootropicsDepotGuru, and Emiel is u/Pretty-Chill. Exactly. So you can always tag us on Reddit and ask us a specific question, and we'll go in there and chat with you and really get into some of the nitty gritty science and the mechanisms of the things that you're wondering about. In addition to this, we're so grateful for those of you who are subscribing and sharing this podcast with your friends. So if you know of someone who might be interested in all of this super technical knowledge, or maybe someone who's just getting into supplements or nootropics, we'd love it if you would share that with them. You can listen to this podcast on YouTube, Spotify, Apple, Google, and SoundCloud. So there's lots of different places to stream In search of Insight. We're really excited to keep developing this podcast, for your continued participation and your listening and to keep adding elements like the visual aides and the video and the question and answer portions so that you can be a part of In search of Insight and understanding and enjoying all of the things that Nootropics Depot is working on for you. So with all that being said, thank you so much for listening. It's time for us to sign off and until next month podcast, we'll see you very soon. Bye.

Emiel

Bye.

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#003 | Will You Use These Supplements to Optimize Your Physical and Mental Health in 2022? | MINDFULNESS

Podcast Transcript

Erika

Hi, and welcome back to another episode of In Search of Insight, Nootropics Depot's monthly podcast. I'm your host, Erika or, Nootropics Depot Guru on Reddit and sitting next to me is our product specialist, Emiel.

Emiel

Hey, everyone.

Erika

So this month is obviously a great time to kind of take stock of where we've been and where we're going. And as the new year approaches, 2022, we really wanted to start diving into a conversation that's a little bit more nuanced and catered toward your individual needs and goals for the upcoming year for your mental and physical health. So in this podcast, we're taking a little bit more of an introspective approach to our topic, which is mindfulness. And an aspect of mindfulness that we often explore with supplements, and in the context of our mental and physical health, is the concept of bioassaying, and determining what is a supplement doing for us? How can we determine their effects and their benefits? And then what's the best way to develop a sense for our baseline, for our body, our mood, our mental health, and then what supplements are doing to help us optimize those things on a daily basis and then long term as well. So for some people, this concept of taking stock of your physical body, your mental health, and the present moment, we talk about this concept of mindfulness. But in the world of supplements and nootropics, there's also a concept quite similar, but a little bit more technical and in depth, and that is called bioassaying. And I'm going to let Emiel give us a general understanding for what is bioassaying and what kind of scientific method goes into bioassaying that connects it with this idea of mindfulness.

Emiel

Yeah. So I think to start this off, we should maybe talk a little bit about mindfulness because I think when we say mindfulness, we're often probably thinking yoga, meditation, spirituality and things like that. But mindfulness is actually a lot more of a scientific concept. It's basically like the scientific way of doing meditation, usually loose from spirituality, which I think is a really interesting concept. And you have programs built around it like mindfulness based stress reduction, which goes a little bit more in depth and has a lot more meditation as a part of it. But it's a really good method of managing stress levels with things you can do yourself. And I think there's a lot of research backing this up. So I really like this concept of mindfulness. And recently I realized we do a lot of mindfulness ourselves when we're testing new supplements. When we are putting stacks together, when we're making new formulations, we need to test them out. And not a whole lot of people are very good at actually testing these stacks out. So we have a pretty small group of people, myself included, and Erika is included in this as well, where we go in and test supplements because we seem to be able to parse out these effects a little bit better than the average person, which kind of makes us analytical instruments to a certain degree.

Erika

And the reason why, sometimes for us, it's a little easier to tell the effects of a supplement, it's not because we're so special or we have this hidden skill, but it's just a matter of familiarity and time spent observing our physical state, taking notes and going through this kind of mental process that we're going to explore in this podcast and tell you about. Something that you can do independently from any other kind of process or interaction to determine what's going on in your body.

Emiel

Yeah. And actually, before we really dive into it, I want to address a Reddit question we got. So for this podcast, we are doing Reddit questions again. Thanks for the submissions, we really had a lot of submissions this time, so we'll have a lot of content and questions to talk about on this podcast! But there's a question from u/Lamanchin93, which I'll have Erika read.

Erika

So u/Lamanchin93 asks, "How do you personally account for confirmation bias in the context of taking new products, of which you may have formed expectations through your research?" And this is an excellent question because confirmation bias is something that can have some serious impacts on our perception of what a supplement is doing. So, Emiel, what are your first thoughts when hearing this question?

Emiel

Yeah. Confirmation bias is one of my biggest enemies. I know it exists. It's always there. There's no way to fool it. It's hardwired into our brains. So confirmation bias is there, placebo is there, the nocebo effect is there, and the more expensive a raw ingredient gets, I'm sure there's some expensive placebo there, all of which affect our experience of what we're taking. So that's a big problem. When we're bioassaying new supplements that we're going to release, it's really important for the owner and I to get a good understanding of what's happening. But we realize our limitations, and we realize that we are sensitive to confirmation bias and to the placebo/nocebo/expensive placebo, all of those different effects. So the way we solve this is instead of solving it for ourselves, because this is probably not really possible, we just enlist other people to help us out. And these people, our coworkers at the office and colleagues and friends and family, they sometimes aren't as clued in about these things as we are. And we'll maybe say this product may help you recover from exercise a little bit better, or this product should have a stimulating effect. But we don't go into the pharmacology, what it does and things like that, and we just see what response they have very naturally to the product. And this really helps guide our process. And the interesting thing is, sometimes we find that we found a particular effect, but no one else found that effect. So is that because we read the research and we have some confirmation bias going on, or is it because we're a little bit more mindful and we have better tools available for determining what's going on?

Erika

Or is it possible that some people are non-responders, and there's actually a moment that comes where maybe a product needs to be reformulated or something needs to be changed in order to get to a more even response from the people who are doing the bioassaying?

Emiel

That happens a lot too. And it happened with sleep support, for example. A subgroup of people who were taking sleep support noticed that it was actually making their sleep worse, not better.

Erika

And this was prior to sleep support being released, right?

Emiel

No. This was actually after sleep support was released. So before sleep support was released, we had a similar problem. This isn't necessarily confirmation bias, but this just goes to show how important bioassaying is. When we were first formulating sleep support, I had put in a compound that on paper seemed to work perfectly fine for sleep. In fact, it should have been a really good ingredient to have in there for sleep induction, and it did work for that. However, 2 hours into our sleep, it became stimulating. Well, we didn't know it was this compound yet at the time, but it became very stimulating and woke people up in a puddle of sweat. So this is obviously not good. But here is kind of where confirmation bias comes in again. We were looking through the formula thinking "What in there could be causing this effect?" And maybe because of a certain confirmation bias about one or two compounds, I could have maybe picked the wrong compound out because I thought that one, if I look through the research, that one has the most potential, maybe for keeping us awake, so I'm going to try and take that one in isolation and then maybe I do find hey, it keeps me awake, but that might be placebo confirmation bias, whatever can be going on there. So that was tough. Luckily, we were able to just bioassay each one, take it, see what the effects are. And we did identify the product and we took it. It made us a little bit sleepy. 2 hours later, it became noticeably stimulating and a few people noticed this effect. So I think when we're talking about confirmation bias, the trick around it is just enlisting more people to do it and not just relying on a single account.

Erika

Yeah. Absolutely. And then to kind of wrap up the story about this great example of confirmation bias and bioassaying for sleep support, then once the sleep support was actually released, there was another kind of discovery which took place because of the variety of people that were trying it. And then the product was reformulated yet again.

Emiel

Yeah. And the second time around, because it happened in such a small subgroup of people, it was a lot more difficult to find which ingredient was causing it. And during our discussions, I think a lot of confirmation bias popped up. We all had an idea. Okay, I think that one might have an effect. I think that one might have an effect, and that could have maybe influenced some of our reformulation efforts. But luckily, we actually enlisted some of the people who were having issues with sleep, and we sent them out a new formulation, and they confirmed for us that this formulation they could actually sleep well with. So, yes, confirmation bias is a huge enemy to any science and any formulation we do, but there are ways around it. They're not perfect, but we can figure out systems that work as accurately as possible for our purposes.

Erika

And also be open to the fact that confirmation bias can be very powerful, and so the more perspectives that we have, the better we are able to determine what's working for most people, and then what's the likely cause for something not working. And this is something that's more on a broad scale when it comes to bioassaying. But then when thinking about individuals and using these concepts, mindfulness and bioassaying for just yourself keeping confirmation bias in mind when you're noticing beneficial effects, or maybe some negative or less desirable effects, this can be really important, too, because it can also help you from feeling like that gut reaction of saying, "Oh, it's definitely this product that's helping me to achieve X" or "This product is really giving me issues with Y," might be true, but the more research and the more time spent really investigating where the source of that issue is from, the more likely you are to find a good solution for yourself, whether that's continuing to explore the supplement, maybe different dosages or trying something different.

Emiel

Yeah. And I think actually, something I missed in my analysis of it was time. Sure, if you take one supplement one time and it has an effect, like a big acute effect, that could certainly be placebo or confirmation bias that you're getting from anecdotal or reports you've read or research you've read. But can that effect be replicatable every day for a week, every day, for two weeks, every day for a month, and it becomes less and less likely then that you are experiencing placebo type effects or confirmation bias type effects. So time is also a factor that can kind of negate some of these confirmation bias issues. And this is also why sometimes we just say, "Hey, take this supplement for two weeks before really diving in and going, what is it doing for me?" And it's because sometimes the supplement just needs a bit of time, maybe you need a bit of time to iron out some of the placebo effects, some of the confirmation bias to really get a solid understanding of what it's doing.

Erika

I think this leads us actually perfectly into another question we got on Reddit, which was from u/MrNotSoSerious. This question is perfectly fitting. So, "What is your take on cycling supplements? The idea of taking supplements with premeditated breaks in between seems to be a common practice among many people, usually to prevent developing a tolerance and to avoid undesirable effects. Nootropics Depot supplements often provide recommendations regarding amounts and dosages. However, it does not touch on the topic of whether or not a given supplement should be cycled or taken every day. Do you think that some supplements cannot reach their true potential because they're being cycled too often?"

Emiel

Yes, I do think that's the case. I think for a lot of what we do and a lot of the supplements that we take, cycling is not really necessary. I think cycling really comes out of the bodybuilding world, in which individuals are taking supplements or other stuff that is really pushing the limits, riding the line for the most maximum amount of benefits. But you can't do that forever. So basically you push it, you push it, you push it as hard as possible, you walk the line, and then you have to stop at a certain point for safety precautions rather than tolerance. But the interesting thing is that this concept has kind of bled into supplements, the nootropic world as well. And here we are a little bit more concerned about things like tolerance, and you could certainly cycle certain things that have acute effects, like stimulating compounds like Dynamine, maybe Sabroxy, Dynamax, Caffeine-NALT, like those kinds of products that have fairly noticeable acute effects. If you want to keep those fairly noticeable acute effects, then sure, cycling it on and off, or, you know, maybe not even getting that complex with it, just taking it once every once in a while. So once a week, twice a week, not really being on a strict cycling on or off schedule. But for most other things, I think there are acute benefits, and there are long term benefits. And I think for most of the stuff we do, we are more interested in the long-term benefits than we are interested in the short-term benefits. So a good example for myself is Sabroxy. Sabroxy has an acute stimulating effect, this is great. Actually, same with Polygala. They both have acute stimulating effects that I really enjoy and over time I start getting used to those, and that's where the tolerance comes in, and it's not as noticeable. But I actually find that taking Sabroxy or Polygala long-term has more benefits. And this could be due to some of the other pharmacological actions of Sabroxy and Polygala, specifically the neuroplasticity effects. But for me, even after taking Sabroxy, 100 milligrams of Sabroxy every single day for six months, it's still stimulating. So I think if we keep our dosages low and we take other things as well surrounding it as support supplements, then we can actually maintain the effectiveness of a certain supplement for long periods of time. And I think once we start getting into the three month plus range, some really interesting things sometimes start to happen. Even in the two to four week area. And you see this with supplements like Bacopa Monnieri, it has a pronounced acute effect. Very pleasant, actually, it's kind of calming actually works well as a sleep aid as well. But the most interesting effects with Bacopa actually pop up two to four weeks after you start taking it. And that's where the memory effects start taking hold. But those still get better after the four week mark, and they will continue getting better. And as far as I'm aware, there's no long term studies of individuals taking Bacopa for years, like two to four years or multiple months. But if there are long term benefits there, you can imagine that over prolonged periods of time, those keep getting more selective and better.

Erika

I really love that broad and long-term idea, sort of thinking about moving into the future in 2022 with a different approach to cycling or dosage of certain supplements. So what you're saying is that the consistency and the long-term benefits can often be different and develop over time, which is really cool. And I think that's something that u/MrNotSoSerious touched on in their question, which is "Are we getting benefits? Are we getting more benefits from cycling?" And the simple answer would be, likely no. Likely it is better to be taking a more manageable or perhaps like a slightly smaller dose over a long period of time and then determining the benefits as you continue.

Emiel

Yeah. So if we're kind of going back to even the Dynamine example, we can also think about coffee. I'm sure most of us consume coffee every single day or other caffeine sources, and we don't take a break. I know for myself personally, it's probably not the best thing to have started drinking coffee around age 14, but I've been drinking coffee for a very long time every single day, and I have stopped for a tolerance break. And when coming back to caffeine again, caffeine was actually very unpleasant. So over time, the effects of caffeine actually got more pleasant, and I think I got more out of it, even though acutely, it wasn't that stimulating. After stopping it, I felt fine too. And overall, I think I was off caffeine for almost a year as a bit of an experiment for myself to see, how can I live my life without caffeine? And I could live it perfectly fine. However, after starting caffeine again and kind of getting over that initial edginess of caffeine and the unpleasant effects once it started to work again, as I knew it from a year before, it was very pleasant and I think my overall quality of life is better with small amounts of caffeine. I only drink one cup of coffee a day, so it's really not a whole lot, but that one cup of coffee over a prolonged period of time has actually been very beneficial for me, probably moreso than just the acute effect.

Erika

Yeah, definitely. And this is something that Emiel and I can relate on a lot, too, because we were both baristas in past lives. So we both have this experience of developing somewhat of a tolerance to caffeine. And then when we left those barista lives behind, the transformation that happens when you're drinking multiple cups of coffee, around coffee, tasting espresso all the time, and then you go back to a different job or back to your life and you're not drinking so much coffee, it takes some time to come down from that tolerance of caffeine. But I had a similar experience recently. I typically drink one cup of coffee a day, but sometimes I just love coffee so much I need to have two, and it's just too much for me to handle, even if I want it. I found that one cup of coffee a day is totally fine. It doesn't affect my sleep, doesn't make me feel too edgy or too jittery, but it did take me quite a while to get to the point where I could say, okay, I love my coffee. I love the flavor, but I also don't want caffeine to be controlling my life or my ability to hold a utensil or have a normal conversation or keep my general mental and physical health in check without feeling like I'm wired all the time. So this is kind of a good example of an everyday example of bioassaying and mindfulness, because no matter how much I love the taste of coffee at the end of the day, I want coffee to enhance my life and not cause, yeah, exactly. Not take it over, not get in the way of my ability to think clearly and to feel generally calm and a sense of groundedness.

Emiel

And how long were you drinking the two cups of coffee a day?

Erika

At least a year and a half, at least a year and a half, and then probably a little longer after that as well.

