Is Melatonin the Next Vitamin D?

Hello everyone. I'm Noel Reid, Vice President of Sales and Marketing for the Dutch Test. Thank you all for joining us today for this webinar featuring Dr. Deanna Minick. Our webinar today will be on Melatonin and Vitamin D. There is a distinct similarities between melatonin and Vitamin D in depth and breadth of their impact on health. Dr. Deanna Minik will evaluate recent data on melatonin's mechanisms and provide a summary of therapeutic considerations considering dietary supplementation, including the different formats, dosing, timing and nutrient combinations. Before we begin, let's dive into some new Dutch educational resources that are now available exclusively to registered Dutch providers. The Mastering Functional Hormone Testing course and the new Dutch Interpretive Guide are designed to help providers confidently use the Dutch Test to treat their patients. With the actionable results found in each Dutch report, providers can sign up for a self paced online course that walks through how to interpret the Dutch results for a variety of patient types. The Dutch Interpretive Guide is a supplement to the course that gives detailed information about report interpretation for complex symptoms and offers support considerations so you can better treat your patients. If you're not already a Dutch provider, you can get started here today. Just click the link that's in the chat to become a provider and gain access to the Mastering Functional Hormone Testing course and the Dutch Interpretive Guide. Current Dutch providers can find both of these valuable educational resources on their provider portal. Now let me introduce today's speaker. Deanna Minick, MS, PhD, CNS, IFMCP, is a nutrition scientist, international lecturer, teacher and Author with over 20 years of experience in academia and in the food and dietary supplement industries. Throughout the years she has been active as a functional medicine clinician, in clinical trials and in her own practice, Food and Spirit. She is the author of six consumer books on wellness topics, four chapters and 50 scientific publications. Since 2013, she has been a part of the faculty for the Advanced Practice Module in Environmental Health offered by the Institute for Functional Medicine and has been teaching at a graduate level course in Metabolic Detoxification at the University of Western States. Currently, she is the Chief Science Officer at Symphony Natural Health where she leads the medical team overseas scientific communication and and provides educational leadership for the company's plant derived nutraceuticals. She is passionate about helping others to live well, using therapeutic lifestyle changes that impact their physical, emotional, mental and spiritual health. Thank you for spending some time with us today, Dr. Minnick. We're ready when you are.

All right, thanks Noah. Thanks for that kind introduction and it's lovely to be here with you all happy afternoon here and I just so enjoy this literature, the science and the clinical application of melatonin. So this is going to be a jam packed webinar. I'm warning you. You do have the slides. Lots of news to use. I mean, I was just updating this presentation as of yesterday so you have a lot of fresh content here. So as you can see by the thought provoking title, is Melatonin the next Vitamin D. I have a little bit of a different angle and I think it comes because my background is actually in nutrition science. It's not in endocrinology. It is taking a nutritional view on something that appears as though it's a hormone. And I use that word appears very judiciously. So I'll unpack that a bit as to what are the similarities and or differences between melatonin and vitamin D. So my disclaimers and disclosures here. As Noah mentioned, I am chief science officer at Symphony Natural Health, which does make a plant melatonin. Okay, lots of different objectives here. I couldn't even summarize them all on one page. We're going to go in so many different directions here. This is just how my brain works with the crosstalk between science, clinical applications. So I'm going to talk a bit, as I mentioned, about melatonin and vitamin D. I am going to get into circadian rhythm and light as a therapy. Before we even get into things like supplemental sources of melatonin, I'm going to go into melatonin beyond sleep. I'm very much fatiguing of all of the different conversations that people are having just about melatonin and sleep. When really and truly, as you start to dive into the research on melatonin, you see that it's so much bigger and broader. Sleep is like a sliver of what we know melatonin to be useful for. And then of course, I hope to give you a lot of different clinical pearls to implement. So why does it seem that melatonin is always in the news? I have one of my, well, I have my PubMed alerts and my Google alerts both set to melatonin. And I think I get alerts just about every day or every other day. It just seems like this is a hot potato in the press and the media and it's very mixed. It's almost very polarizing. It's either it's really good or it's oh, caution, it's a hormone or this shouldn't be on the market or, you know, this is dangerous. You know, some Very strong views either way. And I would say the way that I'm going to present it and the way that I see it after working on melatonin for just about a year now is I would say that I'm that middle path. I'm definitely going to show you where the rubber meets the road in terms of using this clinically, but also where we need to create some guardrails, because I don't think melatonin supplements are for everyone. I think that we need to use it with caution and knowing some of the facts about things that we could be doing from a nutrition lifestyle and then also supplement perspective. But all of these things to some degree, there are some half truths here year. So I think that for a lot of these statements that you see, we're going to address them throughout. All right, so first I want to charm you a little bit with a little bit of how melatonin came to be. And, you know, I started reading the scientific literature, but then I also started reading a book on melatonin written by Russell Ryder. And as I present today, I'm really standing on the shoulders of giants that have walk this terrain for various reasons. You know, sometimes scientists take a path and then it leads them somewhere else. And the way that melatonin was discovered in 1958 was by a Yale dermatologist, Dr. Aaron Lerner. And Dr. Lerner was actually looking for a skin lightening agent. And he had found a paper that I believe was published back in 1917, two scientists that were talking about how they isolated the pineal gland of cows and they happened to throw it into a vat with tadpoles and the tadpole skin got white. So Dr. Lerner was thinking, oh, well, this is very interesting. This could be a skin lightening agent. So there was some traction there early on with melatonin. Soon after it was realized that, oh, this doesn't really whiten skin and also you'd have to extract a lot of pineal glands in order to get an appreciable amount of melatonin. So that project was soon let go and Dr. Russell Reiter took it on. He's at the University of Texas and still, I believe he's in his 80s, continues to work on this very interesting topic of melatonin. And, you know, he was working with, I believe, the military trying to look at hibernation agents and came across some of this research on melatonin and decided to pursue it. And there wasn't a lot there as it related to hibernation. But he went on to do some other research. So, long story short, melatonin has been around for a while, but I would say it's only been within the 21st century that we have started to see all of the many applications of this ancient molecule, which the chemical name for it is N acetyl 5 hydroxytryptamine. It's an indolamine mela coming from the skin connection tone, because some of the early research was connected to serotonin, and it seems that there was a connection, and we know that there is a connection between those two. Where I find it particularly fascinating, if you look at this, this entire chart here that I'm showing is that melatonin is used in plants as a growth factor. In fact, even in some of the agricultural work and studies, what they do is they apply melatonin in order to create more phytochemicals. So for me, as a phytochemical, I would. You know, that's another one of my big