Transcription
So, with melatonin, it's common knowledge for most people that you might have a little bit of a dependency that builds up on it. You take it and eventually you have to keep taking it because you'll just need it all the time. But it seems like that's not always the case. How exactly does melatonin work? Is it something that we should be concerned about building a tolerance or?
Yeah, I mean, I think there's a lot of misinformation in melatonin out there. Uh, and I've never seen any data to indicate that there's any physical dependence uh on melatonin uh that I'm aware of. So, there maybe people can point me to the literature, but uh I haven't dug into the literature in a while, but my understanding, I've been studying taking melatonin, studying it for almost 30 years now, so and published some research on melatonin as a neuroprotective uh agent that could be used under specific contexts. So, melatonin uh has remarkable neuroprotective effects that have been well established. Uh, small molecule, crosses the blood-brain barrier. Highly effective antioxidant, uh, has anti-cancer effects. It has uh effects that could be could carry over to Alzheimer's prevention and cancer prevention and even uh perhaps prevention of age-related chronic diseases in general.
So, I have been using melatonin for quite some time and uh continuously every day. And uh occasionally, I will not use it. And what I found that when I was on a vacation recently, and this has happened previously, but not too often. I'm pretty much taking melatonin every day for like 30 years. Uh, I forgot the melatonin and I slept like a baby, and I didn't, it didn't have any counter-regulatory effects uh of not taking it. So, there was no withdrawal, no dependency from it. So, I became curious uh because this happened in the past. So, I did blood work uh to figure out what my melatonin levels were if I did take it at nighttime. And the next morning, my levels were off the charts of melatonin, my blood levels. And I did um, did I do saliva? No, I did blood levels of melatonin. I used uh two different tests for that. So, I became concerned that this supra-physiological level of melatonin, which is actually a hormone, could be potentially suppressing my own melatonin production, although I didn't really notice anything when I didn't, didn't take it. Um, and so what I did is uh I got off melatonin and then I measured melatonin after being off of it for some time. And just come to by now, uh, I produced normal healthy levels of melatonin after taking it for decades. And this convinced me. This actually sent me down the rabbit hole just looking at melatonin's uh, cuz there's some discussion about melatonin being a hormone that it could suppress the hypothalamic-pituitary axis, suppress uh hormone levels, suppress your luteinizing hormone, FSH, and things like that. So, uh, these are things that I had measured anyway. So, I measured them uh, you know, and they were normal uh at healthy, you know, normal good levels of. And there was no change when I stopped melatonin, no change in my sleep. Uh, the only thing that changed when I stopped me uh taking melatonin is that my sleep latency was uh, it took me a little bit longer to fall asleep.
So, the benefits of taking melatonin are for the neuroprotective effects, the antioxidant effects, anti-inflammatory effects. So, that's why I take melatonin. Uh, an additional benefit to taking melatonin, which I take 5 mg of a chewable form that I chew and hold underneath my tongue, and I start to feel sleepy within about 15 to 20 minutes. I start feeling the effects. So, I generally do it, you know, as I'm winding down, my winding down protocol, and my sleep latency uh has decreased. So, uh, and then my sleep is always like really good. That I get, you know, lots of deep sleep, lots of REM sleep. And which I get good deep sleep and REM sleep without melatonin. The only uh thing it impacts in regard to sleep is the uh, I fall asleep faster. And it has essentially no impact on my hormone levels, luteinizing hormone, testosterone, uh, FSH, those things were were completely normal. And to my knowledge, there's no data out there that would suggest even though it is a hormone, that it would suppress your own melatonin production or in any way have negative effects. Uh, however, that is not the case for certain animals. Hibernating animals, uh, higher doses, I think can suppress uh hormone production. You know, it's not something that I would want to give to a child uh in development. Uh, these are things because they're growing and they're much more sensitive to hormones and the developmental consequences of altering hormone production. Uh, so I, I assume maybe some people may want to give it to their kids if you're not sleeping or something. I would not do that. But uh, for adults, I think melatonin is safe. It's effective and it's a remarkably diverse uh antioxidant that has a wide range of benefits that could help potentially prevent age-related chronic diseases and maybe even cancer has some anti-cancer effects that we're interested in studying.