Emiel

So after doing two cups of coffee a day for long term, how did that compare to doing one cup of coffee a day or even less long term?

Erika

Well, there were definitely a few things that I noticed when I was drinking, like two cups of coffee a day, and the first one was just a general kind of panicky and uncomfortable feeling right when I would wake up in the morning. Like the first thing I would notice was some unsettled stomach and just this kind of panicky, like urgent feeling, which was not something that I had experienced prior to my sort of two cup a day habit.

Emiel

Do you think maybe the two cups a day were impacting your sleep while maybe one cup a day wasn't?

Erika

It's certainly possible, because when I was drinking two cups a day, I would find sometimes it was hard to go to sleep. Sometimes I wouldn't sleep very well. And I would actually wake up quite a bit throughout the night. So I feel like this was just having an overall more negative effect for me. But then at a certain point, my tolerance for caffeine got to be so effective that then I would do a third cup sometimes, and that's when I...

Emiel

Well, you don't want your tolerance to get too effective, you want to keep it under control.

Erika

Exactly, that's what I'm saying. So when I was drinking two cups of coffee, my tolerance was so effective that then I could actually drink a third. However, at that point, my tolerance wasn't helping me out, and it certainly was just a natural factor of taking more and more caffeine over a long period of time that your body adjusts to it in some ways. But what I was experiencing at that three cup a day point was like the not-desirable effects of caffeine. And so I started to kind of reel it back in, back to two cups a day and then down to one cup a day. And I definitely don't have the same issues that I was having at that point when I was drinking lots and lots of coffee. I'm not having the same issues with waking up in the middle of the night, not having the same issues with waking up with an upset stomach or a racing mind. And some of that is certainly because of other supplements that I've begun to take. But I know for a fact that caffeine above one cup of coffee a day has a very significant effect on my mental and physical health, and I've been able to determine that because I've been exploring that for the past, at least three, if not more years.

Emiel

Yes. And for me, it's actually somewhat similar, except I seem to just be able to consume unlimited amounts of caffeine. I never really get to a point where it's edgy or jittery, except for when I had no tolerance at all. And I got into it again, I realized that caffeine is quite powerful. It can have some undesirable effects and some really desirable effects. But after consuming caffeine regularly, I can just consume as much as I want without any undesirable effects. But then it just stops working. So for me, when I drink one cup of coffee a day, I get all of the benefits that I want from caffeine, I don't seem to build up a tolerance as much. It has beneficial, longer-term effects, and I can just stick with that level. I don't have to go over it. So I think to sum it all up because we kind of waffled on a little bit here. But a big thing with cycling is, if you are pushing the limits and you are taking high doses of something that you know you will build a tolerance for and you want to keep those beneficial effects around, then maybe cycling is necessary. However, I would never recommend to push the limits like that. I am always a proponent of more balanced, long-term approach so that we can work to work goals and not achieve a goal and sacrifice other aspects of our life. And to some of you who have been around nootropics for a long time, this concept probably sounds pretty familiar because it is exactly what nootropics are supposed to be: a long term approach, something that is safe, long term sustainable. You don't really build much of a tolerance, too, even though this is pretty much unavoidable for most things, but we can keep those tolerance levels low. So this is kind of what Corneliu E. Giurgea said, and I really hope I'm getting this name right, because he's kind of the founding father of nootropics. So it's always important to kind of go back to those early days of nootropics to really see, okay, what was it? And the goal was just long term. These things are supposed to be taken long term, cycling wasn't really a thing that was talked about. It should just be long term sustainable. And I think that is the approach that I've seen work the best most often, just be patient. Over time, you will reach those goals that you want. Usually when we try and reach them in a couple of days in a week, maybe two weeks, we're maybe pushing the limits a little bit too hard. Then you have to cycle off, then you lose those benefits, then you have to cycle back on and you're not starting from zero again. But you are starting from a disadvantage again because you've lost some of those beneficial effects. Whereas if you just take it longer term, then you can have more beneficial effects. And I think just to kind of wrap it up, a good example of this is creatine supplementation. A lot of people like to cycle creatine, but it doesn't really make any sense. It's better to just take 5 grams of creatine every single day for the rest of your life because it's possible, rather than cycling on and off like a lot of bodybuilders tend to do. They'll take 25 grams of creatine for a couple, for a week, I think. And then they'll drop it a little bit and then they'll get into maintenance dose. But during those week or two where they're taking higher doses, they experience a lot of undesirable effects that you wouldn't get from lower doses of creatine over time. And over time, those lower doses of creatine will reach the same beneficial effects as cycling with higher doses of creatine and then having to go off of it and on and just this constant plan of like, okay, when am I going to start the next creatine cycle? When I do have to go off? How am I going to plan that with my diet and exercise regimen and all of that? It's way easier to just take creatine regularly every day, forget about all of that, get the effects you want long term.

Erika

Absolutely. And not only is it easier in terms of developing a habit, but it also gives you a little bit more of a place of control or consistency so that you can determine what other effects or what other variables in your life might be causing benefits, or maybe not-so-desirable effects in that goal setting and goal achieving period. So, to get back to a question that was specifically relevant to caffeine, we already talked about our personal coffee journey and our caffeine experiences, but u/Zidatris asked a good question about caffeine. "What's your view on cycling caffeine? I've come across conflicting information regarding whether or not to cycle it. Since cycling off, for example, on weekends, leads to a come-down effect, which isn't ideal for performance." Now, for me, personally, if I don't have coffee, if I don't have my one cup of coffee a day, I really, really notice it. But I do this occasionally because sometimes I just want to know for myself, like, how do I feel on a day without coffee? This isn't something I do all the time. Maybe a couple of times a month. It just depends. But generally speaking, one cup a day every single day has worked really, really well for me. Emiel can get a little more specific when it comes to the cycling idea, but I find that that consistent single cup a day really works well. And when I do take that one day off, you know, every once in awhile, I don't experience specific, terrible or very, very noticeable effects. I might be a little bit more tired or a little more sleepy by the end of the day, but that's just how it is for me. What are your thoughts more technically speaking, Emiel?

Emiel

Yeah, it's a bit of a double-edged sword, so maybe we need to get into the neuroscience of tolerance. So how do we get tolerance to certain compounds? And this is a pretty complex thing, and it involves some genes and things like that, which I'm not going to get into here. Let's keep it a little bit simple. We'll just talk about up or down regulation of receptors. So for caffeine, the way it produces wakefulness promoting and stimulating effect is by attaching itself to adenosine A1 and adenosine A2 receptors. Once it's attached, it blocks these receptors. So it is adenosine A1 and A2 antagonist. When it's doing this, the response of those receptors are that they are getting much less stimulation by adenosine, and they want more adenosinergic activity. So a way around this is to just populate some of these neurons with more adenosine receptors. And we call this upregulation. So basically, over time, caffeine needs to block more adenosine receptors to have the same effect. And adenosine likely just has a normal effect because of those extra adenosine receptors however, when caffeine is not present, it means there's a lot more adenosine receptors for adenosine to bind to. So if we're constantly cycling on and off caffeine, then we are going to have specific points in the week where we have more adenosinergic activity, which could be actually quite interesting. So, for example, the adenosine A2 receptor, when it gets activated, it actually helps promote BDNF levels and neuroplasticity. And this is one of the ways by which Oroxylin A actually seems to promote neuroplasticity. Oroxylin A functions as an adenosine A2 agonist instead of an antagonist like caffeine. So maybe there could be a benefit if you take caffeine, for example, five days a week, and then in the weekend you cycle off and you don't have anything to do. You can just sit around and nap a little bit and be more relaxed and you don't need that energy and can handle being off caffeine. Then maybe that's an interesting way to enhance neuroplasticity. So that could be interesting. On the other hand, maybe you do a lot during the weekend and you can't necessarily afford to do that, then I would just recommend taking lower doses of caffeine longer term because there are also positive things to reducing adenosinergic activity. And caffeine has beneficial effects long term as well. So there's kind of two options. Another option, and this is what I've been doing is I just take Sabroxy every day and I take caffeine every day, which means that likely the adenosine A2 receptor is being held in check a little bit by the combination of caffeine and Sabroxy. So my adenosine A1 receptors might be getting majorly upregulated, but the adenosine A2 receptors may not get that up regulated, so that might help. I'm not entirely sure. I do actually think it makes the effects of caffeine smoother, because you are kind of filtering out the adenosine A2 activity, which adenosine A2 seems to cause some of the jittery edgy effects of caffeine. So combining them is interesting. But to get back on topic, take this information and maybe try out a month where you do caffeine five days a week, cycle off in the weekend, see if that has any positive effects, and then the next month just take caffeine every day and then compare those two months together or maybe two weeks, maybe a month is too long, maybe two weeks. Compare them. See how you felt during a single period with caffeine and the subsequent period without caffeine. Compare them. See, maybe did you have beneficial effects cycling off or did you have negative effects cycling off and then kind of weigh it and go for myself personally, what is the best approach? And I think that really ties in with what this whole podcast is about and it's mindfulness and it's being mindful of what works best for you, because we are all different. We all have different biochemistry, different densities of receptors and different absorption parameters and pharmacokinetic profiles. So yes, we can average things out, and there can be an average recommendation of what is the best overall practice, but that best overall practice might not work for everyone. So that's where the mindfulness aspect comes in. Pay attention to what is happening in your body. Pay attention to what's happening in your brain, maybe have a notebook or other ways to keep track of what's happening.

Erika

Yeah. That was actually exactly what was on my mind when we're getting back to this concept of mindfulness and how taking something long term and giving yourself more time to determine the effects can be beneficial. One thing that's really important when thinking about mindfulness and taking a mindful approach is actually giving yourself the tools to determine what was happening when you first started taking the supplement, and then what was happening a month, two months, three months down the line and keeping track of that information. And it doesn't have to be, you know, writing an essay every day, but just making notes and keeping track of where you're at mentally, physically as you're trying something new and then returning to those notes and returning to those observations can really have an additional beneficial effect in your sort of mindfulness and your supplement journey. Another thing I was thinking about as Emiel was talking about what kind of tools we have, what kind of analysis tools we have to determine what's going on in our own bodies, because we are all unique and we have different biochemistry. Another thing that's unique about us is our lifestyles and our goals and what we hope to gain or accomplish on a daily basis, and the way that we spend our energy throughout the day, our stress tolerance, and these different kind of more global and social aspects of our lives. And these can also have really prominent effects on the way that we feel mentally and physically. So in addition to being really in tune of what's happening inside your body, a part of mindfulness that's also really important is knowing what factors in your life that may be not happening in your own physical body, but that are happening around you, to you or with you. These also have a really significant effect, too. And applying mindfulness to...

Emiel

Even the weather comes in here.

Erika

Absolutely, yeah.

Emiel

If we don't get enough sun exposure and we're not taking vitamin D, then this could have an effect on bone strength, immune function, and even mental functioning and mood and all of those kinds of things. So sometimes there are things even outside of our control, outside of our bodies that influence maybe how we respond to certain supplements. Like, maybe if our mood is low and under our normal baseline because of a lack of sunshine, then a supplement that normally elevates us above our baseline is now just pulling us right back to baseline, maybe slightly underneath. And personally, this might feel like, oh, okay. This supplement doesn't work as well now. Or maybe this batch didn't work as well as the batch before. But maybe the batch is exactly the same, and it's just our external environment that's different.

Erika

Exactly. And you can see how quickly these sort of variables of our baseline for our mental and physical health, it starts to stack up so fast. Okay, there's what's happening inside my body. There's what's happening in my brain. There's what's happening in my daily life. There's the people I know, there's the weather, there's my job, my hobbies, my interests. It really quickly can feel very overwhelming to think about nailing down and analyzing and identifying every single variable that might be causing changes. But this is where the mindfulness comes back in, because that overwhelming feeling or that long list of variables that starts to stack up at the end of the day. What we're trying to do is we're not trying to control every last single variable in our lives. It's just not realistic. It's not possible. But what we are trying to do is we're trying to optimize and understand ourselves better and our environment better. And the things that we're taking can have really significant benefits for us long term. So I think it's time to jump into another question.

Emiel

Yes, we got a lot this time, thanks everyone.

Erika

Yes. Thank you for your participation, we really appreciate it. And we're glad that we're able to have conversations, Emiel and I on the podcast, and we really enjoy having conversations with you on Reddit as well. So if you're not familiar with the Nootropics Depot subreddit, you should be, because there's so much information, conversation and activity going on there every single day, pretty much at all hours of the day. So check us out on our subreddit, r/NootropicsDepot. Now that we've talked at length about Emiel and I's personal caffeine journey, we've talked a little bit about cycling of supplements, and we've delved a little bit into the concept of mindfulness and bioassaying, confirmation bias, let's just get really specific and intentional. We're going to give you a simple, stepwise process for checking in with yourself and determining how is the supplement affecting me? What's my baseline and what are my goals? Using mindfulness and bioassaying.

Emiel

And to give you these tools and steps, I'll just walk you through what I do when we get a new ingredient in and when I have to bioassay it. So for me, the most important thing to remember is that I need to start off with a blank slate. Let's say I have a new paint color, and I want to determine what color this paint is. And let's say it's green paint, and I put it on a green background. It's going to be really difficult for me to determine what exactly the color is. It makes much more sense to have it be on a blank canvas. I just put a lick of paint on there and I can see exactly, okay, green. Bioassaying I approach in a similar way: I want to have most everything out of my system so that I can see what I'm looking at in isolation. So the way I achieve this is basically, first thing in the morning when I wake up, I grab whatever I'm trying to bioassay, and I take it before having had coffee, before food, before any other supplements. And then I start a timer and I go, I just kind of sit there. I feel like in the morning after I wake up, my mind is especially blank sometimes. So this is a really good time to actually bioassay, so then I can just sit there and determine okay, I'm starting from this very familiar state waking up in the morning, how is this changing? And I'm used to it changing from things like caffeine. So now I can pay attention and see what is this other thing changing in my morning, feeling, routine, all of that. So I think however you find a way to do this it's really important to start with a blank slate and a clear mind and not have anything else be present, because there can be other interactions of different supplements. I would also say if maybe you wake up and you're feeling kind of grumpy or something like that, skip the bioassaying for the day. Make sure it's on a day where you just feel totally normal and neutral, not super happy, not super sad, just a normal, everyday kind of day. Then what I usually like to do when I start getting the initial tingles of what's going on, and this is obviously a lot easier to determine with supplements that have big acute effects like sabroxy or even lemon balm, start noticing when things start changing and these changes are really subtle. Most people will miss them. But if you slow down enough and you can kind of relax for a little bit and have nothing else going on, if you really pay attention, you'll probably start noticing some little changes. Maybe I feel slightly more clear in my head or I have a bit more energy or I have a bit of a spring in my step. My mood seems to be good. I want to go make myself a nice breakfast or something like that. I'm more motivated to do that, pay attention to those little things, and then think, is this normal for me? Do I normally get motivated to mop the floors in the morning? No, that's a really strange thing. I would never mop the floors in the morning right when I wake up. But if a supplement makes me feel that way, then hey, maybe this is a really good one for motivation.

Erika

So step one would be start with a blank slate, and then step two would be ask yourself a series of questions about how your mental state and your physical state may be responding to this supplement that you're taking.