loves, right, Looking at all things plants. And what we see with melatonin is that it works in the plant kingdom, it's in the animal kingdom, it's definitely in us as humans. But I want you to remember that melatonin, again, being used in plants is kind of this potentiator of things like glucosinolates. So when we start talking about some of the detox aspects, just perhaps remember this history. So, going from left to right here, together with a team that I work with, we decided to publish a pretty extensive review paper on all things melatonin. Like just rolling up our sleeves, getting into the science and making the science clinically applicable. We published that in Nutrients in September of 2022. And then the article got so many hits, I think it had something like 30,000 views. And then we had somebody comment on the article, a Polish researcher, which was actually questioning our posit that melatonin and vitamin D were very similar in the way of looking at beta amyloid and hypertau phosphorylation. So in other words, the connection with dementia. So we responded to Dr. Pluta, and in fact, I'm really glad that he raised a number of these different points about melatonin and vitamin D. And it gave us the opportunity to flesh some of the cognitive work out, which I would say is where we're starting to see the emergence of more and more very interesting work on dementia, Alzheimer's disease. So we expounded on that in that third publication that you see here up on the screen. So all of these, by the way, are open Access so you can download them free of charge. So starting with melatonin, in terms of the body, it's ubiquitous, it's widespread throughout the body. It's in the tissues, it's in the fluids, it's in the, as you can see here throughout the body, the brain, the retina, the skin, the liver, the kidney, thyroid, thymus, skeletal muscle, reproductive system, and that is a short list. I'm not even getting into the nuance of all of the different immune cells, immune types, and looking at the different neuronal cells, the mitochondria, where it's in very high concentration in within the cell, you can also see that there are many different body fluids, amniotic fluid, breast milk, cerebral spinal fluid, bc, synovial fluid, saliva and urine, which will bring us back to testing as we come to a close in the presentation now, one of the features of a hormone is that a hormone needs a receptor. And, and what we know about melatonin receptors is that there are two known receptors at the level of the cell membrane. So that would be MT1 and MT2. And there are some identified gene variants in those respective receptors. So we need to think in that way of personalization of melatonin response in individuals because there can be some variability with those receptors. There are also three nuclear receptors that are connected to more of the closer in DNA and RNA expression type of activity. The two main organs though, if you look at the overall literature, is primarily the pineal gland and then secondarily the gut. The gut makes 400 times the amount the pineal gland does, however, so. So I am going to detail you a little bit about the gut. So in terms of its functions, this is where I have to bring out the precautionary principle of saying it almost seems like if you have a hammer, everything looks like a nail. And we want to caution ourselves against doing that because it almost seems like a panacea. There are so many different things that melatonin could be good for. This is again a short list. Looking at body temperature, sleep, wake cycle, core cortisol secretion, blood pressure, even blood sugar control, cell proliferation. You know, there's just so much here. So again, I think we need to look at the Goldilocks principle of not too little, not too much, just right and just right for the individual can vary. So are there associations between different health conditions and endogenous levels of melatonin? And certainly there are, as you can see on the far left here. So if you are just thinking of the pineal gland and the connection between the eyes, the suprachiasmatic nucleus, and the eventual conversion of tryptophan into melatonin in the pineal gland. So if we're just thinking about just levels in the body without that whole cascade, we can see that there's a pretty long list here. And this is again, I would say, somewhat of an abbreviated list on the right hand side of the slide. What you see is that there can be also some receptor type of alterations like I was talking about with MT1, MT2, so Parkinson's, Alzheimer's disease, and even some involvement of gene variants, so type 2 diabetes, rheumatoid arthritis, scoliosis and PCOS. So some things to consider. And you can see that this is a wide swath of different disorders and conditions to be thinking about. So first and foremost, is melatonin a hormone? You know, I think sometimes this is what gets people a little bit in fear mode about melatonin. Yes, it is a hormone and it's a very different hormone than I would say, some of the others. But just in terms of its hormonal like activity, the way that melatonin is acting as a hormone is actually through the eyes. So through the retina we receive light and we also receive darkness. Right. So I'm going to talk about the balance of both of those things. So within the retina, you have rods which help with black and white vision. Then you have the cones which help with the color vision. There's also a separate type of cell within the retina known as the intrinsically photo cell sensitive retinal ganglion cells. You know, very, very specific and very separate from those rods and cones that are enriched with the melanopsin, which are signaling and receiving blue light, blue light in the environment. Now this is relevant for melatonin because in the presence of blue light, melatonin, endogenous production of melatonin by the pineal gland is suppressed. So the retina is part of the melatonin response. I'm emphasizing that because the eyes need to be considered in our conversation about melatonin. Right. So what the eyes are exposed to, you know, it's not just the pineal gland. The pineal gland is just taking the signal from what we have ultimately through the retina. So people who have visual disturbances, people who are blind or they have cataracts, they have any kind of macular issues, retinal issues, this can translate into melatonin issues. So it's not just about the pineal gland in the traditional sense of it being endocrine. There truly is an extension here through the eye. And as I state here, melatonin can help with falling asleep faster, but not necessarily staying asleep longer. So we'll talk a little bit more about how to use it with sleep sleep. But again, I am stressing this whole connection to the eye. So I have this other love of the circadian clock. As I started to get into the melatonin literature, I realized that, wow, you know, we have this internal infrastructure of the clock. We have so many rhythms that we are connected into. And being that Dutch Precision Analytical is so much connected into hormones. One of the things here to be attentive to is the circadian rhythm of when we are measuring hormones, right. That we are humans that are run by the sun, we're also run by the moon. And I'm going to talk about moon cycles and melatonin as well. So here's the thing about the circadian clock. Essentially, we have this connection from the eyes to the suprachiasmatic nucleus, which is really, I would say, the concentrated place where we have this centralized pacemaker of the circadian rhythm. So again, just to back up to that slide, the suprachiasmatic nucleus is in the brain, ultimately signals to the pineal gland, which then goes on to make the melatonin. So the SCN suprachiasmatic nucleus is responsible for setting the overall tone. The circadian system. I don't even think of it as a circadian rhythm. I think of it as a system because this goes system wide. So it's pretty difficult to do some of these studies in humans because it would require looking at certain types of day, night rhythms, looking at transcriptomics. But basically what we know from animal studies is that if you look at when the circadian rhythm, the clock genes are most active is typically at the times preceding dawn and at dusk. These are referred to, at least in the literature, as transcriptional rush hours. So I want you to think about that, because that would be the time of transition, right, that we have the most activity going on with those