>> How does it have an impact on anti-inflammatory pathways? Do you know mechanistically what it's what it's doing there? It's kind of interesting that this, you know, quote unquote like sleep hormone is so anti-inflammatory. No matter what kind of diet style you're doing, especially if you're doing something more low carb, you definitely want to focus on electrolytes and your mineralization. So, I put a link down below for a free sample variety pack of Element Electrolytes. That gets you their main key flavors that you get for free with any purchase. So, that way you can give that to a friend, you can hoard it for yourself or whatever. They also have these really cool ready to drink sparkling drinks which are really good. It's a like a replacement for soda. So, if you're just looking for something that's going to be low or zero calorie, but still gives you like that taste of a soda while also giving you 1,000 milligrams of sodium, 200 milligrams potassium, and 60 milligrams of magnesium. So, again, I popped that link. It's in the top line of the description underneath this video.
>> Yeah. Well, I think primarily just through uh inflammation is largely driven by uh oxidative stress and oxidative stress is coming from a reactive oxygen species or what? Free radicals, another name for that. And melatonin is a pretty remarkable uh small molecule antioxidant that can cross the blood-brain barrier and has uh significant, you know, tissue suppression of. In our lab, we, I measured the using dihydroethidium, I measured superoxide anion production uh that comes from the mitochondria in the brain, specifically in the hippocampus, the CA1 region of the hippocampus, because we're interested in using melatonin to prevent seizures, which it did not. It had a small effect, but it wasn't um, and that actually, there's there's some indication that oxygen toxicity is triggered by the the the burst of reactive oxygen species in the context of high levels of oxygen. So, this is something that I studied and melatonin seemed to work at suppressing the reactive oxygen species, but it didn't prevent the seizures. So, what we find is that it's it's much more than a burst in reactive oxygen species. But the important thing that we discovered is that melatonin can get to the brain and it has remarkable ability to suppress superoxide anion, which it then becomes can be uh through superoxide dismutase goes to uh hydrogen peroxide, and through catalase can be broken down to water. But uh, it can also in various situations, superoxide can become a more reactive intermediate, including the hydroxyl radical, especially in the context of like high iron or uh, you can drive the Fenton reaction, you get a lot of nasty oxidative stress of of proteins, lipids, membranes, and DNA. And and in that context, in certain contexts, it can be uh superoxide can be very bad. And super and melatonin has the ability to significantly attenuate that. And there are many age-related chronic diseases, uh, inflammatory diseases, and many disease states where essentially that the main driver of the oxidative stress is the overproduction of superoxide anion, which actually comes from the mitochondria. So, taking a step back, mitochondrial dysfunction causes excess uh oxidative stress, and melatonin is very effective at reducing oxidative stress for two reasons. It can uh, there's different ways that it can enhance mitochondrial uh function, but also it can basically sequester and and reduce superoxide anion that's coming from the mitochondria and maybe even um, and other pathways that can develop uh superoxide. So, this I've been very interested in this molecule. It it has uh a very, you know, it's not a subtle effect. It it has a pretty remarkable effect, but there are other things that maybe work better uh as an antioxidant, but there are very few things that are as versatile that your body makes anyway, and that has the added benefit of uh, you know, helping you fall asleep faster. So, uh, and it and it's cheap, it's readily available, and people can access it. However, I think you want to get third-party tested melatonin because
>> There's a lot of melatonin out there and the dosages in many of the supplements are not, you know, what's on the bottle. So, you have to go. I I went with uh, I think Natural is one of the brands
>> That I buy and that's kind of a staple brand and I think someone there was they third-party tested that and I can tell you it's it's legit because when you take the chewable form
>> Yeah.
>> Yeah. You you feel it.
>> What's a How many milligrams does it take to fully saturate your receptors? Doesn't take that much, does it?