Emiel

Yes. And on the flip side, if we want to expand those first two steps, let's say we are determining whether something works for pain for like an ache we are having. Then it makes sense to test out the new supplement when you are having an active ache without having taken anything else. Then you can really go "Is the pain in my knee going away, or is the pain in my lower back going away?" Going through it a little bit there. Of course, here placebo, nocebo, expensive placebo, confirmation bias becomes a lot trickier, because if you really think, hey, this supplement is going to help me with my pain, and I have a lot of hope for it, because I'm in a lot of pain all day, and I don't want to be in a lot of pain all day, then maybe that supplement is not helping as much as maybe the placebo effect is. So that is always something we should be aware of. And that was a really good question that was asked on Reddit. And I think just the main thing is to be aware that we are all susceptible to this, no matter how cognitively strong you are, no matter how experienced you are, no matter how much knowledge you have. If you have a PhD in neuroscience, I don't care. You are susceptible to this effect. I'm susceptible to it. Even after five, seven years of doing this pretty regularly, at least once a week. I know that this is an issue, so accept the issue and think what limitations this can bring in. So this is an important thing to realize in step one and two.

Erika

Yes. So confirmation bias is going to be present throughout the process. But I think it can be especially present in the early stages of the process of bioassaying. Step one, blank slate. Step two, asking these initial questions of what might be changing, what the supplement might be doing for you. And then step three would be, I imagine...

Emiel

Letting those effects blossom. So those initial tingles you get, start paying attention to those and start seeing how they develop. Maybe this is kind of similar to for anyone who's listening to this who's also into wine, tasting wine is a similar type of process. You open up the bottle, maybe you taste a little bit, you smell it first, you swirl it around, see if it smells a little bit different, taste it. And then maybe you want to decant it and let it sit for a while and see how some of those initial flavors you tasted, how those start to develop. Maybe you want to sample it at 15 minutes, at 30 minutes, just another little sip and just see, how is it evolving? How is it changing? Do the same for bioassaying. Those initial feelings, hang on to those and see how those develop, see if they increase in intensity. Or maybe they mellow out. Or maybe they completely change in character. And this is with the sleep support issue we had with this compound that was stimulating, that was a really good example of this type of bioassaying because if you stop paying attention at the 1 hour mark, then it would have been really hard to identify the stimulating effects at the two hour mark. But because we were paying attention to the whole duration of action of this compound, we were able to identify and see how the effects evolved and blossomed, then changed, then became different.

Erika

So part of this step three, then, is also determining the duration of action like Emiel said, of the supplement as a whole. And this can really help us to determine what might be the best time of day to take a certain supplement, depending on how long we notice the perceivable effects. If there are any, we might want to take it in the morning or in the afternoon or right before bed.

Emiel

Yes, absolutely. That's always a good thing to be aware of. How long is something lasting? Is it going to negatively impact my sleep? Maybe if it is a stimulating compound. So that initial bioassaying step, completely on an empty stomach, first thing in the morning. It makes it really easy to determine how long is something lasting for me? What kind of effects do I have? Maybe 6 hours from now, 8 hours from now? Usually that does mean it's a day where maybe you don't want to take any additional supplements. So usually when I do it after about two or 3 hours, I will have like a cup of coffee and some food and just some normal lunch. But usually I will not take anything else that day. Just maintain that semi blank slate for most of the day. Sometimes, though, which is really interesting, and like Erika was saying earlier, I really need a cup of coffee in the morning. But I have actually noticed with bioassaying that sometimes I'll take something that completely negates the need for any coffee, which is also interesting. And those are just kind of small anomalies that happen consistently that you can find here and there and determine and then see how that affects maybe your supplementation.

Erika

So we have step one, two, and three, and that would kind of cover really the basic elements of bioassaying on one particular day.

Emiel

Well, actually, I think there is one thing that we're still missing. So we're bioassaying on a completely empty stomach now, and I think we did a very interesting blog recently talking about pharmacokinetics and how we can change the absorption of different supplements, so we can bioassay this as well. So let's say we try a supplement on a completely empty stomach for the first time. First thing in the morning, it kicks in really quickly. Maybe it kicks in a little bit too quickly. Maybe it kicks in so quickly that it kind of upsets our stomach a little bit, which is not ideal. So if this is the only test we do, just on an empty stomach first thing in the morning, then maybe this is not representative of normal use of this compound. So what we can do is we can try it on a full stomach. Try it before a meal, try it after a meal, try it an hour after breakfast or kind of play around with that. And then we have that initial reference. We have that reference of what does it do on an empty stomach. And then from that reference we can go and determine okay, do the effects get better when I add a little bit of food? And I have found with quite a few supplements that I actually like the slightly slower absorption pattern of taking a supplement with food, because not only does it not kick in as quickly, and sometimes it's a little bit jarring when something kicks in quickly. So a more gradual rise, but a more gradual rise means also a more gradual decrease in the compound, so we can actually extend the duration of action. So this is an interesting point, too.

Erika

And that blog that Emiel is talking about is such a great resource for learning, really the basics and getting into some intense technical aspects of absorption. Talking about Cmax and Tmax for those of you who are aware. So I would highly recommend checking out that blog, it's called "When Should I Take My Supplements?" And to kind of round out and give you a conceptual idea of what we're talking about with the empty stomach bioassaying versus the full stomach bioassaying is that when we're bioassaying, we are forming these manageable variables for ourselves to determine what is happening over the course of a day, a week, a month. So that variable of the empty stomach, and now we have an additional variable to bioassay with the full stomach.

Emiel

Yeah, absolutely. And who knows, maybe we find that certain foods actually enhance the effects somehow there's still a lot we don't know about how certain things absorb. There is some idea that bile salts can really influence absorption, and different foods and spices, especially affect bile salt concentration and bile acid concentration. And that can then influence absorption as well. And furthermore, even if you have, let's say, black pepper salami sandwich, you are consuming a lot of black pepper. And in that black pepper is piperine, a compound that we utilize, for example, in our curcumin supplements to help enhance absorption. But that means that if you were eating a diet that was fairly high in black pepper, then you might actually notice enhanced absorption with certain meals, and certain meals might actually hamper absorption. So, for example, if you were just taking magnesium oxide and you happen to be eating a food that is high in phytic acid, and phytic acid can actually bind to that magnesium oxide and make it very hard for that complex of phytic acid and magnesium oxide to absorb. So now it's starting to get a little bit complex. Of course, there's a lot of variables going on. So this is actually why taking something on an empty stomach is the best way to bioassay, because we're not thinking of foods that might enhance or decrease absorption. And we're not thinking about food matrix effects, like the effect of phytic acid binding with magnesium oxide. So reduce the amount of variables while you are testing, for anyone who's a scientist and who's listening to this, that probably sounds familiar. You want to control your variables and actually have as little variables as possible, usually, and an ability to tweak those variables with a lot of flexibility.

Erika

I like that idea. And I think now that we've talked about bioassaying a little bit with these three primary steps, and then that addition of potentially bioassaying with a full stomach as well, I'm curious, Emiel, what other steps would someone take to kind of give a well rounded and sort of a complete introduction to bioassaying on a single given day? What would be step four?

Emiel

I think step four might not exist.

Erika

Or perhaps step four is just that end of the day reflection.

Emiel

Yeah. And I think that can be step four.

Erika

Or documentation, perhaps.

Emiel

Documentation, if you really want to get into it and you want to document and you can refer back to it, that's a really good approach. I personally don't really like this approach. I like to just experience it and reflect back on the experience and then just do it a few times. And then after I really have a good idea of what's going on, I'll maybe take some notes and form a good idea. But usually what I'm trying to do is form a mental idea of what it's doing for myself and how I can maybe integrate it with other things. And this is a way I learn. Personally, I don't like taking notes. I learn better when I just pay attention and experience and let it all happen. So this will be different for everyone, too. So I think that's another thing to keep in mind. Bioassaying, and we presented a few general practices that will make it easy if you adhere to. But this is not the end-all be-all method of doing it, and you might find that you want to take notes or you might find that you don't want to take notes and you just like the overall experience and getting a good feel for that experience. Because for me personally, sometimes I have a hard time putting into words the experience of what I experienced. So then maybe writing it down is not advantageous, and just knowing what you experience is the most advantageous thing. It's also the least scientific, I know. It's the least replicatable, and it's the least, well, I don't know how to say this, but basically it doesn't have staying power if maybe a year from now you wanted to reflect on your experience. You can easily go through your notes, but that experience might be out of your brain already, unless you're taking some really strong memory enhancements, which we might talk about later.

Erika

Absolutely. And I think it's important what Emiel is talking about for you personally, taking notes isn't something you'd like to do, and in fact, it might actually distort your memory or give you kind of a false sense, depending on how you're reading those notes at a later date. For me, it's the exact opposite. I really love taking notes and archiving and organizing and putting down the details and the descriptors and the words and the sensations that I am experiencing so that I can go look at it at a later date. But I do have to say, because I know you, Emiel, you're a very mindful person, and I know that you really ground yourself in the present moment, and that's a really big part of how you think and how you approach the world. And for me, I'm thinking 10 miles a minute, and I'm often thinking ahead. And so archiving and writing down and documenting things can be really helpful for me, because no matter how much I may try to be mindful in a given moment, sometimes I've just got too much on my mind, but I do want to keep track of what's happening in those subtle changes when I'm taking a supplement and then I can revisit that in a moment where I have some time and I'm at a little bit calmer state, maybe I'm a little more mindful and I can look back through those notes and remember and recall, oh, yeah, I was having this feeling or the sensation was really surprising to me. So it's really different for everyone. And now we're getting kind of into the other side of the bioassaying, which is mindfulness, and whether you are really familiar with mindfulness or it's something that's completely new to you, mindfulness is also going to be a very specifically individual experience and something that you can practice. But at the end of the day, the goal that we're trying to achieve is we're trying to be aware of what's happening in our body, and we're trying to be more cognizant of how the things that we're putting into our body are affecting our daily lives. And that has really incredible opportunities long term when you're taking those different steps to be more observant and more aware of yourself and of your environment.

Emiel

Yes, and what Erika was saying a little bit too maybe mindfulness might take a bit of practice to it, might take some developing. So I do a couple of different training exercises for myself to stay mindful and one of the big ones, and when we are traveling to a direction, and we do this over and over and over, you might have noticed that if you are commuting to work in your car, you might not remember how you actually got to work.

Erika

Or like, if you locked the door of your house.

Emiel

Or if you locked the door of your house, like things that you do routinely and just start leaving your consciousness I guess. I guess we don't really know exactly how this process works super in depth, we have a general understanding, but basically, sometimes our brain kind of just takes over on autopilot, so we don't have to spend all too many cognitive resources on basic things like, well, I guess it's not basic. Driving a car is very complex.

Erika

Or locking your door.

Emiel

Yeah, or locking your door. It is kind of scary that we do these things on autopilot sometimes. But what I like to do is when I get to my destination and I have that feeling, I immediately try and retrace. And sometimes this is like a good training exercise. How did I get here just in physical space? And I tried to mentally reroute how I came there so I can visualize the route that I took and how I got there so kind of breaking through that and I think at its core that is kind of mindfulness. So it kind of allows you to realize how mindfulness can maybe help you. And I do the same thing in conversations, actually. Sometimes I think "How did we get to this part in the conversation?" And I try and retrace the steps back. And that actually helps in the podcast a lot, too, because I can pull up things that we talked about 50 minutes ago in the podcast and still talk about them because I'm retracing my steps backward. And I think tracing backwards is a pretty mindful thing to do because you have to kind of think and experience your life in the past through your own observations of what was going on inside of your brain and inside of your body. So I think that's potentially a really good training method to get more mindful whenever you get somewhere and you realize, hey, I don't really know how I got here, try and retrace those steps and try to maybe get more mindful. Maybe try and break out of that pattern and see if you can be more mindful and present in the moment.

Erika

Absolutely. And what Emiel is talking about, too, with retracing steps, this is also a similar kind of concept that you may be familiar with if you're an athlete or maybe you're a musician, or an artist, or a chef, when you are training and learning a new skill and you're trying to improve and you're really trying to develop a technique that's both mentally and physically demanding. Those initial early learning stages when you're moving really slow, can feel kind of frustrating and maybe can feel a little bit challenging, maybe more challenging than you'd like, but allowing yourself to stay in that moment where you are feeling challenged and you're really perceiving, "How is my body feeling? What am I intending to do where am I trying to go, what is this action? How do I feel about it emotionally? What's my intended goal for this action?" All of those questions, allowing them to be present, giving yourself time to ask them in your head and perhaps answer them, or maybe set them aside. These are also important skills that we develop at different points in our lives with different hobbies or interests we have, but we can apply the same concepts of learning and reflection to every aspect of our lives and specifically in this context, like we're talking about on the podcast, to the process that we have when we're taking supplements and we're trying to optimize our physical and our mental health.

Emiel

I actually think this is a perfect segue into another question from Reddit. There was a question from self justice.

Erika

u/SendJustice actually.

Emiel

u/SendJustice, sorry. So there's a question from that person and I will let Erika handle this one because it is more specific to her experience.

Erika

Yeah. So u/SendJustice asks "I have noticed hormones affect the efficiency of certain supplements. Also, considering that women have a monthly fluctuating hormonal profile, do you have any recommendations as how dosages should be adjusted and what is your opinion on the lack of taking women's cycles into account when testing drugs?" This is a great question, and this really ties into what I was speaking about before with mindfulness and having a mindful approach to every aspect of our lives. For those of you who menstruate, menstruation and the menstrual cycle is something that is a really great opportunity actually to practice mindfulness and to develop a sense of what's happening in my body and what's happening to my mood and my mental state throughout the month, throughout the day, specifically related to my menstrual cycle and my hormones. Over time, as I have become more practiced and more developed in my personal bioassaying and my mindfulness practices, I've found that there's about one day of questioning that I have in the month where I go, why am I feeling so hungry? Why am I feeling really argumentative and excitable? And I'm feeling kind of more social and I'm also just feeling a little more on edge but creative and excited and maybe a little bit more aggressive or a little bit more sarcastic than I normally am. And this can come in positive forms, for sure, but it can also have some more negative effects because I just feel a little bit more sensitive and there may be like one or two days where I'm wondering what's causing this. And then as soon as I start to feel these questions build and these sensations really like taking over my daily mental state or causing some issues and my ability to stay focused or maybe my ability to stay calm in a certain conversation or a moment, that's my cue of going, what day is it? What week is it? And where might I be in my menstrual cycle that is causing these really, really specific and noticeable effects to my mental and my physical health. While I don't have the exact ability to track my hormones or know exactly what's happening at each hour of the day when it comes to my menstrual cycle, because I don't personally do that, I do ask myself these questions.

Emiel

Can't really do that with current available technology, and maybe we can address that in the next question from Reddit?

Erika

Totally. Totally. But I do make it a point to ask myself these questions and check in with myself because the hormonal changes and the effects that these have on our mood and our physical state throughout our menstrual cycle are significant. And for some people, they can be really difficult to manage, and it can make physical and mental health more challenging. But it's also a good opportunity, like I said before. So I think Emiel probably has more insight when it comes to how supplements would be affected by hormonal changes. So, Emiel, what do you think in terms of dosages or just how to approach supplements when keeping in mind people who are menstruating?