clock genes. And I would encourage our friends at precision analytical, especially Mark Newman, who's that, the brain trust of all of these different tests, to figure out how we can assess clock clock genes specifically and marry that to hormone measurements. Because I think it's great, big, huge, not a lot of people. In fact, nobody I know specifically is doing that kind of work of connecting clock genes because everybody has their own clock, right? So we're not all set to 24 hours. Some of us are a little bit over. Some of Us are a lot over. So I think understanding one's clock genesis would be really interesting to get an overall assessment of our rhythm and how we work and then how that translates to the level of the cell. So as you can see here, about 7 to 13% of a cell's transcriptome is under circadian control. And what really, really surprised me was that the liver, well, maybe it's not so surprising because if the liver is truly the hub of metabolic detoxification, what we, and it's like the general of the army, what we see is that the liver has one of the highest levels of circadian genes. Now, keep in mind, this was done in animals. And when you look at the bar chart of all of the different organ systems that these researchers tested, what you see is that the liver far and away is the highest. It does have a high concentration of these, these circadian genes, followed by the kidney, followed by the lungs, which again is very interesting to me. So we need to be thinking of liver. And when people say, well Deanna, why do I wake up between 2 and 4am well, let's think about the liver and how the liver is connecting into these circadian signals. So this is the point of marrying hormones to detoxification to circadian rhythm. I don't think we can leave the liver out of the conversation. And in fact, the liver is a key. I would even refer to it as an endocrine organ. It has hepatokines. Right. So again, when you look at the Dutch test report, you see a reflection of so many of the different, different liver pathways of hydroxylation, Phase 2 conjugation with sulfur and a number of other constituents. So keep in mind the liver think of that clinically. And I do think that eventually we're going to move into this space of not just chrono therapeutics in the way of pharmaceutical delivery, but also thinking about when people should actually be taking vitamins, minerals and plant actives. You know, I think for the most part people just toss in their mouths or first thing in the morning a bunch of supplements, but maybe they shouldn't actually be designed that way. We know that about melatonin supplements, that there's a certain way to take melatonin and perhaps some of the other compounds specifically relating to detoxification need to be more prime to the circadian rhythm. So you can see here, I made this infographic which is based on this publication that you could see at the bottom, basically showing how cortisol testosterone are what get you out of bed in the morning. Melatonin puts you to sleep at night. Insulin weaves your day together through the eating response. So eating is a zeitgeber, a time giver. And thyroid hormone, which is very interesting, you know, that is earlier in the morning, you know, 1 to 2am, 2:30 to 3:30. So you know, to even be thinking about when people take thyroid hormone. So the GI tract, I'll just mention this briefly because I think that there's so much research that still needs to be done. This is one of the greatest concentrations of extra pineal melatonin. So in other words, melatonin made in the body, but not made through the pineal gland. So when we think of the endocrine system, we think of autocrine, paracrine and endocrine. When we think of the, the GI tract, I want you to think more autocrine and paracrine. It's kind of like that phrase what happens in vagus stays in Vegas. Right. So like what happens in the gut as it relates to melatonin for the most part stays within the gut or at least in adjunctive type tissues. Right. So this is not to the same level of going and changing systemic wide clock genes, something like the pineal gland would have that, that type of command to the rest of the body. Right. The gut seems to be using melatonin differently, much like the other neurotransmitters produced in the gut are also used a little bit differently than we would see them potentially in the brain. So what's interesting about the gut derived melatonin is that we see it in the lumen, we see it in the mucosa, we even see it in the muscularis, so in the smooth muscle portion. So melatonin seems to play a role in even intestinal motility, gastrointestinal secretion. And some newer work is coming out looking at its ability to even modulate the gut microbiome. I don't feel like we're there yet in terms of making specific recommendations, but I do think that we're starting to get more information and it would be nice from a laboratory perspective to actually have a panel fusing together the endocrine and also looking at the gut microbiome. Right. So that we can start to see those shifts because we know that much of the endocrine system is actually housed within the gut. Another thing, I'll just toss this in as a tidbit because we're hearing so much about short chain fatty acids these days, especially in relationship to prebiotic fiber. And quite interestingly, this is why we need to have patients on fiber, especially the kind that make things like butyrate. What we see is that short chain fatty acids produced in the intestinal lumen do stimulate the enterochromafin cells to release serotonin and enhance melatonin production. So there is a benefit there on behalf of getting in more fiber and stimulating that release. So this is. You might have seen this type of graph before, although not with all of the anecdotes that I have added here. This is basically how we produce melatonin throughout our lifetime. So in the first three months after a baby has been born, there's not a lot of melatonin, but then it starts to go up sequentially up until about one year of age, and it's peaking in early childhood. And really and truly, this is where you have the highest levels of melatonin that you're probably ever going to have in life, is when you are a child before you go through puberty. Now, if you are nursed by and you have the influence of melatonin coming in through breast milk, that may facilitate that even more for an extended period of time. What's really interesting is if you look at the citation that I have, even pre birth, what we see is that maternal melatonin supplementation has been shown to shape the gut microbiota in early life in offspring. So that is very, very new work that just came out in May of 2023. But it's just interesting to me how maternal melatonin can actually give an imprint of the gut microbiome to the newborn and then further on with breast milk, if that should be the choice. So early childhood, you know, we see that peak and as a child goes through puberty, we start to see that, that melatonin declines. I just had somebody emailed me this morning asking me about her seven year old, who she gives Melatonin to. She was saying that he doesn't seem to sleep otherwise. And you know, my response back to her is, you know, that would not be my first line of approach if a child is not sleeping well at all. You know, there could be so many other things that we need to be looking at under the hood before giving melatonin, because melatonin should be high. This is one of those areas of where I do not see kind of that first line approach for using melatonin supplements and especially looking at all of the gummies, the chewables, all of the child desirable formats where it could be easy to take more than indicated. Now, if a child has something like adhd or autism, where there is some literature and some clinical support of using melatonin supplements under a clinician's guidance, then that's a different story. But in general, children have very high levels. So going through puberty and as you can see, there's like a. It's like a roller coaster, right? We start to see that melatonin come down and by the time we hit our mid-50s, unfortunately, we're hitting rock bottom. Very similar to things like perimenopause, menopause, post menopause, andropause adrenal pause. So I was on a podcast not too long ago talking with Dr. Dickon Weatherby, and he came up with the term. He said, deanna, it sounds like what you're describing is melatoninopause. And so I said, that's brilliant. I'm