>> Yeah, that's a good question. I think uh, you know, probably one 35 milligram amounts are sold. I think these things are saturating the receptors and uh, I was contacted by numerous patients. Some of them were taking 3,000, 5,000 milligrams per day. So, they're buying the powder and basically taking like, you know, a quarter of a teaspoon of just pure melatonin. And and when they told me this and then I was like, you know, communicated with them, I was like, wow, this is really interesting. Well, how do you feel when you take that? And I was like, I just feel like I have less anxiety. I feel good. I feel great. So, uh, they were taking it through for cancer therapy, through, uh, preventing uh, chemobrain and and protecting the brain from, you know, chemotherapy and and other and but they had no negative effects by taking massive supra-physiological doses of melatonin. And uh, as far as I know, everything else in their blood work was was fine. And this is pretty standard. I'm sure there's Reddit groups that are out there, you know, using melatonin. And I don't think it's maybe something remarkably effective as an anti-cancer, but there's quite a few um papers out there suggesting the anti-cancer effects. And also people, uh, melatonin may have a preventative uh benefit when it's taken especially for breast cancer and some other things. But uh, people are interested in studying melatonin as something that can be used alongside a standard of care. So, one way to reduce uh side effects and maybe, you know, just promote healthier. However, in the in the context of chemotherapy, chemotherapy and radiation kill cancer cells through an oxidative stress mechanism. So, my recommendation to cancer patients is actually to be cautious with the use of melatonin because if you are doing standard of care chemo radiation, uh, you could be maybe effectively, you know, blocking some of the effects of the the cancer-killing effects of radiation. Just something to consider. But, you know, just taking a step back, uh, I, I think microgram amounts would be physiological and maybe that would have, you know, a sleep-inducing effects. But I, but I think when it comes to the neurological benefits, the anti-inflammatory effects, the neuroprotective effects, uh, I think you're better off taking milligram amounts, you know, one to, you know, five milligrams upwards of that. I've been taking it for three decades and no no apparent side effects that I've witnessed in my blood work or otherwise.
Do you think uh like above any amount above saturating the receptors does that get used still as an antioxidant or is it you're only going to use as an antioxidant what hits the receptor?
No, I think, you know, uh, microgram amounts will hit the receptor and produce effects related to, you know, maybe mild sedation and sleep-inducing effects because that's its sort of evolutionary, you know, role. And then any spillover from that is in circulation, and then that has the ability to cross biological membranes, incorporated into membranes, and and protect the membrane from membrane lipid peroxidation, which we measured in the lab, uh, in something called, uh, we measured membrane lipid peroxidation with the T-bars test. So, it measured membrane, you know, oxidized membranes and oxidized lipids. So, it's very effective at mitigating that. So,
>> Too many seed oils popping melatonin.
>> Yeah. Yeah. Absolutely. So, uh, has the ability to get incorporated into membranes and be uh, protect against not only superoxide, but other like peroxynitrite and other uh, other reactive species that could spawn from the precursor free radical, which is superoxide, in addition. Yeah. And also incorporating into biological membranes to prevent uh, membrane lipid peroxidation.
>> What's your take on, you know, just quick thing, combining with melatonin with something like honokiol or have you heard of honokiol before?
Oh, never mind. What is it? It's um
>> I like to learn things.
>> Yeah. No, honokiol is Dang, I'm trying to blank on uh. It's funny that I know the actual like the fancy term for it, but it's Oh, magnolia bark. So, um, so no, honokiol is is magnolia bark and it's uh, I mean, it's a very potent GABAergic compound, right? So, it's like, cuz I take one. It's like a half a milligram of melatonin, honokiol, and nicotinyl GABA. So, B3 GABA. Yeah. um, which evidently helps it get through the brain-blood barrier a little bit more.
>> So, um, what's your take on just GABAergic compounds to induce sleep?
>> Yeah. Um, well, I'm familiar with the efficacy of GABAergic compounds for sleep because I teach on this subject, right? I teach uh pharmacology. Uh, there is a potential problem. I think the go-to GABAergic compounds that we're maybe familiar with, I mean, God, they were used in the 60s and 70s, overprescribed are the benzodiazepines,
>> Which they do have a nice sleep-producing effect.