Emiel

It's a really interesting topic, and there are some real neurological changes that happen during certain parts of the menstrual cycle. So right before menstruation, the period leading up to it, dopamine D2 receptor density goes up, which you mentioned, actually, that during that time, you feel a little bit more creative. And this actually seems to be related to dopamine D2 receptors. And it seems to be a pretty reliable thing that happens for a lot of people. They tend to get more creative right before menstruation happens, or, like, a week before menstruation happens. And there's some really interesting studies about that, too. One of these studies, it's a little controversial, maybe. But they did a study on exotic dancers, and they found that right before their menstruation, these exotic dancers were getting significantly more tips.

Erika

Earning way more money.

Emiel

Earning way more money because they were a little bit more aggressive. They were a little bit more creative. They were more motivated to show off their moves. And this seems to be related to Dopamine D2 receptor density going up.

Erika

And without getting too Freudian with it or going too far into the ideas of finding a partner or thinking about fertility or these things, the specific mechanisms that we're talking about are a lot simpler than that. So we don't have to go too far into, like, the nuance of the specific study. But this is really, really relevant.

Emiel

Yeah. So we'll stay away from the actual psychology of it. But if we look at the neuroscience of it, it makes a lot of sense, because compounds that actually act on dopamine D2 receptors quite strongly have a very similar effect both in men and women. So when women experience a rise in dopamine D2 receptor density, it's almost like they're taking a compound that is affecting dopamine D2 receptor activity. And as we mentioned earlier, dopamine D2 activation by itself can actually make you a little bit more creative. Another thing it can do is it can make you a little bit more likely to do risky things because a lot of pleasure is associated with dopamine D2 activity as well. So when that dopamine D two density goes up, there is actually more rewards to rewarding activities like eating food. So maybe that's another reason why you might become a little bit more hungry and maybe have a stronger emotional response to food. But more importantly, to get back on topic, it does mean that because of these hormones, your receptors function differently. So it does stand to reason that a supplement that works well most of the month might not work all too well during that period or right after that period of time, just because of different densities of receptors. So a very specific supplement I could think of that would be susceptible to these changes would be Sabroxy. Sabroxy, being a dopamine transporter inhibitor, enhances the level of dopamine present in the brain, and when this occurs potentially with enhanced dopamine D2 receptor density, then the effects of Sabroxy might be more pronounced actually during that period of time than after that period of time.

Erika

That's really fascinating. So when it comes to the last part of this question, "What's our opinion on the lack of taking the menstrual cycle into account when testing drugs?" My opinion is quite simple, and it's more of a call to action rather than an opinion. And that call to action is for people who are menstruating, take the tools that you have available to you, the mindfulness tools you have, the bioassaying and tools and the research that's available and learn. Learn about how the supplements that you're taking are affecting you and do your research and explore and really dive into the information that's available to you, because the more educated we are, the more educated menstruating people are about what's happening in our bodies and ways that we can be mindful and optimize our physical mental health during our menstrual cycles, the better equipped we are to face the world and some of the lack of research and the obvious lack of resources for menstruating people to understand what's happening in their bodies, and we can actually do something about it because we have the tools available to us and the information available to us that might motivate us to make a change in how we live our lives and also the things and the information that we demand from people such as scientists and doctors and researchers. Because this is a really important part of science is pushing forward these issues that are important to us and really digging in for ourselves and for the world at large into these issues that are really important and that affect our daily lives.

Emiel

Yeah, and I really think we don't pay enough attention to this, obviously because we probably live in a, well, we do live in a bit of a sexist world, of course. So the focus on healthcare is oftentimes more on men. Even I recently discovered that most crash dummies are actually modeled on an average male body, and airbags being developed are just being developed for an average male body, and they actually don't really work all too well sometimes for the average female body. So with supplements, it seems totally normal that you would have these variations between men and women, and women have variations throughout the month, so we should pay more attention to that because we can optimize, maybe supplementation and maybe to smooth out some of those curves, too. Maybe you want less peaks of certain hormones. Maybe we can actually focus on that, and we can focus on some of the more downstream pathways that happen, like some of the inflammatory compounds that get released due to these hormonal changes, which then causes cramps and pain. Maybe we can actually help attenuate that. So I do think it would be very interesting to dive into this topic in more depth and do more research about it, and maybe if all of you are interested in a podcast specifically about this, then we can do a podcast dedicated to this topic, because I do think that this factor is oftentimes left out of research, too, because I read a lot of research that's using both men and women, but I hardly ever see them controlling for menstrual cycles. So I think this is very important. On that same topic, time is also very important. And this just brings me quickly back to the bioassaying thing. A very interesting thing that I discovered recently is that CYP enzymes or the cytochrome P450 enzymes, which metabolize a lot of the compounds that we take are under circadian control, which means that they are expressed more or less at different points of the day based on our circadian rhythm. So in terms of bioassaying, this is also something to think about. Maybe a compound in the morning gets metabolized much quicker than it does at night or in the middle of the day. So that's another thing to keep in mind. Maybe with this duration of action or magnitude of effects, maybe it's changing with circadian control of certain things, or maybe it's changing with hormonal control of certain things. I think time is an interesting aspect to think about and how time changes things and how we ourselves are in different cycles. And of course, women have hormonal cycles. But men certainly have hormonal cycles, too. Maybe when our testosterone levels are a little bit lower, maybe certain supplements don't work as well. So this is another interesting thing to think about. But most of the time we are in the dark about this. We kind of have to guess and use our best judgment, which I think the next question will give us a bit of an interesting segue.

Erika

Absolutely. So u/BRM1851 asks "If you had $100 million dollars to spend on health tech and no red tape, how would you spend it?"

Emiel

So very easy for me. And $100 million is probably not anywhere near enough to develop this kind of technology, but, we have blood pressure cuffs that we can use at home. We have scales that we can use at home to weigh our body weight. Some scales, I don't think it's very accurate, but some scales can even measure your body fat percentage. So having these tools, we can kind of adjust how much we eat, adjust our caloric load to stay at a certain weight. And we can verify this with an analytical tool by just standing on a scale and going, okay, I weigh this much. Or if we want to ensure that our blood pressure is in a healthy range, we can just slap a blood pressure cuff on and we can measure our blood pressure, and it's easy to get some actual data to know okay, the diet that I'm doing works because I can visually see that it's working, and I can verify on a scale that it's working. But a lot of the stuff we do, we don't really have a good visual marker or a number that we can put on it. So I think my $100 million would go to developing some sort of technology where we could do rapid at home blood tests similar to taking a blood pressure measurement. So maybe if we have this tool, this magical tool that I don't know exactly how you would develop it, maybe some sort of compact FTIR type technology if we could analyze very small amounts of our blood, maybe on a daily basis, and then get a better idea of what are our hormone levels at? What are our vitamin levels at, our mineral levels at? Then we have a much more accurate way of supplementing. So, for example, year round, I take vitamin D3 at 5000 IU, and I think this is enough year round, but when the sunshine goes down in winter and I'm spending less time outside, is this 5000 IU still enough? All of the research I've read tells me yes, it's enough. But maybe I need a particularly large amount of vitamin D. Or maybe I'm very efficient with my vitamin D, and I actually don't need that much. And I have been chronically overdosing vitamin D, and maybe it's better if I take a slightly lower dose, like 4000 IU. I think having the tools available to put a number on it to have analytical results would allow us to develop even better supplements, even better stacks, even better regimens. And hopefully that's something we will have in the future.

Erika

I like that. And I think that would be really fascinating. And I certainly would enjoy having that technology available for myself as well. My approach for the $100 million, keeping in mind that these ideas would probably cost significantly more than that, is actually a little bit more of a general approach and kind of what we're hoping to do with this podcast. But the way that I would spend that money is literally to just provide and develop the best tools for educating people on how to determine what foods and supplements are doing to our bodies and just general education on healthy practices and how to really determine our state of physical and mental health, because a lot of what we're talking about is related to science education and information, research, and personal experience and access to supplements, so I think providing more general access to accurate and incredibly important information so that more people can have these skills to be mindful and to be able to bioassay would be the way that I would spend that money.

Emiel

I think both of these approaches are doing one specific thing, which is also kind of what we've been talking about in this podcast. It is allowing us to take ownership of our own health and how we can influence our own health with minor interventions such as supplements. So understanding this more, being able to do this more independently and successfully, I think, is a really interesting way forward.

Erika

Absolutely. And it also links into the second part of this question from u/BRM1851 which is "What is one thing that your company has done for your customers that you didn't expect in a surprisingly good way?" So I'll have Emiel take this one.

Emiel

Yeah. So I think from the very beginning, the main focus has always been helping all of you to reach your goals and enhance your overall health. And more specifically, at Nootropics Depot and the focus being on brain health supplements, it's enhancing our cognitive function. So that's always something we have hoped for. But we've gotten in a lot of reports of life changing effects of some of these supplements, and I think that's been surprising to hear that other people are having these effects. I've definitely had these effects myself.

Erika

I have, too.

Emiel

So I guess in a sense, it's not that surprising, but it is very nice hearing these reports and hearing that these effects are not just limited to us, and a lot of people are having life changing effects from these supplements.

Erika

It's motivating, and it really kind of gives us a reason and that kind of intrinsic sense of the value of what we're doing, beyond the business, in terms of actually helping people improve their lives and helping people have these benefits and really be able to live their lives fully and continue to push the boundaries of the things that they're passionate about, just like we are for supplements.

Emiel

Absolutely. If it wasn't for supplements, I don't think most of my hobbies would be viable because they are usually very complex and scientific still.

Erika

Cognitively demanding.

Emiel

Cognitively demanding. But they give me a lot of pleasure and relaxation. But honestly, without some of the supplements I've been taking, it would be really hard for me to learn about acoustics, for example, and design my own speakers and design listening rooms and run sound systems here and there. It's so complex that I really need the help of these supplements to help me understand it. All right, but enough about us. Let's get back to you guys. So there was actually a question that kind of ties into the 100 million dollar question as well.

Erika

Yeah. So the question from u/ Infinite-Emphasis560 is, "Hi, everyone, I have a question. I've done an amino acid blood test, and my tyrosine levels and phenylalanine levels are quite in the optimum range." We're going to leave out their personal levels, but just skip to the end of their question. "Is there a rationale behind supplementing L tyrosine or L phenylalanine or both together?"

Emiel

Yes. This ties into the 100 million dollar question in the sense that it would be really nice if we could do this consistently and test our tyrosine, phenylalanine levels and maybe some other amino acids. And see, do we actually need some of these amino acids? Are they going to have a benefit for us? Because L tyrosine and L phenylalanine works a little bit through a slightly different pathway, but L tyrosine turns into L-DOPA, and then from L-DOPA into dopamine. And what we're trying to get to is the dopamine portion, which is why we take L tyrosine. But the enzyme that transforms or turns L tyrosine into L-DOPA, tyrosine hydroxylase, it's what we call a rate limiting enzyme. So at a certain point, it just gets saturated and it's not going to turn any more L tyrosine into L-DOPA. So it's a bit of a protection mechanism as well. But that does mean if your L tyrosine levels are particularly high, that means that the enzyme tyrosine hydroxylase, may already be saturated and may not actually turn any of that L tyrosine into L-DOPA. L tyrosine can do some other things like it is a precursor to melanin, which is a great oxidation regulating compound as well. So there are some benefits actually to taking L tyrosine rather than just dopamine production. However, if we are going for that main effect, then yeah, if our L tyrosine levels are high, then there really is no reason to take L tyrosine. So this oftentimes is not the case. I don't think we are often at a level of L tyrosine where the tyrosine hydroxylase enzyme is fully saturated. So usually there is a benefit to it. But if we had somewhere insight and we could actually test our blood levels of L tyrosine, then we could make better decisions about it. To answer the question of taking L tyrosine and L phenylalanine together, that could actually be an interesting stack. And there might be some synergism there because they produce Dopamine through slightly different pathways.

Erika

So maybe some of you are curious, and I'll just ask the question for all of us. How does this tie into mindfulness and bioassaying?

Emiel

So it's a bit of a stretch to make it fit, of course. But I think if you're taking L tyrosine and you're not really noticing a big change, then maybe that enzyme is saturated and you're not actually getting the intended effect. So bioassaying and mindfulness might help you identify that. But to a certain degree, maybe this being able to test your own blood levels is like the next level of mindfulness and bioassaying, because rather than relying on our own subjective analysis tools, we actually can put a number on it. We can have a bit of a reference, and that might also actually circumvent some of the issues with placebo, nocebo, expensive placebo and confirmation bias.

Erika

I see. So this would be like an additional tool to add to your bioassaying and mindfulness kind of toolbelt.

Emiel

Absolutely.

Erika

Okay. So moving on to another question, we combined two questions because they were quite similar. So one came from u/SolotheASensei and the other came from u/Future_Ad7642, so we just kind of paraphrased this question. "On dopamine specifically, since we're all looking for extra focus and motivation, I've heard that dopamine breaks down into neurotoxic metabolites. So should most supplement users even be trying to increase dopamine levels in the first place? Or is this not such a huge concern if we take specific measures?"

Emiel

That's a tough one, that definitely does happen. So dopamine breaks down into a compound which produces large amounts of oxidative stress, especially if it finds its way back into neurons from which it was released. So that's something we need to keep in mind. Usually this is more something that we find with very large increases in dopamine levels and not something likely that we are to find in some of our own supplements. It's a little bit more of a subtle effect. However, the likelihood of some more oxidative stress, because there is more dopamine floating around and being metabolized, could be an issue. And I think we are in a little bit of luck, because a lot of the compounds that we have that promote dopamine levels actually act as oxidation regulating compounds themselves. So, for example, Oroxylin A, while inhibiting the dopamine transporter and promoting overall dopamine levels, also acts as an oxidation regulating compound. So in that sense, they probably balance each other out a little bit. But it's hard to say with precision. However, I would say at the levels that we are promoting dopamine, more optimizing dopamine rather than dumping a bunch of dopamine into the synaptic cleft like some other things can do, I think this doesn't apply a whole lot to us. However, what I will say is that it applies to all of us always. Because Dopamine is always being overturned and being turned into these metabolites that can have oxidative stress. And this is just something that happens all the time, and our neurons and brains are pretty well equipped with handling this oxidative stress. This is just the way the brain works, and it has worked for thousands of years. So we are equipped to handle it. But it's something to think about just in general, to keep our dopaminergic system optimized, we might actually want to look at compounds that help regulate neuro-oxidation. So not only just for individuals who are taking supplements that promote dopamine levels, just for everyone in general, it's good to be aware of this aspect of dopamine, and good to be aware that there's a somewhat easy way to go around this.

Erika

Now moving on to our next question from u/Hormesis, "In your experience, which compounds most frequently seem to improve short and long term memory? Have you tried any that surprised you? I.E., rarely reported as having a beneficial effect on memory, but seems to improve it."