going to use that. And he's like, you take it. You know, he just came up with that as we were having the conversation about how we get these pauses, an endocrine pause, later in life. And the same thing happens with melatonin. And sequentially we start to see the increase in chronic disease risks, don't we? Right. It kind of comes up later in life. And I'm not saying that it's because of melatonin that's low or even estrogen, progesterone, testosterone, corticosteroids, but, you know, we need to bring them into the conversation to see how they might play a role, play out in terms of giving us reduced risk of certain of these chronic diseases where hormones could be playing a bigger role. Now, within the day, if we're just thinking of that more or less that 24 hour day, what we see is that there is a certain pattern, a certain pulsed pattern to melatonin. It's kind of funny because melatonin goes by a lot of different names. It goes by the darkness hormone. I've even seen it referred to as the vampire hormone. I don't know. But basically, during the day when it's sunny, your body's not producing melatonin. You're flatlined in melatonin for the most part, but as it starts to get dim, your body starts to produce smaller amounts of melatonin. And then as it becomes darker and darker, you start to produce more and more melatonin. So, yeah, think of melatonin as true tracking with darkness. Think of melatonin coming down when it's bright. So in terms of using light and dark as modulators of your circadian rhythm, it's huge. You know, it doesn't make sense just to go to a supplement or you know, try to override something that is huge in our day to day lifestyle, which is light and darkness. And I think that there are self imposed aspects of where we're bringing in too much light and, and not enough darkness. And we referred to that as darkness deficiency within that publication that we had in the Nutrients Journal. So as you can see here in the peak of darkness and in most literature publications where they've looked at these curves, what we see is that the peak levels of melatonin are between 2 and 4am and then precipitously they start to drop and then by early morning they're almost non existent because now we have cortisol and testosterone coming up with light. Right. So keep that in mind also for testing as we talk about that. So I'm going to give you a lot of tips here as far as what you need in terms of day and night and light and dark. So as we all know, we've got electric lighting and it's interfering with our physiology in large ways, especially within our endocrine system. And in fact I would call light, light pollution the most socially, I would say accepted endocrine disruptor. You know, I know plastics are on the other side, right. Plastics are very detrimental and I definitely see that that is pervasive. And everybody knows that they're bad. Not everybody knows that excessive electric lighting is bad for the endocrine system. They think it's kind of cool. It's like to be on your phone late at night or to be on your computer to work long. This is a huge endocrine disruptor. So our natural rhythm is to have a lot of light during the day and not so light at night. Right. But what we have is actually an inverse relationship with light and dark. So we get more light at night than we should. So this can influence our nocturnal melatonin levels. And that early bright light can also change melatonin at night. So keep in mind that it's not just the darkness that we need for healthy melatonin. It's having that early bright light in the morning, going outside even if it's kind of cloudy. I know, you know, for much of the group at Dutch, you know, and for myself, we live in the Pacific Northwest. Even going outside when it seems that it's kind of rainy and cloudy, stay still, getting that, that full spectrum light, some degree of that is important. So LED and other bulbs can suppress melatonin by over 50%. And I've seen estimates up to 80%. Now, LED bulbs are pervasive. And the reason why they're pervasive is because they're seen as energy saving bulbs. And this is my latest thing. I am so into this because, you know, Washington, I think one of the Washington Post, some other publications were talking about how this is something again, that we need to look at the effects on it, on the animal kingdom, on our physiology. We need to not buy such high intense light bulbs if we can. Right. You know, just if you're buying LED bulbs, making sure that you're buying like the least intense strength that you can. So light is measured in lux, and one lux is equivalent to one candle flame at three feet away. So there was one study that showed that 30 lux at night suppressed endogenous melatonin by greater than 50%. So I want you to become very acquainted with what lux is. There is a great app that you can get. I have it on my own phone and I think a couple of these apps cost a couple of dollars. But basically through an app, you can use the camera on your phone to assess the amount of lux in your space. And I would say to do this test, what is the lux, what is the light concentration within your office space? So even me working with that with a window in front of me changes my retinal response. So that's going to be healthier and mimic more of the natural light response than if I was just facing a wall as an example. Right. I've actually done that test. I've gone outside. You know, typical sunlight during the day is anywhere between 10,000 to 20,000 lux, just to put it in perspective. So I know it's not reasonable that we are going to live by candlelight, but candlelight, red light at night will have less of a suppressive effect on that endogenous melatonin production. So I've got some recommendations here for you on light, because I think that this is where you need to start with patients, for patients who have disrupted rhythms, or there are shift workers, they've got jet lag, or they're just not having a healthy endocrine response for various reasons. So daytime light is recommended as much as possible just to get outside, even for short bursts of light and specifically in the morning. And as I mentioned, trying to work in front of a window with natural light if you're indoors most of the day. So I mentioned that if you're outside in the sun, that's about 10 to 20,000. So I measured for myself and just even with my phone, I'm at about 4500 lux. Just having this window in front of me, if I happen to turn and face the other way, away from the window, I go down to 200 lux. So again, we want to be optimizing lux light as much as we can. Having your patients go into the bedroom and to assess their luxury before they're sleeping to get a sense are my less than 1 lux. We want to be less than 1 lux, if possible, in our sleeping space. So that will help to foster more of that endogenous melatonin production. Right. So evening light recommendations, I have them listed here for three hours before bed. As you come into that dim light, melatonin onset, you want to naturally bring down the light and have that light be minimally blue. So, so you can use dimmers, you can use warmer hue bulbs. Like, you know, I even have some bulbs at my home where it's more of a reddish hue. So it's not to say that the red hue helps per se, because it's red, but it's just not bringing in the blue. So that's really what you're after. So the nighttime light recommendations, again, you want to be at a maximum of 1 lux, but if you have to get up and go to the bathroom or, you know, there needs to be a night light up to 10 lux if there has to be any kind of activity. So don't forget to use this app and I'm happy to give you some, some recommendations on, on the app that I use and, and perhaps others. All right, so my advocacy for artificial light at night and quelling this, putting a kibosh on it, it is again changing our planetary health. It's changing our endocrine health, not just our melatonin, since so many of the hormones are run by the circadian rhythm. We're changing thyroid hormone, we're changing glucocorticoids, and we're even changing gonadal hormones. So think of this as a broad spectrum endocrine disruptor. Very detrimental. And being that I lecture so much on detoxification, this is going to be my new toxin to talk about. It's light, light pollution. And I hope that all of you will get that message out to your patients, to whoever you teach to as well. Now, the other thing about melatonin is that the response is highly individualized. You know, there's