>> But the withdrawal dependency is kind of really bad, right? So, I think the benzodiazepines are probably as big as a problem as opioid
>> The problem.
>> Uh, well, with Yeah. And these things are very problematic when you come off. You could have life-threatening withdrawal symptoms. So, I caution people, you know, I I caution people looking for GABAergic. There's GABA, but GABA typically does not cross the blood-brain barrier unless you have a permeability. Uh, and you can get some weird kind of flushings with just pure GABA. Now, phenibut is something that has a phenyl ring on the GABA molecule, and that can cross the blood-brain barrier. And if you're going to use it for sleep, I think, you know, maybe 25 to 50 milligrams, that's not going to produce any kind of major dependency, but I think you want to be cautious with you using it in that context, you know. And I have to mention that ketogenic agents increase the the production of GABA through the conversion of glutamate to GABA. So, GABA levels in the brain and in circulation even will be elevated if you're in a state of ketosis. And that may reflect why, you know, some people report, you know, getting better sleep with GABA. Uh, but there's probably some other compounds, naturally occurring compounds that I'm not aware of. I know there we got Kava, you have uh valerian root and some other things that are out there. I'm not sure they're GABA related, but I think they maybe weakly interact.
>> Kava is is GABA related.
>> Kava. Yeah. Yeah. Yeah. Kava is it can be it can be liver toxic. It can't, you know, especially if you're you're using a lot of it. But, um,
>> My understanding that the Kava liver toxicity was due to the part of the plant.
>> Exactly. How it's extracted. Yeah. There's I mean, I'm not associated with them, but Cameron over at True Kava, I mean, he he educated me on this. He's like, "No, how it's extracted makes all the difference."
>> Um, and it's not just a little difference, but the world of a difference because you can do damage with Kava that's not extracted properly.
>> So, yeah, I in that I think his products are great. He had sent me his products and I'm I'm a fan of them. And there's also uh I think Yogi Tea makes a Kava tea that is like pretty legit. Like I took it and yeah, it definitely has you definitely feel it.
>> I feel calm. I sleep pretty well with it. But I noticed that um and it has a reverse tolerance. So you start needing less and less and less. But I do notice
>> That if I don't if I use it for a couple weeks and then stop, I do notice that like I don't sleep as well. So that is one route that I think it is
>> Very common with GABAergic compounds when you use them, they work great, but the dependency is pretty ubiquitous across.
>> Yeah, that's that's problematic. So, I mean, that's that's something where it's like, okay, I'll use Kava
>> As I don't drink alcohol, so like in a social event, that'll be a one-off where maybe I'll I'll have some Kava. It loosens me up. I feel relaxed. I feel cool. I feel more social. That's that's a time when I would use it. But I didn't, I was for a while using it regularly to help me sleep because my sleep scores were amazing. But then when I stopped and I went on a trip, I'm like, why can't I sleep? So, there's something there. I do think from um
>> I noticed a difference just as someone that trains a lot and works out a lot that
>> Actually simple glutamine supplementation seemed to help make me feel a little more calm and relaxed. And I think I was depleting glutamine just through overtraining or not necessarily overtraining but training a lot.
>> Um, particularly with running, right? Because we've seen that evidence with like endurance work where yeah, glutamine helps that. So maybe it's leaky gut related, maybe it's, but that's something that I've noticed kind of tilts me to that calmer scale.
>> Yeah. Yeah. Uh, and also glycine. So, glycine can be used. You could take glycine in and of itself as just an amino acid upwards of 1, 2, 3 milligrams or 3 grams per day is is safe. And uh, and then there's also magnesium glycinate, which is great. So, you have the calming effect of magnesium in addition, and that's coupled bound to glycine, which is an inhibitory neurotransmitter. It tends to work on the neuromuscular junction. So, inhibitory interneurons, actually. So, I teach the neuromuscular junction to to students, and it has it's a a very unique neurotransmitter at the level of the interneuron on the for muscular contraction. So, it has like actually a relaxing
>> The NMDA receptor that it's
>> Uh, no, there's glycinergic receptors.
>> Okay. The NMDA is the magnesium. It's the NMDA receptor.