Emiel

Yeah. So I'll start with the one if we've ever tried something that was surprising. And for me, one of the ones that was surprising was actually alcohol defense. So for a while I wanted to try out just some ginger, but we didn't have any ginger extracts. So I just tried out a single capsule of our alcohol defense formulation once a day, just a single one. The normal dose is two capsules, but I just took a single one, and the effects of the ginger were really pleasant. But surprisingly, what I noticed after a week is my memory started to get a whole lot better and looking into it a little bit more dihydromyricetin, which is one of the main ingredients in it, it blocks GABA receptors, and this is a good thing in the context of alcohol defense, and was always something I thought about without the context of alcohol, what would it do? And there's a lot of recent interesting research that has been starting to look at GABA antagonists for the purposes of promoting memory. So GABA, as we probably all know, maybe after a heavy night of drinking has a pretty significant effect on our memory function, and this is being done through activation of certain GABA subunits. So the GABA receptor, it's not just a single thing. The GABA receptor is made up of certain subunits to which different compounds can bind specifically to those different subunits and produce different overall effects in the whole GABA neuron, which is a pretty complex process, so we won't get into it all too much here. But the interesting thing is, if you activate certain subunits, you get relaxing and calming effects without any effects on memory. If you activate other ones, other GABA subunits, then you also get those relaxing effects. But you get those effects combined with memory issues. So they found that if you block some of these specific sub units, then you can actually promote memory without having any of the undesirable effects of blocking GABA. And dihydromyricetin doesn't seem to cause any edginess or uncomfortableness for me. So I think dihydromyricetin probably acts on some of these specific GABA subunits that helps promote memory without inducing some of the undesirable effects of GABA antagonism. So this one was really surprising to me and actually led me down a research path of looking at different compounds that could work as GABA antagonists while not producing undesirable GABA antagonist effects while also promoting memory. So alcohol defense was one of the first ones, and actually alcohol defense also contains pyroglutamic acid, which has been found to have quite pronounced nootropic actions. So an interesting one, maybe to take for a little while just daily is actually our alcohol defense. There's some really interesting things in there which might help promote memory, and I think I might use this as a step-off point for maybe some other things that we can look into for promoting memory. And actually one of those things is Ginkgo biloba. So one of the ways by which Ginkgo biloba helps promote memory is through its bilobalide content. And bilobalide actually is a GABA antagonist too. And it seems at these specific subunits, Oroxylin A is also a GABA antagonist at some of these specific GABA subunits, it seems, and that also appears to really promote memory in addition to some of its neuroplasticity effects. So I think for me, the supplements that seem to work the best for long term memory enhancements are things that selectively block certain subunits of GABA . And in our current catalog, I would say alcohol defense is one of the top ones, and then Ginkgo is one as well and Sabroxy. And I actually take Ginkgo and Sabroxy every day together, and I find that my memory has been really good recently.

Erika

That is a great amount of specific information for the combined question. Thanks to all of your questions, we've had a very long and luxurious conversation, but we are running out of time, so we're going to ask one more question for this podcast, and this one comes from u/mmmilner, "I would love to see water/fat soluble on your labels. I often can't remember and go into the website looking. I would also love to see you give stacking advice."

Emiel

So for that first question, the water/fat soluble. It really doesn't matter mostly for supplement absorption. This is one of the reasons why we don't have it on our labels. It would be a lot of work for us to determine whether something is water or fat soluble, because oftentimes compounds are both water and fat soluble. So this is what we refer to as the log P of a compound. So basically how efficiently it can transition from aqueous to lipid phases, which plays a big role in bioavailability. And that's another topic, but basically determining whether something is purely fat soluble, purely water soluble is pretty much impossible, and it doesn't really matter all too much anyways, because a fat soluble compound doesn't need to be taken with fat. So that's totally fine. That's one of the reasons that's not on our labels, and you'll probably never see that on our labels because it wouldn't make a whole lot of sense. So then in terms of the second part of the question, the stacking advice, we actually have a few resources already for this. We have some stack guides, so we have a few different ones. We have one for fitness, we have one for focus, mental energy and motivation. We have one for just general supplement combinations with different intended goals, so we can link in the description of this podcast, we will link to some of these buying guides.

Erika

That are on our website, and the stack advice.

Emiel

Yeah. So those, I think really help and help get a good initial idea of how to stack different compounds. On a lot of our newer product descriptions, at the bottom of the product description, we also actually tell you some basic stack ideas of what to combine with the product on the product page and how you can enhance the effects with some other supplements for specific goals. So that's the way to do it. And sometimes in our blogs we will also touch on stacking. We can do a whole podcast probably on stacking, that could maybe be interesting. But another thing to remember is if you need stacking help, this might be a good topic to post on Reddit. We can help you, but other Redditors are also very knowledgeable and tend to jump in and help out whenever necessary to help build stacks because we have a lot of combined experience on our subreddit for stacking.

Erika

Absolutely. And that is the perfect segue into wrapping up this really awesome and fascinating conversation between Emiel and I. So if you're interested in a podcast about stacking, let us know on Reddit and tell us what you would like to hear or if there's another question that you have another topic, a specific botanical, make a post on our subreddit, that's r/NootropicsDepot and we would love to interact with you. You can tag me, Erika, I am u/NootropicsDepotGuru on Reddit, and Emiel is u/Pretty-Chill. So you can tag either of us. You can also tag u/MisterYouAreSoDumb if you feel so inclined, and we would love to read and answer your questions. We want to say thanks again for listening, for your positive feedback, for your critique and for your participation in In Search of Insight. This podcast is such a great opportunity for us to dive into so many different research directions and questions and really get a sense for what you, our listeners are interested in, and how we can better equip you with information and questions for you to ask yourselves to go out into the world and to find ways to optimize your physical and mental health. Mindfulness and bioassaying are just two of the many tools we have available to us to help optimize our health, and we hope that you have a very fruitful and smooth and exciting entrance into the New Year.

Emiel

Yeah, well, said Erika. Thanks for tuning in and see you next year!

Erika

Thanks so much for listening and bye bye for now.

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#002 | Andrographis Paniculata: The King of Bitters and Tackling Inflammation

Podcast Transcript

Erika

Hello and welcome back to In Search of Insight with Nootropics Depot. I'm your host, Erika or u/NootropicsDepotGuru on Reddit, and sitting next to me is our Product Specialist, Emiel.

Emiel

Hey, everyone. And you might also know me as u/Pretty-Chill on Reddit.

Erika

We were so pleased at your warm reception of last month's podcast episode on Tart Cherry, our very first episode of In Search of Insight. And we were so excited to see that you were enjoying it, getting a lot out of the information we were able to share with you, and we wanted to give you an opportunity to ask questions to help shape this month's episode of In Search of Insight. So the thread that we started where you're asking us questions really helped us to form kind of the overall arc of this month's podcast. We're talking about Andrographis paniculata.

 

Emiel

Yeah. And those questions were really good because it helped give me some further research directions to look into, and I think because of some of these questions, I went down a rabbit hole that delivered some pretty groundbreaking results, which we will discuss later in the podcast.

 

Erika

Thanks for participating, and thank you again for listening and coming back to this second episode of In Search of Insight. Before we dig into all of the details and the exciting research that Emiel has uncovered about andrographis, we just wanted to remind you that if you ever have questions or you want to start a discussion, you're curious about the development or the research that we do behind the scenes for the podcast or for other aspects of Nootropics Depot, you can always start a post thread on Reddit and tag us - tag u/Pretty-Chill or me, u/NootropicsDepotGuru, and we'd be happy to chat with you. So I think it's about time to get into it. We're talking about andrographis paniculata today: the king of bitters and tackling inflammation.

 

Emiel

Yeah. So andrographis paniculata is a fascinating plant, and the "King of Bitters" name is really true to how it tastes. It's incredibly bitter. It's disgusting. I opt out of the powder for that reason and just take the capsules. But if you're really into super bitter things, maybe you are an amaro or Fernet enthusiast, then this one might be for you in the powder form, but the bitterness, obviously, is not the most important thing here. The thing here is that andrographis has some fascinating effects. But before we get into that, let's just kind of discuss what andrographis is and where it's from. So, andrographis is native to Southeast Asia, specifically, it seems to come from India, Sri Lanka, Malaysia and Thailand. And that's where its use is quite high, especially in Malaysia and Thailand.

 

Erika

And in my research, andrographis has been used for thousands of years in traditional Ayurvedic practices and traditional Chinese practices.

 

Emiel

Yes, that's correct.

 

Erika

Another thing about andrographis is that it's a very dark, leafy green. And while the roots and different parts of the plant do have benefits, the leaf is really what we're focusing on, and typically what we're looking at when we're thinking about the active compounds in andrographis.

 

Emiel

Perfect, this actually answers one of our first questions that we got on Reddit. So I'll try to pronounce this Reddit name, it's a little tough for me. Let's see. So u/2020crsyngatheart, hope that's correct, asks "Does ND use stem, leaf, or both in its andrographis extract?" So, as Erika put really well, most of the bioactives are in the leaves, so we're using just the leaves.

 

Erika

So now we're getting into the fun part of the podcast, which is talking about the specific bioactives in andrographis. So Emiel, give us a breakdown: what are we looking for in these dark leafy parts of the andrographis paniculata?

 

Emiel

It's a bit of a tough question because there's a lot of bioactives in andrographis, but there is a class of compounds called andrographolides and that's what we're standardizing our extract for. So our extract contains a really large percentage too of these compounds, 50%. So within the class of andrographolides there's a few different ones, one of them is actually just andrographolide, then you have neoandropholide, 14-Deoxyandropholide, 14-Deoxyneoandrographolide, and a really interesting compound, which we will be spending quite a bit of time on today is bisandrographolide.

 

Erika

Okay, so now that we know a little bit more about what active compounds are in andrographis, you gave us a nice little segue; bisandrographolide. What's going on with that compound? What is it and why is it so special? And why are you getting so excited about it?

 

Emiel

I'm getting excited about it because I'm a nerd.

 

Erika

Truth!

 

Emiel

I get really excited about these compounds. So the main reason I'm excited about this is because it helped me answer a Reddit question that was actually a really tough one to answer. And it took me a long time to really put all the pieces together to get to a working theory as to why andrographis promotes sleep. So this was a question by u/SavageDetective, and the question was "Anecdotally and with some confirmation from my Oura ring, andrographis paniculata seems to greatly improve my sleep quality when taken before bed. What mechanism might be responsible for this?" This really sent me down quite a few rabbit holes because I thought, perhaps it could be inflammation related, but there's a lot of different plant extracts that interact with inflammation, and I don't really see those plant extracts, for example, curcumin necessarily promoting sleep quality in the way andrographis does, because I hear it in this question. But when we talked about it around the office, a lot of people are reporting this effect, so I decided to dig a little bit deeper. One of the things that I found was that bisandrographolide is a TRPV4 agonist. So this is a pretty special receptor. It's in the class of vanilloid receptors, and you're probably already intimately familiar with one of these receptors, the TRPV1 receptor. If you've ever eaten a chili pepper, and Erika, have you ever eaten a chili pepper?

 

Erika

I have eaten quite a few chili peppers, primarily from being convinced to do it by u/Pretty-Chill, because apparently, and I can also confirm from my own experience, they do have some pretty cool effects, not only for your taste buds, but also on mood as well.

 

Emiel

Yeah. So over the years, we've become chili pepper enthusiasts. And one of the reasons why I'm a chili pepper enthusiast is because of its effects on the TRPV1 channel, and this is basically the heat receptor. So when we consume chili peppers, there's a compound in it called capsaicin. Capsaicin binds to the TRPV1 receptor and actually produces a pain response. That's what we perceive as spiciness. But there is a few different ones. And specifically, the TRPV4 receptor seems to not necessarily respond to heat like the TRPV1 receptor does, but it responds to stress, mechanical stress. So, for example, when our cells swell a little bit, TRPV4 receptors become activated. So they are mechano-receptors, basically.

 

Erika

Can you give another example of mechanical receptors or something mechanical that's changing in the body that would activate that particular pathway?

 

Emiel

Yeah. So, for example, intraocular pressure. So pressure in your eye, that seems to activate TRPV4 receptors. And this is actually where I got one of the most important pieces of information. So in the eye, when eye pressure goes up, they see in individuals with high eye pressure that they also have high levels of melatonin in their eye.

 

Erika

So does this have any relationship to TRPV4?

 

Emiel

Yeah. So when eye pressure goes up, the TRPV4 receptors get activated. And when this activation happens, it seems like the activity of an enzyme called AANAT, A-A-N-A-T, becomes upregulated. And for anyone who's dug into melatonin and melatonin biosynthesis pathways, this probably rings a bell. So the AANAT enzyme converts serotonin into N-Acetylserotonin, and then N-Acetylserotonin can be converted into melatonin. However, this is the rate limiting step in melatonin production. So the higher AANAT activity is, the more melatonin gets produced. So it's very fascinating that TRPV4 receptor activation can actually enhance melatonin production. And I think this is where the sleep effects of andrographis are coming from, because one of the compounds in andographis, bisandrographolide is a selective and potent TRPV4 receptor agonist. And to be honest, this is maybe one of the first botanicals that I've come across that contains a selective and potent TRPV4 agonist. So I think this kind of illustrated to me why andrographis is potentially so special, and not just because of sleep. So we'll get into it a little bit deeper. But as you may know, melatonin itself actually does a pretty good job of controlling inflammation and oxidation levels.

 

Erika

This is really interesting, because I already knew that melatonin had benefits when it comes to regulating oxidation, but I wasn't aware of its benefits when it comes to regulating inflammation.

 

Emiel

Yeah. And to be honest, this is kind of a new concept for me, too. And we have to look a little bit in the opposite direction first before we can answer this question about melatonin. So, let's actually talk a little bit about how inflammation comes about and how it gets ramped up in cells. So under normal conditions, inflammation mostly is coming from immune cells. So actually, the immune system uses inflammation as a tool, and sometimes that gets taken out of context. And then we have inflammation that is not desirable. So if we look at these immune cells, normally, these immune cells need a source of energy, and that source of energy is derived through oxidative phosphorylation, which is abbreviated to OXPHOS. So under normal conditions, these cells are at a pretty low energy state, OXPHOS. But then, as inflammation ramps up, they do something weird. And this is loosely referred to as a glycolytic switch. So basically, cells can reprogram themselves, rather than depending on OXPHOS for energy, they can actually switch to aerobic glycolysis using glucose as an energy source. This means that these cells become much more energetic because using this glycolytic pathway, it's easier to generate ATP.

 

Erika

And we talked about ATP a lot in our last podcast, tart cherry. So I'm starting to see how the threads are coming together.

 

Emiel

Yeah. In biology, and in the way the body works, ATP will keep coming up and up and up because it's the main driver of cellular function. But in this case, it's... Something weird is going on. So as we switch to this high energy state, these immune cells also produce more inflammation. And it seems that both andrographis and melatonin can prevent this glycolytic switch. So this brings up a really interesting concept, because we always thought for inflammation regulating effects, we would have to act directly on enzymes related to inflammation. For example, cyclooxygenase 2, COX-2 and andrographis certainly blocks COX-2. And this is where some of the inflammation regulating effects come from. But I was reading a really interesting research paper that was reframing inflammation as potentially a metabolic disorder. So potentially how glucose is metabolized could influence inflammation and andrographis hits on a lot of different metabolic pathways related to glucose. And apparently, so does melatonin. One of the biggest factors that they both work on is hypoxia-inducible factor Alpha.

 

Erika

You're going to have to clarify what that means and what it's doing in the body, because this is very new to me.

 

Emiel

Yeah. And actually, it's a little bit new to me, too. So let me say that again, it's actually hypoxia-inducible factor 1-alpha, not Alpha, 1-alpha. So this is abbreviated to HIF-1. And HIF-1 mediates some of this glycolytic switch, and both andrographolide and melatonin appear to act on this mediator of the glycolytic switch, and this means that both andrographolide and melatonin can prevent this glycolytic switch.