a gender difference, there's an eye color difference. So in general, people with light colored eyes, meaning blue, green, or even light brown, are going to be more susceptible to the suppressive effects of blue light at night. So they, their eyes are going to be more primed to picking up that light signal at night. So these are the type of patients that you have to be even more, I would say, you know, giving them recommendations, giving them guidance, and really emphasizing the importance of shutting down light, whether having some kind of filter on their computer, dimming lights at home, they are going to be most susceptible to the effects of blue light. Now, on the flip side, I just want to maybe not sound so, so downer on light colored eyes, because those with light colored eyes are also less prone to seasonal affective disorder, which is also connected to light exposure. So light colored eyes could work well during certain times of the year, but we need to take precaution at other times of the year. And, you know, it's very similar to even vitamin D. And depending on our skin color, we need to make more effort to get more vitamin D from the sun. So speaking of vitamin D, I mentioned that, you know, if we think of our lack of darkness because we have so much artificial light, I would almost call it even an artificial light toxicity, as, you know, putting it side by side with a darkness deficiency. So as we were writing this article, seeing that there were some similarities here between vitamin D and melatonin, now if you want to actually figure out whether or not your patients have a darkness deficiency and have that a little bit more codified and actually quantified, together with our medical team, we did put together a questionnaire that you're free to use. So this is something where it could give your patients an aha as to, oh my goodness, you know, I'm scoring pretty high in my darkness deficiency scale here. So that is something that we have put together based on what we were reading in the literature and what we knew to be true clinically. So with melatonin and vitamin D, with vitamin D connected to the sun, you know, there's been so much about ensuring that we have proper amounts of sun, sunlight, especially during the pandemic, and also seeing that melatonin is a counterpart to that. Right? Making sure that we have adequate darkness, that these two together and others, other nutrients, other signaling agents in the body are connected into what I refer to as a circadian system. It's not just a circadian rhythm, it's a circadian system. So this includes all of the genes, the output of those genes and vitamin D and melatonin to me seem very much like brother and sister in this orchestration. So within the paper, we put together this table of comparing vitamin D and Melatonin, I'm not going to take you through it. I think that there are enough similarities here. You'll see that if you kind of go through and look at that. The only feature I do want to call out, though, is that vitamin D is considered to act as a hormone. We do have receptors for vitamin D, Right. So again, that makes it a little bit more hormone, like, just like vitamin A is also keyed into receptors. I think that if we were to go back into nutritional science and start to dismantle and define things a little bit differently based on what we know in the 21st century, we might see that many different, what we call vitamins are actually hormones or at least flex to being a hormone. And many of what we consider to be hormones might actually have other functions. And I saw that specifically with melatonin. In terms of interesting research on vitamin D, melatonin in sleep, there was this article that just came out in March 2023, 79 women, they took blood samples to measure vitamin D and melatonin. They also gave these participants a sleep questionnaire. And what they showed. Now, again, this is an association, not causal, but I think it's still relevant to think about by way of our conversation between vitamin D and melatonin, what the researchers found was that a majority of the women were either vitamin D deficient or insufficient. Really no surprise for all of us, probably on this call. Right. But what I found surprising was that higher melatonin levels were associated with reduced risk for vitamin D deficiency. So just think of how many patients you have with vitamin D deficiency and looking at kind of that seesaw of, well, how was their melatonin level then? And how is their exposure to light as well as darkness? Again, it's kind of that yin yang. There was also a positive correlation between serum melatonin and 25 hydroxy vitamin D3. So I think it's kind of interesting to see these two. And I also toss magnesium into the mix because I don't want to leave magnesium out. We know that magnesium is required for hydroxylase activity, and the two hydroxylations of vitamin D through the liver and then the kidney are actually what make it active. And magnesium, as we know, is helpful for sleep as well. Right. It's pivotal for so many different reactions. But I do see it being connected into melatonin and vitamin D. So in my mind, melatonin is the ultimate multitasker. We see it's doing a lot of different things here. It's not exclusively a hormone. And I'm going to whip through some of these functions. Just so you have, in kind of the broad sense, all of the many functions that melatonin is being considered to act and do within our bodies. So the first one that many people aren't aware of is that it is an antioxidant that is both fat soluble and water soluble. And it's pretty potent. It's very interesting because when, when melatonin gets metabolized in the body through the liver, through hydroxylation, and then eventually through sulfation and and other processes, what we see is that even the metabolites act as antioxidants. So I think that that's very interesting. So one molecule of melatonin and its metabolites can scavenge up to 10 free radicals of different types. Now, if you compare that to vitamin C, it can scavenge Something like 1 to 2. So vitamin C is water soluble, so it has some limitations. Still very important for a number of different reactions in the body. Though it's twice as effective as vitamin E, it's five times more potent than glutathione at neutralizing hydroxyl radicals, which feels kind of strange to say because we know that glutathione is already so potent as an antioxidant. So that's what makes melatonin unique, is that it is amphiphilic. It likes fat, it likes water, so it crosses the blood brain barrier, it's found in the blood, it basically does not have a lot of limitation and it can lead to the production of more antioxidants like glutathione that has been shown in different animal studies. Superoxide dismutase, glutathione peroxidase and glutathione reductase are all antioxidant enzymes that are stimulated by melatonin. Now, the other thing to consider here is that, and perhaps correct me if I'm wrong, but melatonin seems to also be unique in the fact that it's the only hormone that can flex to being an antioxidant in this way. I'm not aware of other hormones having this amphiphilic antioxidant activity. So again, you know, how do we define a substance in the body? You know, I think hormone just feels like it's a set category, whereas with melatonin, that category feels like it's a little bit more permeable, like it's actually many different things. We know that at nighttime, this is when the pineal gland derived melatonin is highest. I mentioned 2 to 4am and we also see that a lot of these different enzymes are also high during that time. So rather than go through that the bullets, I'm just going to show you that this is where a number of these different compounds were measured. And you can see the reference at the bottom looking at the influence of circadian rhythm on the activity of all of these different enzymes. And the 2am mark is the one that is the highest for all of them. So truly we have this army that is in the mode of rest and rejuvenate, trying to repair our bodies as we are sleeping. So I like to think of adrenaline, cortisol and even testosterone as the get up and go hormones right early in the morning we have them for stress response. But melatonin is more of the rest and rejuvenate type of hormone as you can see here, especially during the nighttime. So I'm married to an acupuncturist and we have these east west conversations all the time. And so and even when I'm presenting and talking about