>> Yeah. So, the magnesium is actually a co- uh, is sort of uh, is involved with uh, the activation of the NMDA receptor. So, uh, but but glycine does too. So, so sorry. So, glycine is a co-agonist to the NMDA receptor, but it's complex. So, so glycine, so you don't find a whole lot of glutamatergic pharmaceuticals out there, right? Because glutamate is a ubiquitous neurotransmitter, one of the most abundant neurotransmitters in the system. So, you don't drug. So, you have uh like MK-801 and like you have research compounds that we use in the lab that'll block NMDA and APA, but they tend to be fatal or like there's a lot of side effects associated with them because glutamate is such a ubiquitous neurotransmitter. So, pharmaceutical companies, what they do is actually focus on u on the co-agonist, and glycine is a co-agonist to the NMDA receptor. So, if you tweak the uh, the glycine molecule, and then serine too. So, serine, I think can be can weakly interact with that co-agonist and can have u sort of antidepressant effects. So, there's like serine is being looked at as a as an NMDA receptor modulator. And then you have the NMDA receptor has magnesium inside the pore of the of the channel. So, the NMDA receptor is a ligand-gated and voltage-gated ion channel, and it has the voltage gate of the NMDA receptor is dependent upon magnesium, and once the membrane potential of a neuron reaches uh, it gets depolarized below -50 millivolts, that releases the magnesium gate of the NMDA receptor. So, experimentally, what we used to do is uh, uh, low calcium, high magnesium. When when you're recording from neurons in a petri dish and you want to block the synaptic activity, you use low calcium and then high magnesium. And the magnesium would actually fill in, uh, kind of block the pore to a little greater extent of the NMDA receptor, and basically, you get suppression of glutamate hyperexcitability. So, what that means to the listener who's probably not interested in all the the the neuropharmacology here is that when you consume uh higher doses of magnesium, it gets into circulation, it gets into the brain, and the magnesium has a suppressing effect on the N-methyl-D-aspartate receptor, the NMDA receptor, and suppresses the uh, hyperexcitability that could happen and be associated with anxiety. But also, correspondingly, makes the NMDA receptor are just as robust in its physiological function for learning and memory too. So, it doesn't block the, it blocks the some of the negative effects of glutamate hyperexcitability, but it doesn't block the physiological role of. So, so that's and typically what needs to happen is that you have AMPA receptors that are activated through glutamate, and you have more AMPA receptors, and the AMPA receptors will depolarize the resting membrane potential of the neuron to a degree where it releases the magnesium uh block. And once the magnesium block of the NMDA receptor is relieved, and then you have glycine as a co-agonist and glutamate as the agonist, then that activates the NMDA receptor, and that's the difference between uh, sort of of that that needs to happen to stimulate long-term potentiation, which is the formation of new memories. So, for this to happen, you need to get excited. And when you get excited, that activates the AMPA receptors. And then if you get really excited, that causes enough of a depolarization in the neural network to relieve the magnesium block, activate the NMDA receptor. And then the NMDA receptor then activates a whole cascade of events including calcium calmodulin protein kinase 2. And um, that is actually needed for early LTP, and that activates a cascade of events that then can stimulate protein synthesis for late LTP, which is actually the strengthening of synaptic activity. So, this is just like classical neuropharmacology, but
>> Basic stuff.