 

Erika

Okay, so real quick, before we continue in this really amazing technical conversation, I'm sure you're all wondering, does that mean that taking melatonin alongside andrographis is going to have more benefits than just andrographis by itself?

 

Emiel

Yes. Very good insight there. I was hoping to get to that a little bit later, but let's just talk about it now. They both affect similar pathways. So there's certainly going to be a synergistic effect. However, remember what we were just talking about through the TRPV 4 channel bisandrographalide from andrographis can actually speed up melatonin synthesis. So yes, taking andrographis and melatonin together would be synergistic. But what we can get at a little bit more here is that the inflammation regulating effect of andrographis might actually be mediated partially through melatonin. So this is where we are getting sleep promoting effects from andrographis, which was a big surprise for me, as was finding this mechanism, but going further than just the sleep promoting effect, it seems that by enhancing melatonin production, andrographis can prevent this glycolytic switch. Which gets further amplified by the fact that andrographolide from andrographis itself can already prevent this glycolytic switch. So the two together, and they are always kind of together in the context of andrographis, both work to tackle inflammation. And when we reframe it in this context, it makes a lot of sense that out of the probably 20 or 30 inflammation regulating compounds that I have tried for prolonged periods of time at this point in time, andrographis really comes out on top. That's why we had a little bit of fun with our title, "The King of Bitters and the King of Tackling inflammation," because it really seems it's taking such a multifaceted approach to inflammation. There's very little things that seem to be able to compete with it.

 

Erika

And it's pretty fascinating that it also seems to be very synergistic with a lot of other familiar botanicals and things that people are used to taking to benefit sleep and kind of their daily life and habits and things that are important just for overall health, but maybe not so specific to oxidation or inflammation.

 

Emiel

Yeah. And whenever we find a compound that acts through novel pathways that aren't really being done by other plants or extracts or compounds, the potential for synergy starts going up and up and up. And actually, this is a great point to answer another question from Reddit, we got some really good ones this time! So this question comes from u/Reasonable_ Ad507, and their question is "It looks like most research pairs this with Eleutherococcus senticosus, otherwise known as Siberian ginseng. Is that on the roadmap at all, perhaps as a combination?" So right off the bat, we have actually looked at eleuthero. It's a very interesting one, perhaps in the future we will carry an extract. But more importantly, let's look at the combination. So this combination was actually developed by the Swedish Herbal Institute, and they call it I believe it's Kan Jang, and it's actually been used in Sweden for the last 30 years and appears to be really popular as a combination for immune function. And they did a really good amount of research on it, and likely because of the really novel effects of andrographis, it is very synergistic with a lot of different things and one of those is eleuthero. And in some research studies that I was looking at, it seemed like as mono plants, they both had effects that completely changed when the two were together, and actually some of the effects were being filtered out and some of the effects, there were new effects popping up. So this doesn't necessarily mean that andrographis needs to be combined with eleuthero, but there is some indication that there is good potential for synergy, but I believe because of the novel effects of andrographis, the potential for synergy exists with a lot more compounds than just eleuthero. So this will be in a very interesting next research project to look into: what kind of stacks can we develop with andrographis that really help tease out some more interesting effects that already exist in andrographis, but perhaps we can exploit them a little bit more, make them a little bit more pronounced.

 

Erika

So speaking of ways to exploit or, make the beneficial effects of andrographis more pronounced, I'm curious to go back to our conversation about melatonin because knowing that melatonin and andrographolides are working together to tackle inflammation, I'm also curious about their effects on the respiratory system, because this is another really popular and common aspect of andrographis paniculata that was coming up in my research. So is melatonin having an effect on respiratory systems as well in its relationship to andrographis?

 

Emiel

Yeah. And earlier I said I found some groundbreaking things and I think this is it. So those TRPV4 receptors that we've been talking about are very widely expressed throughout our lungs, and that means that theoretically, if there's also some serotonin in our lungs, which there is, then this enhanced TRPV4 activity could actually enhance melatonin synthesis in the lungs. And because the lungs are a site where inflammation can be very damaging, it makes sense that melatonin plays a role here, too.

 

Erika

Obviously, respiratory health is important all the time, but I think everyone can probably think of some really specific examples and recent examples in the last couple of years in which we're all a lot more concerned and aware of our respiratory systems and perhaps looking for ways to address inflammation and oxidation when it comes to respiratory systems. So how does andrographis act in these pathways?

 

Emiel

Yeah. So because of these events that have transpired, there's been a lot of very recent research, and one of these research studies was actually focusing on melatonin, showing that low melatonin levels in the lungs would be a risk factor for inflammation. So looking at this, and then looking at the connection between andrographis and melatonin and the TRPV four receptors, and the fact that TRPV four receptors are very highly expressed in the lungs, it stands to reason that some of these respiratory health effects that we see with andrographis and why andrographis is so popular, might have a relationship with melatonin. So basically, using andrographis and relying on this bisandrographolide content in activating TRPV4 receptors, we might have a selective and targeted way of elevating melatonin levels in the lungs as a protective mechanism. And I think that this is where a lot of the respiratory health benefits are coming from. So if we go back to this glycolytic switch, and I actually forgot to mention this earlier, but this glycolytic switch is also called the Warburg effect, and this is an effect that's not often talked about. And actually the Warburg effect is named after a researcher whose last name was Warburg, I forget his first name at this point, but this research he was doing in 1921 about the glycolytic switch and inflammation being related to this glycolytic switch. And this is actually the 100th anniversary of the Warburg effect. So I think it, not today, of course, but this year, it's 100 years ago when this effect was discovered. And I think the Warburg effect is actually very relevant again. It's interesting to talk about, and it's interesting to discover that there are two easily accessible botanicals and natural compounds that seem to have positive effects on the Warburg effect. So the Warburg effect, of course, is this glycolytic switch, and when that is happening in the lungs, we can get a very rapid rise in inflammation and expression of cytokines. This is not good.

 

Erika

What's a cytokine?

 

Emiel

A cytokine is a compound, actually, that produces inflammation. We can get into it quite deeply. But I think for the context of this podcast, let's just say cytokines are compounds that are released by immune cells that promote inflammatory responses.

 

Erika

Ok, that makes sense.

 

Emiel

Not good. And it seems like andrographis potentially through its effects on melatonin, but also the fact that andropholide itself acts via HIF-1 Alpha, which we talked about earlier to halt this glycolytic switch effect, it seems like these two effects together are really what are enhancing respiratory function. And to get back into maybe a little bit of a different effect, it also seems that TRPV4 receptor activation does a really cool thing called or, it enhances something that is quite a new concept for me, so ciliary beat. So basically, the ciliary cells in your lungs act kind of as machinery to expel mucus.

 

Erika

I'm very curious about this, particularly because of the time of year and also because of, you know, recent world events that are going on.

 

Emiel

Yeah. So actually, in one of the studies I was reading, they made a really good comparison, and they were saying that the ciliary cells are kind of like a machine. And then mucus is like the transport belt. So particulate matter gets stuck in this mucus transport belt, and then the ciliary cells, they move it around and they expel it. And this is a concept, like I said earlier, it's still a little bit new to me. But ciliary beat basically is describing how this process works and how the mucus can be expelled over and over to kind of keep the lungs clean. It seems like TRPV4 receptor activation actually speeds up the frequency of the ciliary beat. And in addition to that, the TRPV4 activation actually seems to enhance the cellular barrier within the lungs. So actually being able to keep undesirable stuff out of the lungs, TRPV4 activation seems to help with that. Another thing that TRPV4 activation seems to help with, and this is not just in the lungs, but because there is such a high expression of TRPV4 receptors in the lungs, it's an interesting thing to touch on at this point in the podcast. And that's that TRPV4 receptor activation appears to cause pretty significant vasodilation and within the lungs that actually helps decrease pressure in the lungs, and that's also a good thing.

 

Erika

Ooh! I'm starting to think about what you were talking about earlier, which is related to andrographis and how it responds to mechanical things that are happening in cells. So when you're talking about pressure within the lungs, is this a similar pathway, are these related?

 

Emiel

Yeah. Actually, we weren't necessarily talking about andrographis responding to pressure, but we were talking about what the actual function of the TRPV4 receptor is. So the actual thing that the TRPV4 receptor responds to is indeed pressure. So you're probably remembering the interocular pressure thing we were talking about. So within this context, we can also think that maybe these positive effects of TRPV4 receptor activation are actually a protective mechanism. So if we see pressure rise in the lungs, which is not really a great thing, or pressure rising in the eyes, which is also not a very desirable thing, then TRPV4 channels get activated and protection mechanisms start kicking in. But with andrographis and bisandrographolide, we don't ever have to get to this state of pressure, interocular pressure or lung pressure, or any of these undesirable mechano-pressures in the body. But we can still achieve a similar protective effect. So basically, by activating the TRPV4 receptors, we can trick our body into thinking there is pressure, even though there isn't.

 

Erika

So you're kind of circumventing that natural response from those immune cells because andrographis is doing something similar.

 

Emiel

Yes. So basically just kind of mimicking the pressure without there being pressure. So we still get those protective effects, even though we don't first have to get into a state where potentially there's damage. So kind of an interesting and quite a smart way, perhaps to promote lung function and also even just blood flow and things like that, because like I was saying, the TRPV four receptors are not only expressed in the lungs, they're also expressed in the brain. So this could potentially cause some vasodilation in the brain, more blood flow in the brain that could enhance cognitive function. And actually, I won't go into it all too much in this podcast. But certainly TRPV4 activation probably has some interesting cognitive effects. So if we're talking about the AANAT enzyme, we're getting production of N-Acetylserotonin, which is being elevated because that's the thing that the AANAT enzyme does, it turns serotonin into N-Acetylserotonin. And if you're interested in N-Acetylserotonin, definitely look into this compound because it has some really interesting effects on BDNF and neuroplasticity, and I feel like it's maybe a bit of a stretch at this point to really get into that too much, I haven't done enough research there, but I think there might be some interesting mood effects that are related to this anode enzyme and TRPV4 activity. And actually, it has been shown that andrographis has mood elevating effects, so it could be because of this pathway.

 

Erika

And now I'm starting to think about what kinds of effect inflammation and oxidation have on mood. So this is something that we can kind of have a follow up discussion with, too, perhaps in a Reddit thread. If any of you are curious about these specific pathways and mechanisms that we're talking about, and you want to get a little deeper and get into some more research, just a friendly reminder you can always post on our subreddit. That's the Nootropics Depot subreddit, and we'd love to discuss these more with you, and it will help shape future episodes of In Search of Insight. But let's not get too sidetracked. Let's head back to andrographis and talk about what's next. I think now is a great time to read a couple more questions that will lead us into some different material that we have to discover with andrographis.

 

Emiel

Yeah, and actually, maybe right before we jump into those questions because there are some really good remaining questions, I think now that we're on the topic of lungs and respiratory function, and we've kind of discussed inflammation already, one of the other big things of andrographis is that it obviously has very pronounced immune promoting effects, and this is what it is traditionally used for a lot, too. Unfortunately, due to some of the mechanisms by which andrographis works to promote immune function, we can't really discuss the specifics here because this will include some language that is not FDA compliant, so I won't get into it too much. But one thing I will mention is that andrographis works on replication mechanisms on things that we don't want in our body. So it helps kind of slow down these replication mechanisms, and that should help enhance overall immune function and our resistance to potential stressors in the environment. But to be honest, that's really all we can say about it. Otherwise, we're going to veer into territory that is not appropriate to discuss on this podcast. All right, so now let's jump into some more Reddit questions.

 

Erika

Cool. Okay, so u/Hormesis asks "What surprised you most about andrographis? To put it in another way, what qualities does it possess that not many people seem to know about? I'm trying to wrap my head around its main use, whether it's for immune boosting, longevity, performance, et cetera." Emiel, what do you think?

 

Emiel

Yeah. So everything about andrographis surprises me. It's a fascinating plant, and I think the TRPV4 effects are very interesting, and I haven't really seen that in any other botanical. So that's one of the main surprising factors for me. But there are also a whole lot of other surprising effects behind andrographis, for example, andrographis seems to have an effect on hair growth. It seems to have an effect on skin function through TRPV4 receptors, and it appears to even have some effects on sexual function. And I believe this was another Reddit question, right Erika?

 

Erika

Yeah, exactly! So u/SolotheSensei asked, "Are there any interesting studies on andrographis besides the general use case for immunity and inflammation? I remember seeing a study on sexual function and was wondering if there have been any reports of benefits in that regard." So Emiel, what say ye?

 

Emiel

Yeah. This was one of those things that was surprising to me as well. When I read the question, I thought that's really not one I have seen yet. And indeed, there is a study that is looking at this effect. And in that study, I found something interesting that I didn't really know about andrographis yet. Andrographis seems to significantly promote testosterone levels. And recently, when we released Tongkat Ali and Cistanche, it's been a very popular product for this exact reason. And I've been taking both of these myself, and I've been taking andrographis, so it's interesting to me that all of these different ones can help enhance testosterone production. But it was surprising to me that andrographis was doing this too. It doesn't really seem like a classical supplement that people have talked about for testosterone production, even though it has been around for such a long time, and it is so widely used. In addition to the testosterone promoting effects, which seem to be enhancing sexual function, the same research study was looking at adrenergic functioning and how this might affect blood flow to penile tissue, so this is where the potential erectile enhancement, I guess, boner pills.

 

Erika

Oh, yeah.

 

Emiel

So if anyone is a longtime reader of Examine.com, maybe you'll get this joke. They would send emails of their "boner pill" updates. So basically, supplements that pretty much did nothing except give you a boner. Andrographis, luckily, is not one of those supplements, but it's kind of an added bonus. You get all of these cool effects, and it's potentially a good erectile function improver. So in the same study, they were saying that in a research study they did looking specifically at Alpha-1 adrenergic receptor antagonism in participants that received these Alpha-1 adrenergic antagonists, they reported self-perceived sense of sexual satisfaction was significantly improved from baseline. So if andrographis is working through the same mechanism, and there seems to be some indication that there is, this could be underlying the sexual function benefits of andrographis which is really cool.

 

Erika

Absolutely. Immune function, inflammation, oxidation, sexual function, sleep benefits, sounds like a good realm to be in, especially during this time of year stress of the holidays, current world events, I think andrographis is definitely one of the more exciting botanicals that I've done research on as well.

 

Emiel

Yeah. And I think we have actually one more question from Reddit, which is to me also actually a very interesting effect. Erika, you want to read this question?

 

Erika

Let's do it. So u/Zidatris asks "How exactly is andrographis paniculata stimulating? How does that compare to other stimulants such as caffeine, for example, and could andrographis paniculata potentially be used as a focus aid when off caffeine?"

 

Emiel

Yeah. So this is a really interesting question, and I don't actually think andrographis itself is stimulating, yet, I do understand where this question comes from. So actually one of the first times I tried andrographis and a few people around the office, we also noticed a slightly wakefulness promoting effect, which is really interesting, but it doesn't really seem to be classically stimulating. And I tried looking for pathways in which potentially it might be increasing locomotion or something like that in research animals. And I was coming up kind of dry. But in my research for the question about sleep, I came across an interesting aspect of andrographis. It blocks the activity of the NLP3 or NLPR3 inflammasome. And this seems to be really involved in sleep deprivation. So during sleep deprivation, the activity of the NLPR3 inflammasome goes way up, and this seems to maybe underlie some of the cognitive deficits due to sleep deprivation, some of the tiredness throughout the day, potentially some inflammation in the joints potentially some difficulty getting to bed. So andrographis affects this positively by blocking NLPR3 inflammasome activity. So potentially through this activity, andrographis is potentially not stimulating, but it might be offsetting the effects of sleep deprivation. So that is something to keep in mind with many different supplements. Sometimes potentially it feels like it has a stimulating effect. But all it is really doing is offsetting the negative effects of sleep deprivation, allowing you to kind of get back to a normal baseline, which in a very tired state, might actually feel a little bit stimulating.