melatonin in that 2 to 4am window, some of my traditional Chinese medicine type of friends and colleagues will say oh well that's the time of the liver and and it also happens to be the time of the lungs as you can see here. So and again, remember what I mentioned about these clock genes that seem to be oscillating particularly in the liver at the times of dawn and dusk. So there's a lot of activity there. So the second one is that it's an anti inflammatory. I'm going to share with you some of the comparison cell work between a plant melatonin and synthetic melatonin. And this is why I believe we saw a lot about melatonin during the pandemic. There were references looking at Covid, now even looking at long haul Covid. So I do think it's interesting from its anti inflammatory perspective. The one that I find also pretty intriguing is that melatonin acts as a neuroprotective, it even has some features as a nerve growth factor. So there's some emerging work looking at the literature there. So here you can basically go into this article and see all of its many different types of effects and how it's acting as this neurotropic agent. So I do think it's very protective in a number of ways within the brain and within the central nervous system. And in fact again some of the more emerging work would suggest that it helps to reduce the permeability of the brain. So the blood brain barrier is even More in integrity with the actions of melatonin. Now that has been shown in cell studies and in animal studies. And again, there is a whole mechanism for why this happens through helping with expression of a certain protein that tends to tear down that barrier. The other part that I find very intriguing, and again, this is not set in stone, but still, still emerging and very interesting is that of the glymphatic fluid. So as we know when we sleep, there is this exchange and transport of toxic metabolites out of the brain into the glymphatic fluid and ultimately through the lymphatic fluid. So this is where the cerebral spinal fluid and the interstitial fluid come together. So it's very active by the arteries and by the veins. So we need these portals in order to release things like hyperphosphorylated tau proteins, even toxic amyloid beta compounds. And we know that those are the two hallmarks of Alzheimer's disease. Well, what we see is that melatonin may actually be an important molecule for that process. There was an interesting article that was titled Brief Brainwashing that was connecting melatonin through this whole process. And also just talking in general about the glymphatic fluid. I'm not going to belabor this too much. You will have this slide, of course, but you can see that when we sleep at night, there are some changes in the dynamics of the brain matter versus the vascular tissues within the brain. And this is also happening by the way, through the eye. So really important again to have that connection between eye, brain at night, making sure that the eyes are in complete darkness. So what we see is that when there is inflammation in the brain, and potentially I would say also probably in the eye because of this whole glymphatic flux, what we see is that there can be constraints on what is actually released from the brain. So in states of chronic neuroinflammation, we can see less of those toxic amyloid compounds as well as any other kinds of proteins or other types of waste products that need to get out, that actually can't because of the cytokines and different immune cells that may be impeding that process. And again, enter in melatonin, which is anti inflammatory and seems to be playing a role in that glymphatic fluid flux. And that could be because of its amphiphilic nature. Right? It's fat soluble and water soluble. So very quickly on this one, number four, liquid, liquid phase separation. You may have heard of phase separation. I'm just going to shortcut this for you, because it's a lot of cell biology. But basically there's some investigation about using melatonin to reduce the setup of viruses within the cell. So what viruses tend to do is they set up in their own way, in kind of their self aggregating way, kind of a factory within the cell and they start to make proteins. And that can also happen with amyloid or any number of different types of proteins as well, not just limited to viruses. So what it seems as though we're seeing with melatonin that there can be a connection here between the mitochondria, the cell biology dynamics as it relates to viral replication and preventing the aggregation of certain of these compounds that we don't want to just self aggregate and take over a cell. There's too much here to go into. But I find it very interesting to look at this combination of exposure to red light, changing the viscosity within the cell and then melatonin coming in and again preventing the buildup of a lot of toxic proteins. So that's again more mechanistic. But I think that if you can think in terms of mechanism, you can understand how to apply this clinically. Number five, chronobiotic. This is how most people think of melatonin. It's a chronobiotic, meaning that it sets the circadian rhythm. And in higher doses it can be a sedative or a hypnotic. So it can influence the phase and or the period of the circadian clock. It can help you to be a morning person when you are a night person. Right. You can actually entrain your circadian rhythm a bit differently. Can also be helpful in blindness, shift work, jet lag. It can also help with lowering core body temperature. So think of here, you know, just even bringing in some melatonin to perimenopausal women who are having night sweats. So indeed it can be used to advance or delay the sleep phase. We're not going to get into that in this particular webinar, but there are all kinds of protocols to do that. And I have a slide after this one which really speaks to just some basic principles there. All right, so if we want to set the circadian clock earlier or advance our phase response as it relates to the circadian rhythm, taking melatonin supplementally two to four hours before the dim light melatonin onset. So that might be, you know, if you go to bed at like 9 or 10, that might be taking it at like 3pm, taking a lower dose, and then for phase delay, setting the circadian circadian clock later, taking melatonin earlier during the day, and a higher dose if it can be tolerated, and it doesn't give that kind of sleepy effect. In fact, I would say that the only side effect of taking melatonin is sleepiness. Right. That soporific effect of just kind of having, you know, kind of the relaxed feeling, but it can also become more sleepy. So. So that's why we don't want melatonin in high amounts during the day. Right. And then finally as a mitochondrial regulator in helping with things like autophagy, mitophagy, the mitochondria are key in this. And in fact, I'm talking at Dr. Terry Wahls summit, talking about some of the newer work, even within multiple sclerosis and certain types of autoimmune conditions. So by way of talking about circadian rhythm and also the mitochondria and even metabolism, I'm not going to go into blood glucose, but we also see some connection there. It seems that melatonin supplementation may be helpful with modulating body weight. And even when there are perturbations and metabolism because of disruptions to the, the circadian rhythm, that melatonin can be useful to help in resetting that. All right, spectrum of uses. They are wide, they are vast for melatonin. All of this is in the paper that we wrote. Right. So the biggest, I think, is the central nervous system. The second biggest, in my opinion, is the immune system. But there's a lot of granularity here. Cardiovascular system, reproductive system is getting some newer work looking at the use of melatonin, the gastrointestinal system, which makes sense, and even things like bone health, looking at osteopenia, looking at osteoporosis, that type of work is coming to the forefront. So I guess the question is we. And Noah did say I could just go till I finish here. So I'm going to go over a bit, so if you can stay on, that would be great. I'm not going to go over too much longer, but I just want to cover off on foods and supplements and leave you with some final summary points here. So, in terms of food sources of melatonin, I love plants. I advocate eating phytonutrients. I would consider melatonin to be a phytonutrient. You can find melatonin throughout the plant food kingdom and typically