>> But yeah, so glutamate is uh hits the AMPA receptor, and then you hit a bunch of AMPA receptors and you cause excitation, then you activate the NMDA receptor, and it's that NMDA receptor that actually needs to be activated for enhancing learning and memory. And when I was in grad school, there was a Dr. Chen in Princeton created the smart mouse. It was called Doogie. So, there was a show called Doogie Howser, MD, you might remember. So, he was like a young kid. And so the mouse was super smart, and it had an overexpression of the NMDA uh, the the NMDA2 receptor. So, or subunit. So, there's various subunits of the NMDA receptor and NR2B. So, yeah. So, there's various subunits that make up the receptor, and the NR2B subunit was overexpressed, and that made the mice super smart, and they could learn faster in different learning paradigms. What that the take-home message was that glutamate receptor activity is like really important for learning and memory. And to to do that, to learn something, you have to be excited about it and while you're learning it. And also, if you make a mistake while you're learning something, that triggers your brain, it gives you like a little bit of anxiety, and you get frustrated, and it gives you a pulse of glutamate, and then actually reinforces the learning effect. And then you have to chill and let the memories consolidate. Then you have to revisit that learning paradigm again. So, if that makes sense. So, to learn something and you want to be super proficient and master something, you have to be excited about it. You could take a stimulant. So, or you could just be we're excited about talking about ketones and ketogenic diet and fasting. So, we're excited about it. So, we're going to learn faster because there's emotion tied to it. But if we're learning and then I correct you on something, I was like, "No, that's not the case." And you kind of course-correct and be like, "You made a mistake saying something," which we didn't do, but we're just talking. Uh, you're more likely to learn and reinforce that concept that you might have had not had like the ideal, the correct uh internal representation of.
>> But I'd have to step away for a minute and come back.
>> Yeah. So, for a second, so you were corrected. So, if your professor corrects you, uh, if you say something and your professor corrects you, uh, you're more likely to retain that memory. So, you have to be excited about something and then you like, if I was fixing a tractor and I screwed up something on the hydraulic system, I had to go to YouTube and figure it out. Now, I really know how the hydraulic system works. So, that's an example that just popped into my head. But basically, be excited about something, study, learn it really hard. And then if you find out you're you were thinking about something incorrectly, and then you're corrected, just by studying or someone tells you, you know, corrects you, then that actually reinforces your memory better than anything else. That's great.
>> Like Yeah. And then and then that happens, and then you go to sleep, you get good sleep. That's actually when memories are consolidated. Then you revisit that material and study it again. And then boom, that's when you're activating AMPA receptors, you're activating your NMDA receptors, and these things are stimulating long-term potentiation, and then ultimately early LTP, and then late LTP, and then those your physical brain actually changes, you know, its structure to to retain that memory. So, that's exactly why I mean it's like if you take melatonin to help you sleep,
>> It's going to I even if it was potentially problematic, which is not
>> The benefit of actually getting the sleep
>> On memory, on all these things that we might, you know,
>> Is probably much better, right? It's like it's like I'd rather take a melatonin supplement
>> And get the sleep, get the memory consolidation, get the actual brain changes that are in, you know, happening from what I the stimulus than not sleep because I was afraid of taking melatonin. Right? That's I mean, if we bring it back full circle and just to kind of, you know, recap on it.
>> So,
>> And I'm just going to interject one thing, and melatonin tends to dampen inflammatory pathways that make glutamate receptor signaling less effective. So, uh, so it sort of it becomes like an amplifier and enabler of effective glutamatergic, uh, long-term potentiation of memories. So, it enhances the memory process. Yeah.
>> Okay. So, melatonin, talked uh, pure glycine, magnesium glycinate, talked about uh, potentially Kava, talked about um, what were the other ones we mentioned just to recap?
>> Uh, I mean, we went down the p. Yeah, phenibut is one. So, use very sparingly. So, don't recommend it. Maybe maybe once or twice a month or something like that if you have a problem sleeping, but that's actually something I take maybe the first day of a of a one-month day fast. Okay.
>> Yeah. To induce sleep. It's very effective. Yeah.
>> Okay. So, I mean, then there's benzodiazepine or gabapentin. So, a little dose of a gabapentin will also, but that's a prescription drug. So,
>> So, something like, but even something like
>> Safer than a benzo though.
>> Like a nicotinyl GABA or something that might potentially, yeah, that would be, you know, a better choice there.
>> Well, Dom, where can everyone find you, man?
>> Yeah, thanks for asking. keoutrition.org or org, and we have an educational platform, uh, the uh, metabolic health initiative. And part of that platform is the metabolic link, uh, podcast, and the platform is also ACCME accredited. So, it's an platform where people can, practitioners can learn about metabolic-based therapies and the implementation and the science behind these therapies.
>> Right on, man. Thanks, brother.
>> Yeah.