 

Erika

And that makes sense because when it comes to focus, sleep deprivation is something that can really get in the way of your ability to focus hard on a task. So even though andrographis might not be specifically stimulating, if you are a bit sleep deprived, a lot of us are, you might notice that this benefit that you're experiencing does help you focus, even though it's not happening in the same route that you experience through the stimulation from caffeine or Sabroxy, perhaps.

 

Emiel

Yeah, this brings up a good point. While it probably can't substitute for caffeine, it will probably make caffeine more effective, because a lot of us obviously use caffeine to offset the effects of minor sleep deprivation to kind of wake ourselves up in the morning or to get us over that afternoon slump. But in that context, potentially a little bit of andrographis will help you get back to a more normal baseline. And then when you add in caffeine, you need a lower dose of caffeine to get the focus enhancement and energy mood enhancement effects of caffeine, rather than relying on caffeine to get you back to that baseline and then having to actually supplement or drink more coffee way above the baseline, which then gets you into jitter territory, which is not great. So potentially actually the combination of andrographis and caffeine would be interesting to look at.

 

Erika

Or other stimulating compounds for that matter.

 

Emiel

Or other stimulating compounds for that matter. But of course, caffeine has a very specific effect on how we perceive tiredness. So in that sense, caffeine is a very good stimulating compound specifically for promoting wakefulness. But you can obviously also use other stimulating compounds if you're a little bit sensitive to caffeine, for example, a slightly lower dose of Sabroxy. In fact, I drink coffee every day, but sometimes I'll take Sabroxy in the morning, and it can actually substitute relatively well to a certain degree for caffeine.

 

Erika

Cool. So now we have a lot of different ideas for synergistic compounds that would go well with andrographis. Talking about potentially stimulating effects or just overall focus enhancing effects of andrographis because of its effects on sleep deprivation. We also talked about Siberian ginseng. In the beginning of the podcast, we talked about combining andrographis with melatonin. Are there any other notable or exciting combinations that you would suggest to take alongside andrographis?

 

Emiel

Yeah, that's a good question. So because of its unique pharmacological effects, you can definitely combine it with a lot of different plant extracts and compounds. But of course, we can focus on some specific goals. So I think, like Erika was saying, a really good stack would simply be andrographis and melatonin together, just to further enhance that melatonin effect. I also find that andrographis is a fantastic compound for controlling inflammation, and so is curcumin. I personally take the two together just because they work through slightly different pathways, and curcumin has some effects that I'm missing a little bit in andrographis, perhaps. So combining them really makes for a good overall inflammation stack. And I think if we're looking at the TRPV4 receptor activity, it will also go well with potentially endocannabinoid type compounds. So the cannabinoid system is also highly linked to these vanilloid receptors, so potentially taking andrographis alongside something like Palmitoylethanolamide, which is an endogenous cannabinoid, or even Oleamide, could prove to have very interesting effects. And on that note, I think because Kava has some mild cannabinoid-like activity, that could be a good stack as well. So I think now we're getting into, we talked about inflammation and what we didn't necessarily hit on is pain management, but inflammation and pain obviously go hand in hand. So andrographis is a fantastic supplement to utilize for pain, specifically inflammation-based pain. But with that in mind, it goes really well with other pain management supplements like Palmitoylethanolamide and since Palmitoylethanolamide and Oleamide and some of those other ones have endocannabinoid type effects, and because vanilloid receptors seem to be involved there too, taking it all together likely makes for a very comprehensive and rounded pain management/inflammation/joint health control stack. And if, like me, you are also very into chili peppers and capsaicin, and things like that, actually adding in some capsaicin would be interesting since capsaicin interacts with TRPV1 receptors in the same family as the TRPV4 receptors, and both of these receptors also have an effect on pain. So the combination of capsaicin and andrographis would be really interesting. Another combination that I can think of when we're talking about the glycolytic switch, we're also talking about glucose metabolism. So just for overall metabolic health, I think andrographis is a very interesting supplement. And with that in mind, I think a really good combination would be andrographis with Berberine. Since berberine has such fantastic effects on metabolic health and specifically glucose metabolism. So the two together will probably work quite well because when we're talking about glucose metabolism issues, we're sometimes also talking about inflammatory issues. So controlling overall metabolic health and glucose metabolism with these two might be a very targeted and quick solution for just ensuring overall general health.

 

Erika

Wow, that's a lot of things to consider and to potentially combine for a stack with andrographis! Thanks so much for all of your questions, by the way. We really love interacting with you on the Nootropics Depot subreddit, and your questions gave us lots of awesome material to discover and to really dig into with research and led us down paths that we certainly would not have found without your involvement and without your insight. So thank you for being a part of this second episode of In Search of Insight, and we really hope you enjoy this podcast. If you have suggestions, if you have more questions about this episode or future episodes, make a post. Let us know, you can tag us again, I am Erika, your host, u/NootropicsDepotGuru on Reddit and sitting next to me is Emiel, u/Pretty-Chill, product Specialist, and just overall big brain here on the In Search of Insight Podcast. Thanks again for listening. We're so excited to keep sharing more information with you and I'll sign off for now. Emiel might have some closing words, but keep listening, keep asking, keep digging in and we'll see you on Reddit.

 

Emiel

Yeah. My closing remark is just stay curious, keep researching and keep those questions coming. Because we base a lot of what we do on feedback that we get from all of you. Without real world experiences and questions and suggestions, we lose an aspect of our product development I think that makes us really special, and that's that we are a very human brand. We listen to people. We make products for ourselves, and we make products for you. So the more feedback and questions and research directions we can go in, the more interesting products we can bring out in the future.

 

Erika

And the more fun we can have on In Search Of Insight.

 

Emiel

Absolutely!

 

Erika

Thanks so much for listening. We'll see you next time. Bye bye.

 

Emiel

See ya!

Read The Andrographis Paniculata Blog

What Is Andrographis Paniculata?

The "King of Bitters", otherwise known as Andrographis paniculata, is quite a unique plant. Its popular name, "King of Bitters", speaks for itself as Andrographis paniculata is incredibly bitter! Andrographis paniculata is very widely used in South East Asia and is native to India and Sri Lanka. Traditionally, Andrographis is used to promote immune function (specifically to support the respiratory system). Another common traditional use is for supporting balanced inflammation levels which goes hand-in-hand with the immune-promoting effects. More modern research has confirmed these effects have shown that Andrographis may be a promising immune health promoter and inflammation balancer. Furthermore, some modern research has suggested that Andrographis paniculata may help... (click here to read more)

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#001 | Tart Cherry & Its Unique Effects On Exercise Recovery

Podcast Transcript

Erika

Welcome, everyone. You are listening to Nootropics Depot's podcast "In Search of Insight." I'm your host, Erika, and sitting next to me is the product specialist, Emiel.

 

Emiel

Hey, everyone!

 

Erika

So today, Emiel and I are going to be talking about three big topics. The first is uric acid, the second is exercise performance, and the third is tart cherry extract. So to get started, Emiel, can you give us just a general understanding of what is uric acid?

 

Emiel

Absolutely. So uric acid is a compound that is produced during purine metabolism.

 

Erika

Oh, hold up right there. What is a purine?

 

Emiel

That's a bit of a tough question to answer, actually. Purines are a class of compounds that contain nitrogen, and these compounds are present in our food, they're present in our DNA, they're present in our RNA, and they're present in a lot of different signaling molecules and energy molecules throughout your body. One of the main ones being ATP.

 

Erika

Oh, yes. Adenosine triphosphate.

 

Emiel

Yeah. And we probably all know that comes from Mitochondria, the powerhouse of the cell.

 

Erika

Yes, that was my favorite.

 

Emiel

Yeah. So that's kind of maybe one of the main sources of uric acid. So when I'm talking right here, my muscles need to contract, and while my muscles are contracting, they need some sort of energy source to make that contraction happen. And that energy source is ATP. When a muscle contracts and it goes through ATP, it generates ADP, adenosine diphosphate. So basically, the way ATP can power different reactions and muscle contractions and things like that is basically by losing a phosphate group.

 

Erika

I see. Okay, so adenosine triphosphate loses a phosphate, becomes adenosine diphosphate. I'm guessing... well, actually, I already know- it becomes adenosine monophosphate after that. And then what happens, Emiel?

 

Emiel

Well, and then after that, it loses another phosphate group and it becomes adenosine. And adenosine is one of the main purine nucleosides.

 

Erika

Okay, so when we're talking about purine metabolism, we're going from ATP all the way down, losing the phosphates, and we're getting to adenosine. Keep going.

 

Emiel

Correct. I do just want to say that's only one of the purine metabolism pathways. There's a few other ones, too. For example, Guanine turns into Xanthine. That's kind of where we need to go back to the purine metabolism pathway of ATP, because xanthine is really important here, and that will become a little bit more clear as we talk about it. So let's revisit ATP again. So in the normal process, like we were saying earlier, we're going from ATP to ADP to AMP to adenosine, then adenosine is turning into homoxanthine and homoxanthine is turning into xanthine, and xanthine is turning into uric acid.

 

Erika

Coming full circle now. Okay, so now that we know where uric acid comes from, I also want to know, what is uric acid doing?

 

Emiel

That seems to be a bit of a hot topic for debate, because we're not really sure. It's a really interesting compound. A lot of different animals have an enzyme called uricase, which directly breaks down uric acid. But that enzyme seems to be missing in humans and in primates. That's led a lot of scientists to consider the role of uric acid in human health. And the really interesting thing about uric acid is that it's actually a really potent antioxidant that's naturally present in our bodies. So a lot of the thinking about uric acid is considering its role as an antioxidant. But the interesting thing is, while we were talking about this metabolism pathway of ATP turning into uric acid, once we hit homozanthine, xanthine and uric acid, that portion of the metabolism, something interesting happens.

 

Erika

What is going on? Tell me.

 

Emiel

So there's an enzyme that is converting, or there's an enzyme that is responsible for that conversion. And that enzyme is called xanthine oxidase. But xanthine oxidase also requires oxygen and H2O. So when oxygen and H2O are present together with xanthine oxidase, then xanthine oxidase can take homoxanthine and turn it into xanthine. But during this process, you also generate a really strong oxidant compound. And that oxidant compound is called superoxide. You also generate hydrogen ions, and we'll touch on that a little bit later. But basically, when we're thinking about hydrogen ions, we're thinking about acidity. We're thinking about acidity within our muscles, and we probably know this a little bit already with lactic acid. You know, that burning feeling, the muscle fatigue. It is based partially on PH changes. So that's happening here, too, with purine metabolism, you're generating a really strong oxidizing compound, superoxide, and you're getting some hydrogen ions. So maybe some PH changes. But the interesting thing here is uric acid is working as an antioxidant. But while it's being generated, it's actually producing oxidizing compounds.

 

Erika

Isn't that kind of paradoxical?

 

Emiel

Yeah. So that's kind of what I've been thinking, reading a lot of these studies. So, yeah, uric acid might act as an antioxidant, but in the process of its creation, it's creating oxidizing compounds. So it might have its hands full already with taking care of the oxidation during its own formation. Furthermore, uric acid is actually quite a strong inflammatory compound. So it might have some good antioxidant effects. And it does seem like at certain levels of uric acid concentrations throughout your body, it does indeed have a positive effect on oxidative status. It also has a positive effect on immune function. And that's probably no surprise because of its inflammation inducing effects.

 

Erika

I see, because we know that inflammation, it's not always a bad thing, right? Sometimes inflammation is necessary, like, for example, during exercise to build muscles.

 

Emiel

Yeah. So while we're exercising, we actually need some inflammation, and we need some oxidation to drive the adaptation to exercise.

 

Erika

And so then when it comes to your immune function, talking about inflammation, how do these things relate and is inflammation okay when we're talking about its relationship to your immune function?

 

Emiel

Yeah. So basically, and I hate to break it down this simply, but your immune function is basically a positive inflammatory response. And sometimes it's not positive. But it's one of the main tools our immune system has to fight off certain things that we don't want in our body. So it's the main tool. When it goes out of context a little bit, or it happens when we don't want it to happen, then it's not really good. But during exercise, it's actually kind of important to have some inflammation. So there's some really interesting research actually on that looking at arachidonic acid, which is one of the main inflammatory compounds in our body. When body builders are supplementing arachidonic acid before exercise, it seemed like it was having an ergogenic effect. And that's probably because the inflammation is being driven up and is causing more muscular damage. And because of that, we need to rebuild a little bit stronger.

 

Erika

Okay. So how does this all circle back and relate to what we were talking about with uric acid?

 

Emiel

Yeah. So this is a really interesting topic because we know that uric acid partially comes from ATP breakdown, and we know that ATP breakdown starts when we need to use ATP. So, for example, when we're exercising and the harder we exercise, the more ATP we burn through, the more ATP we're going through, the more xanthine compounds you have. And then if xanthine oxidase is working at its full potential, you get quite a bit of uric acid. And like we were mentioning earlier, we don't currently have a functioning enzyme (uricase) to take care of uric acid levels.

 

Erika

And when you say "we," you're talking about humans, right?

 

Emiel

Yeah.

 

Erika

Okay. Cool, just making sure.

 

Emiel

Humans and primates.

 

Erika

Okay. Humans and primates, got it.

 

Emiel

So looking at kind of some of the other metabolism pathways where you can get rid of uric acid, one of the main ones is through the kidneys. So the kidneys filter an insane amount of uric acid every day. But the kidneys actually let through 90% of the filtered uric acid and let it be absorbed back into your body.

 

Erika

Okay, so when uric acid is being produced, like during exercise, some of it is being filtered by the kidneys. But then a lot of it is actually staying present in the body.

 

Emiel

Yeah. That's why scientists are a little bit confused. It seems like we need it. But do we really? And maybe one of the arguments for uric acid, and if we look at some research at heavy exercise, we can see that the harder we exercise, the more purine metabolism we get because we're going through more ATP and the more uric acid we get. So maybe an interesting theory here is that uric acid is part of the adaptive process of exercise. It is maybe one of the compounds that is inducing that muscular inflammation that's signaling to our bodies, "Hey! Something is going on here. We need to be more resistant to this." And that's kind of where a lot of the benefits of exercise come from, but it's likely also where delayed onset muscle soreness comes from.

 

Erika

Okay, I see. So when it comes to the intensity of your workout and maybe the soreness you experience afterward, where does uric acid really fit into that experience of your heavy workout, your recovery, and then eventually some soreness, especially if you're hitting your workout super hard. Where does uric acid come into play in that process?

 

Emiel

So in that process, I really just think that uric acid is causing some of that inflammation in your muscles, but it's also probably a main factor of delayed onset muscle soreness. I was reading a research study recently that showed that directly after high intensity exercise, uric acid levels go up by about 40%, which is a pretty rapid increase. The next day, however, uric acid concentrations were also higher. In fact, it increased another 23%.