within the reproductive portion of plants. So seeds, nuts and fruits is typically where you're going to find melatonin. However, the amounts that you find within of these different foods Even some of the ones that we would consider to be on the higher side are still in nanograms or picograms per gram of food. So you'd have to have a lot of these foods. And actually, I took on the challenge of just finding articles where they actually assess the amount of melatonin in different plants and in different foods. I took that amount and many times there was a lot of range. Right. Because a plant isn't always predictable in its environment. So taking that range, looking at the calculation of even a physiological dose of melatonin, which is 0.3 milligrams, and what you can see here, I did the math and I had other people check my math, and they basically what we're looking at here is that it would take a lot of different foods in order to get to even a replenishment dose of melatonin during our aging years. Right. So back to that. When that roller coaster slide down, you know, when those levels start to plummet, if we can just even bring them up a little bit, that's all we're looking at here. We're not even looking at higher doses, like 3 milligrams. So it would take a lot. And with the advocacy to not have so much food before bedtime to help with circadian rhythm and, you know, having that more primed within our, our day and night rhythm, it doesn't seem to be advocated to be having a lot of those foods so late. So, yes, you can make melatonin from tryptophan. Tryptophan is an aromatic amino acid. The thing about going from tryptophan to serotonin to melatonin is that it requires a lot of small steps. It's not to say you can't do it, and that's how the pineal gland actually does make that conversion. But what ends up happening here is that you do need a number of cofactors, different nutrient cofactors to run that pathway through. And many people are deficient in a lot of those co factors. So I just want to briefly mention the kyurenin pathway. Many of you may think of the kynurenin pathway way when you think of tryptophan. Most of tryptophan goes through this pathway. And this is one of the pathways that our body uses to produce energy to produce nad. So out of this pathway, you know, if you think of most of tryptophan is going through this, only 5% of tryptophan is being shunted to serotonin and melatonin. So just put that in perspective for a second because if somebody is highly stressed or has energy needs, they're going to be running through this pathway and put a lot of demand on it. So the conversion again could be stunted or halted by an excessive use of this pathway. And this pathway too is also implicated in so many different things. Like we can see that in depression kind of running levels in the brain tend to be high. We can start to see that the overload of some of the metabolites can be neurotoxic. So Dr. Rhonda Patrick actually did a nice video about how exercise increases the throughput to the serotonin melatonin pathway and thereby modulating things like mood and cognition. So there are ways to override this, this kinaren pathway, right? Giving the body more energy precursors, getting a handle on stress, and by way of helping stress, you know, bringing in more physical activity. All right, so the supplement aspects, you know, I think that there's a lot here. I'm going to highlight what I think is most important because again you're, you will have the slides, the. I'm not a huge fan of the chewables and the gummies because, you know, it's a liquid matrix, right? It's a hydroc matrix. There can be a lot of interactions there, a lot of stability issues. I don't like the idea of people getting sugar and a number of other ingredients with melatonin, but they are very popular right now. I know that people have pill fatigue. The thing about melatonin, if it is to be taken supplementally, is that it can be a very small capsule and it can be taken just at bedtime. It's like a once a day supplement. This is not like three times a day, this is once a day. So it gets easier in terms of starting with a supplement. You know, so many papers say this, so many opinion leader organizations say this, and so many clinicians say this, going with the lowest dose for the shortest duration. So pretty similar to many other types of hormones, if a person is taking too high of a dose, they can start to see changes in their dreams, their headaches, they may get groggy, they may feel more sleepy. And I want you to keep in mind too that there are personalized kinetics for melatonin. So it goes through cytochrome one, a two, so that's how it's hydroxylated. And then typically it's sulfated. Right? So that's why with the Dutch test, we're looking at that 6 hydroxy melatonin sulfate. So if somebody metabolizes very quickly through their cytochrome one, a two, they're going to have lower amounts, they're going to exhaust their melatonin quicker, faster. Right. And the half life of melatonin is pretty short at, you know, a rough 40 to 60 minutes. Again, this varies depending on the individual. So it's all about finding the right dose for the right person at the right time. Some people need to take it a little bit closer to bedtime. Some people need to take it a little bit further away from bedtime. Okay, so again, more is not always better. We need the Goldilocks principle here, precautionary principle. Physiologic dose is something on the order of 0.3 to 1 milligram. And there are, there are cases where higher doses can be used. And I do have a slide that says, summarizes some of the research on those doses. So I'll, I'll show you those and I, this is a, an article looking at older adults. And that's what I'm thinking about is when we get into that melatoninopause, how can we actually bring up the dose levels? So bringing in that lowest possible dose and starting there, so just an immediate release formulation, having that and starting to see how does that affect sleep. And just the traditional use is about an hour before bedtime. So that's a good starting place. And I have here a number of the clinical indications, the goals, different dosing strategies. So I'm giving you all of that as you will have that in the slides. And then this gets more into the nuance of therapeutic conditions. So now we're looking at, okay, what do you do with a number of these? And you can see that there are, there's a wide range here and variety of different references. Excuse me. So this is a reflection of Dr. Kim Ross's work. She put this together and also put together a number of the different references that would support these different dose ranges. So you have that. I think the other question that commonly comes up is can you take melatonin long term? And so I would say to that, that of course you need to constantly be assessing a patient's needs. Right. But overall, oral melatonin is considered to be safe. There are more than 40 studies on the use of melatonin in different health conditions showing the safety of up to 8 to 10 milligrams for six months to two years. That's basically what you're going to find if you go to natural products database. You know, we start to see adverse events when the dose starts to get high into the double digits over an extended period of time. Although in some cases you don't even see toxic effects there. You just can see some, some changes like again, being sleepy or seeing changes in sleep patterns. So in general, you know, some of the therapeutic value, the extrapolations from studies have been primarily through these animal studies. I do think that we need to look at if we're going to take higher doses, we need to do studies on those higher doses. And we don't have a lot of those studies in place at this time. So I'm just being honest in terms of the literature and what's available and considered to be safe, we don't have research to support higher doses and also higher doses for an extended period of time. A lot of those are just based on more animal studies. The other question that comes up a lot is does taking melatonin result in decreased production in the body? And the short answer is based on what we see in prospective trials to actually address that question. We do not see, see that that is the case that there is no change in endogenous production. And especially if we're thinking about later in life when we've already bottomed out on endogenous melatonin production, there's not really that risk for thinking