 

Erika

On top of that initial 40%?

 

Emiel

Yeah.

 

Erika

Oh, wow.

 

Emiel

So if we think about this progression and we think about how delayed onset muscle soreness kicks in, it kind of makes sense that uric acid may be one of the main mediators of delayed onset muscle soreness.

 

Erika

Okay, I see. So now that we understand where uric acid is coming from and what role it plays in exercise performance and then also exercise recovery, how do we address uric acid? Because there's both positive aspects to this compound in our bodies. But then I don't like being sore after a workout. So how much uric acid do I actually need? And how do I know what amount is good for me? How do I know what scenarios I would want more or less uric acid present in my body, if I really had the choice?

 

Emiel

Yeah. So I'm going to have a bit of an unscientific statement here and just say that in general, we probably just want less uric acid.

 

Erika

So how much uric acid do we want?

 

Emiel

Less!

 

Erika

Okay, got it.

 

Emiel

And that's where tart cherry comes in. So as we were talking about, to get to uric acid, one of the main pathways is xanthine oxidase. So if xanthine oxidase is in full swing and we're having a lot of purine metabolism, then we have a lot of feedstock basically, for this enzyme, so we can make a lot of uric acid, which is why it makes sense that uric acid concentrations go up during exercise. Tart cherry has a really unique effect due to its anthocyanin content, and it blocks the function of xanthine oxidase. And that's not really a common mechanism of action when we look at different plants, and it's certainly not a mechanism of action when we look at a lot of different recovery supplements for exercise. So that's why I personally think tart cherry is a really unique option to look at for exercise recovery because it's targeting a pathway that very logically seems to be related to delayed onset muscle soreness. And in fact, tart cherry has very quickly become one of the most popular supplements for athletes for recovery. And if we just look at the general antioxidant effects of tart cherry, this doesn't really make sense. So there are a lot of different supplements that we can take that regulates oxidation. And while some of those help a little bit with delayed onset muscle soreness, it kind of just seems to mask the symptoms of delayed onset muscle soreness, but it doesn't actually seem to help us recover all too much. It just kind of puts a bandaid on it. Whereas with tart cherry, that bandaid type effect is still there. You get some relief from that delayed onset muscle soreness, but it also really just seems to go away. And people seem to recover a little bit better when they take tart cherry, maybe an hour or two after their exercise.

 

Erika

Yeah, that was going to be my next question. If tart cherry is so useful for exercise recovery, and like myself, I think a lot of people don't enjoy the soreness after exercise, maybe a little bit, but definitely not that second day, that delayed onset muscle soreness you're talking about. So is there any reason why I shouldn't be taking tart cherry every single day, or is there a best use for tart cherry? Is there a place where tart cherry really shines as far as its ability to regulate uric acid production?

 

Emiel

Yeah. So that's a really good question. So I personally take tart cherry every day. We can get into some of the reasons why I do this a little bit later because there are some other really interesting effects associated with tart cherry and uric acid that are not related to exercise. But in the context of exercise, timing is really important. So if we take tart cherry right before we exercise, then we might be shooting ourselves in the foot.

 

Erika

How so?

 

Emiel

So, like we were saying earlier, that increased oxidation and inflammation in your muscles is really important for training purposes, for adapting to exercise, to getting stronger. So if we take that away, then what do you think will happen?

 

Erika

We would probably get less strong and it's going to take longer.

 

Emiel

Right. Which means you have to do more work for less returns. And we don't really like that. At least I don't like it. So I want to optimize the exercise I do. And because of that, we don't really want to take oxidation or inflammation regulating compounds right before exercise because we want that inflammation and oxidation. So with that in mind, if you take tart cherry before a workout, maybe not the best use, it probably won't negate all of the effects of exercise, there are also other mechanisms at play here, but the best use case would be to take it after exercise. So you still get some of that initial burst of uric acid. You get that initial burst of oxidation and inflammation and minor muscle damage, and your body can start rebuilding this getting stronger, actually benefiting from the exercise you're doing, and then taking tart cherry right after is going to blunt that response of uric acid the next day and the day after, et cetera. So it's kind of a nice strategy to manipulate how our body recovers from exercise through a pretty smart way. Rather than just throwing some antioxidants and throwing some inflammation regulating compounds at our bodies, we kind of go to the root cause with precision. So here we can be really precise. Uric acid is probably causing a lot of delayed onset muscle soreness symptoms. Let's get rid of it with tart cherry, and this seems to be a really good strategy, which is why it's so popular.

 

Erika

Yeah, that makes sense. I think one thing when it comes to exercise and training that I know is important to me and to a lot of other people is that we don't want to do anything to take away the benefits of our exercise. So now that we know that taking tart cherry after an exercise session is going to be more beneficial to strength building, what about activities that require more endurance or are, like, a little bit longer in duration or for people who are going on long treks or maybe like a marathon runner, how does tart cherry relate to training and recovery in those instances where we need lots of energy over an extended period of time?

 

Emiel

Yeah, so there we want to do the opposite. So like we were talking about when we're going through a lot of ATP, we have more potential for uric acid because of xanthine oxidase. But like we were also saying, while xanthine oxidase is performing its conversion, you're also getting superoxide anion, and you're getting hydrogen ions, which can negatively impact muscle fatigue, or negatively impact muscle fatigue? It just causes muscle fatigue.

 

Erika

Which I guess we could all say is generally negative.

 

Emiel

Yeah. But actually, with tart cherry, we are going to be negatively impacting muscle fatigue, which is then going to cause the opposite reaction, which is less muscle fatigue.

 

Erika

Okay, cool.

 

Emiel

One of the things is when we block the activity of xanthine oxidase, not only are we getting less uric acid, we are also probably getting less superoxide anion and less hydrogen ions, which should promote muscular endurance. It will probably take away a little bit from the adaptive process of exercise. But if you've been training extensively for a marathon, you don't really care about coming out of that marathon even stronger. The marathon is the day where you put everything on the line. You test out the abilities of your body, you kind of go until you fall down dead at the end of the marathon.

 

Erika

Yeah, I would hope not. But maybe tart cherry can help smooth out the process a little bit more with regulating some of those less than desirable effects of really hard exercise. Certainly, if you're going to be running a marathon.

 

Emiel

Yeah. So in that use case, taking tart cherry before, during and after would be a really good strategy to enhance your muscular endurance.

 

Erika

That makes sense. So understanding how uric acid is forming in the body, where it's coming from, and what kinds of activities are going to be producing greater amounts of uric acid, like heavy exercise or high intensity exercise. Now, we know a little more context when it comes to when is the right time to take tart cherry and why we might want to take it for training versus for performance and just generally regulating that uric acid production and hopefully pushing away some of the less than desirable effects that we have from this particular compound in the body. What other kinds of benefits does tart cherry have for us, aside from that uric acid regulation?

 

Emiel

Well, actually, let's keep focusing on that uric acid regulation because uric acid doesn't only play a role in physical endurance and exercise and things like that, but it actually has neurological effects, too. This is the one area that I'm really excited about myself, and it kind of seems to be unexplored territory. So I always really like getting into these rabbit holes where I get to explore something that not a whole lot of people are talking about, but a mechanism that might be really important to understanding our own brains better, cognitive health, how we can improve things. And uric acid doesn't really seem to be part of the conversation at this point, and I kind of want to make it part of the conversation because it's a really interesting compound. And within the brain, uric acid can accumulate in quite high amounts in the hippocampus, and the hippocampus is really important for memory processing, for overall cognitive function and even for mood. So when we have excessive inflammation in this area of the brain, it's pretty much bad news all around. So we might see cognitive deficits. We might see poor mood. We kind of want to avoid this. So this is one of the other areas where tart cherry may help out by inhibiting that enzyme that produces uric acid. And it's not the only pathway by which uric acid gets produced, but it's one of the main ones. So by inhibiting this pathway, there's potentially less uric acid floating around in the brain, too. And this could have really good cognitive effects and not only in the hippocampus, it also seems that uric acid has an effect on sleep.

 

Erika

Okay, so not only does uric acid affect exercise and energy and my recovery, my muscles soreness, it may have effects on my mood and cognitive health and effects on sleep as well. So now I can really understand why you're so excited about it, because aside from sleeping, waking, exercising and then eating, it's not a whole lot else to human life. And I think sleep is probably one of the more important aspects of health as well, especially when considering the fact that we don't really understand sleep that well, but if uric acid has a part in sleep, then it must be super important, since it also seems to have an extremely valuable part in pretty much every other human activity.

 

Emiel

Yeah. And it seems that high levels of uric acid actually have a negative impact on sleep, and there's a few explanations for it. So one of the explanations might be that structurally, it's somewhat similar to caffeine. So there's some theories that perhaps uric acid itself has slightly stimulating effect, that this could negatively impact sleep. So let's roll with that theory for a little bit. We have a lot of uric acid in our brain. Maybe it's keeping us awake, similar to caffeine. And in studies where they see high serum levels of uric acid, they do see a kind of similar effect. And this brings up a really interesting point for me. A lot of people talk about tart cherry and its effects on sleep, and the conversation always goes to melatonin. There are some research studies out there saying that tart cherries, in their natural form, contain melatonin. And while this is true, I've done the math on it, and I can't really remember exactly what it was, but I helped out a customer with this once. Basically, you have to eat a truckload worth of tart cherries to get any appreciable amount of melatonin.

 

Erika

Okay, so not really practical in terms of addressing sleep concerns.

 

Emiel

No. Well, maybe, but it doesn't seem like melatonin is the main compound of interest here, and we were actually really interested in this, too. So we tested one of our tart cherry extracts, and it contains no melatonin at all. However, I have personally also noticed that it has a positive impact on sleep and anecdotally a lot of people say it has a positive impact on sleep. So if it's not melatonin, it has to be something else. And I think that something else is uric acid, especially looking at the link between high uric acid levels and poor sleep.

 

Erika

Okay, so what you're saying is that the xanthine oxidase regulating aspect of tart cherry is perhaps the reason why you're getting sleep benefits from it.

 

Emiel

Yeah. So that's kind of my running theory at the moment, because it's pretty undeniable for me. I notice those effects, and the only thing that really makes sense at this point, unless there are some other pathways at play here. But the uric acid pathway seems to make a lot of sense, especially because there seems to be a link between uric acid and sleep. It seems to be an under explored pathway for sleep, and the whole uric acid conversation doesn't really come up a whole lot with tart cherry. So I think when we take all of those factors together, it's likely that the xanthine oxidase regulating effect is causing both positive effects on sleep and overall cognitive health, perhaps also mood.

 

Erika

Pretty amazing that uric acid seems to hit the trifecta of affecting our sleep, affecting our exercise recovery, and also affecting our cognitive functions as well.

 

Emiel

Yeah. And that's honestly one of the reasons why I'm so interested in tart cherry. If I'm taking it, it doesn't really have a very noticeable acute effect. So it kind of hangs out in the background, which is nice, because I can stack it with some other products. But the research on uric acid is interesting enough for me that just trying out something that helps regulate uric acid levels is a pretty interesting approach to nootropics, so not something you can maybe feel right away. It's not stimulating, like Sabroxy, it's not calming, like Kava. It's kind of neutral. I mean, in taste, too. It doesn't really taste like anything.

 

Erika

Yeah. But I have to say the appearance of it is pretty phenomenal because it's a gorgeous, like, really dark purple color. And then if you add it to something that's just a little bit acidic, like a drink or maybe like drinking vinegar in your water, it turns red because of the anthocyanins, which I think is just the coolest thing ever.

 

Emiel

Yeah. So actually, Erika brings up a really interesting point here. Anthocyanins can be used as environmentally friendly PH meters, because when they are exposed to different PH levels, they actually change their color. So that was one of the interesting things about tart cherry that I discovered accidentally. I was making a drink with it with some lemon juice, and the purple color turned into a red color. So really, just the change in PH changed the color, which then reminded me of oh, yeah, anthocyanins can actually be used as PH meters. So not really important for the effects of tart cherry, but if you want to try it at home, it's a pretty interesting thing to see happening in real time. Just make up a tart cherry solution, add some sort of acid to it. It can be lemon juice. I tried it later with citric acid, ascorbic acid, malic acid. I even tried some vinegar. Those all work. So that PH change is really what's causing that color change. So that's a pretty interesting thing. But other than that, it's tasteless. You can kind of add it to anything, hangs out in the background. But its effects on uric acid are really interesting. And I think this is an area that deserves a little bit more attention.

 

Erika

Yeah, it certainly seems like it because if uric acid is really having this much of an effect, perhaps negative effect on sleep quality or just general fatigue and muscle soreness, I think it's something that is a big concern for a lot of people on a daily basis. And I know beyond the fun color taking tart cherry and that experience of seeing it in my morning elixir, I also do notice effects of it overall, throughout these three kind of big areas that we talked about. So thanks so much for going really deep in depth with just the processes of how we get to uric acid and where uric acid is hanging out in our bodies and what it's doing. I feel like I have a totally different and deeper understanding now than I did earlier, which is amazing because that's what we hope for you as well. You listeners who are tuning into "In Search of Insight" with us here at Nootropics Depot. So, Emiel, thank you so much for just exploring all of this and sharing your wealth of knowledge.

 

Emiel

Of course, it's really exciting that I get an opportunity to talk about this outside of a blog. I can talk a little bit more freely. We can kind of go a little bit more in depth and really break things down. So I hope you guys like this format. We'll be doing a lot more in the future and, yeah, check us out on our subreddit, too. And if you like this episode and you want to ask us a few questions about it, start up a thread. We'll be in there. I'm u/pretty-chill on Reddit and Erika is...

 

Erika

I am u/NootropicsDepotGuru. So here you have two great resources. We can answer your questions. We'll chat with you. And really, if you're curious about uric acid, if you're curious about tart cherry, if you want to know more about this metabolism process and really get into the nitty-gritty of what's happening in the body in these different areas, sleep, cognition, and exercise, feel free to send us a message, make a post, because we want to interact with you, and we want to hear what you are curious about learning, because that's going to help us guide "In Search of Insight" as well, because naturally, we're all looking for something. In this case, we want to know more. And Emiel has got some answers. I've got lots of questions and we have lots more podcast ideas for you, hopefully coming very soon. So thanks so much for listening. And that's all we have for you today. Until next time, bye bye.

 

Emiel

Bye.

 

Read The Tart Cherry Blog

What Is Tart Cherry?

Tart cherry, also known as sour cherry or Prunus cerasus, is a fruit that is closely related to sweet cherries. Tart cherries are much smaller than the more common sweet cherries. This has earned them another popular name, the "dwarf cherry." As the name would suggest, tart cherries are also significantly more sour than sweet cherries. It is believed that tart cherries originated in either Eastern Europe or Iran where Prunus avium (sweet cherries) and Prunus fruticosa formed a natural hybrid, which stabilized and resulted in an entirely new species.

Tart cherries were incredibly popular amongst the Romans and Persians, who brought the tart cherries with them to Britain. The British, in turn, were also very fond of these tiny sour cherries. So much so that they brought the cherries with them to America. Specifically, the British brought the tart cherries over to Virginia where they were cultivated on a large scale. Tart cherries are also still very popular in Iran where they are used in various dishes such as albaloo polo which is a rice dish that incorporates tart cherries... (click here to read more)

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