about blunting any kind of endogenous production. So that is something to consider there. As far as supplemental sources, I also think we need to be aware of different topics terms. I've been in the dietary supplement industry for a long time and so there are different terms that are tossed around. Also the bioavailability can be different depending on the format. So in females it's double that of males. So that's kind of an interesting statistic there. So from the pineal gland derived melatonin, what happened was because those sources weren't considered to be priority practical nor safe, what ended up happening was that melatonin became chemically processed and in fact 99% of melatonin supplements are now synthetically made. So even if you see on a label plant based melatonin, that can mean that it was derived from a plant source like corn or soy, but then subsequently went on to use a more synthetic mechanism. Since I've been talking about melatonin, I've also learned about and have people come to me wanting to talk about bioengineered forms of melatonin from microorganisms. So those are also on the horizon from a detoxification perspective. I have concerns about some of these synthesized melatonin there's an article that suggests that there have been up to 13 different contaminants that have been identified in synthetically produced melatonin. And one of them happens to be serotonin. So for people with serotonin syndrome or sensitivity and having this unknowingly in their melatonin type of supplement, and you know, sometimes when people say that, oh, you know, it had a melatonin had a paradoxical effect for me, I often think, well, is it the melatonin or is it something, something else that's in that melatonin supplement? I don't know the answer to that, but it does lead me to ask a lot of those questions. So there is a plant melatonin. It has been researched and studied against synthetic melatonin. It's a green plant material and it's in a small capsule and it's made from rice, alfalfa and chlorella. And it was tested and there was a publication, as you can see at the bottom here in molecules 2021, in which the researchers, and they were out of Poland, where they did a number of cell assays looking at antioxidant potential, looking at anti radical activity, cellular health and anti inflammatory activity, finding that the phytomelatonin outperformed the synthetic melatonin in every case. So just very quickly to flip through these, the blue bar is the, the plant melatonin. The other bar here is the synthetic melatonin. This shows greater anti inflammatory activity. This shows greater free radical scavenging compared to three synthetic melatonin samples. This shows improved reactive oxygen species levels in a, in a, this was specifically a skin scale line. So you can see the blue bars were the plant melatonin. So lowered reactive oxygen species. That's the first bar here compared to synthetic melatonin and also higher orac value with the plant melatonin. So all in all, plant melatonin is a safe, efficacious form of melatonin. And what I really like about it is that the way that the plants are grown, it's using xenohormesis in order to optimize naturally those melatonin levels within the plant. No excipients, no fillers or binding agents, and no contaminants. So whoever you buy melatonin from, you need to be asking about whether or not they're assessing melatonin for toxicants in terms of laboratory testing. I don't feel like I'm expert expert here. I know that the folks at Dutch are, but in general, when you're measuring Urine, which I know that the dust Dutch test features, what you're looking at is basically a marker of metabolism of melatonin, right? You're looking at the morning sample, morning urine, looking at how that person produce melatonin and metabolize it and excreted it. So it is on a, on the various lab reports and separately from or in conjunction with lab testing, if that is your choice. There can be other indicators. I'm not going to belabor these because they're all right here for you. But this is an extensive list of all of the many indicators suggesting that endogenous melatonin may be imbalanced or insufficient. So there are a number here, a number of food, dietary aspects, even exercising and different activities, home environment. Again, don't forget about light. How do we sleep? What about those LED bulbs? Are we using a light meter type app in order to assess the lux of where we're sleeping? And in terms of contraindications, I don't think that everybody should be taking melatonin supplements. There are certain contraindications. I mentioned children already in certain cases of autoimmune conditions. Because melatonin can stimulate the immune system, there has to be guidance in using any kind of supplemental melatonin with any kind of immunomodulatory type of conditions or immuno, I would say compromised conditions as well. So that needs to be looked at. So whenever there's a use of any of these types of pharmaceuticals that are listed here, or even nutraceuticals that would have those kinds of effects, there needs to be some type of oversight because there can be interactions, there can be potentiation and changes in metabolism of those drugs. So I'm not going to go through this. This is just for you, some clinical considerations. I'd like you at your leisure to really go through these though, in terms of thinking about genes, what are triggers? You know, I think in functional medicine terms. So I'm thinking through the matrix. I'm thinking of antecedents, triggers, mediators. I'm thinking of the nodes of the matrix. How do I put it all together? So consider this more of like the functional medicine type of considerations with melatonin. And how do you personalize it? Lifestyle factors as well. Don't forget to focus on light and dark, but then also physical activity. Nutrition plays a big role as well. And just looking at the overall, I would say the endocrine web and even stress, full moons can also change melatonin levels. And this is irrespective of the increase in moonlight so this study was done in a sleep lab where they controlled for light, they controlled for the menstrual cycle. And, and I tried as best I could to recreate the graph in their study. But basically you can see that before and after a full moon is when melatonin is most suppressed. That's just natural, endogenously produced melatonin. So that's kind of interesting. Right? So you might even want to think about primed times of the month in certain people to be having melatonin if they don't normally have melatonin, especially if you see disruptions in sleep or circadian rhythm. So I'm going to leave you with this. This is the, the infographic that is also in the paper. These are my, my mantras. Right? Get your light right and get your, your darkness correct. Those are really important. You got to start there. Protein and plants are really important. And then up at the tippy top bringing in any kind of supplemental melatonin sources. And again, plant melatonin I think is, is safe and efficacious. And I just wanted to, you know, I know I'm well over, so apologies for that. But I just want to leave you with this about even the spirituality of melatonin. It's so fascinating to me. The more you research something, the more you find out with respect to all of its many layers. And if we think of the pineal gland as the seed of the soul, which it has been coined by the mathematician Rene Descartes. Right. Well, as you start to go into the literature, and I posted some of this on my social media because I'm so enamored with this, how tryptophan and serotonin are seen as these compounds related to conscious activity, like brain activity, plasticity, even the transfer of biophotons in the brain. And there are some indications that serum levels of melatonin and serotonin are higher in people who meditate versus those who don't meditate. So I just think that there's something really beautiful about not just the science but also the spirituality of melatonin. So I'll let you have your own summary here. There have been a lot of different things. There is a non commercial research website if you do want information on like the latest studies or the latest news blips and kind of like a balanced take on that. So I want to thank you all. Thank you for staying over. Thank you, Dutch team. Thank you for listening in. It's been a pleasure talking with you about melatonin.

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Bye bye.