I'm on HRT Too: The Case for Melatonin Replacement | Supplement Review

[Music] hello friends welcome to a new series that i'm doing i'm going to be reviewing more supplements uh not supplement brands individually but just supplements in general and telling you my opinions of their value mostly from research reviews so for every one of these videos including this one you'll find a blog post linked down below in which you'll find all the citations that i dis that i take from in what i'm talking to today it's gonna save me a lot of time instead of putting the citations on the videos basically what i'll do is for

each citation i'll just write a bullet point saying what you can what i mentioned in the video that you can take from that paper so you can open the paper and read it yourself um and by the way if you guys just see the citations all you have to do is go to google scholar and paste the citation which is an apa format and you'll get the paper so most of these videos what i'm gonna do is i'm gonna discuss uh supplements in general but i decided to start with one that i'm extremely fond of

and today actually i probably titled this hormone replacement therapy because i don't replace my testosterone and i don't actually replace any of the sex hormones but i do replace melatonin and i've never talked about this before i think on the channel but my clients know a lot about this because i asked most of them to try to do this them as well the way i learned about this personally was because of obviously i used melatonin when i was younger most people do sparingly because we're scared to use it because we don't want to mess up

our natural body's circadian rhythms actually if you look at the interviews of top sleep scientists or read their books what you'll find is that most of them are also quite averse to using melatonin as a sleep aid they're basically concerned that we don't produce much melatonin naturally and they are concerned because they haven't seen long-term studies of what natural supplement i mean what exogenous supplementation with melatonin does to endogenous production of melatonin as well as what it does to melatonin receptors maybe down down regulating those receptors because there's too much melatonin so people are regularly

taking 10 milligrams of melatonin whereas the body produces less than one milligram a very low amount actually so what these sleep researchers will tell you to do is try not to take more than three milligrams knowing that the bioavailability of melatonin orally consumed is about 15 percent now i have a different view because a lot of what i do is spend time researching how to improve brain function and the reason why as you guys know is because i'm very interested in living the best life i can and the way i see it is the brain

is our soul so if your brain can be uh in its best state you'll most likely be your happiest and be able to function your best in life and to me the brain is more important than our cosmetic looks and then our physical performance in sports or anything else and we don't pay enough attention to it in my opinion and so that's why i read a lot about it and a lot of the studies that i read about the brain are about neurodegenerative disease because the the bet the most interesting research being done on the

brain tends to be on uh molecules especially pharmacologically tends to be on molecules that are used to improve the lives of people with alzheimer's disease or parkinson's disease or prevent the progression of the diseases and these molecules are interesting because in both of these diseases these people suffer from anxiety and depression but in all all people okay i'm going a little off topic but all people lose neurons as they age especially after the age of around 25 and all neurodegenerative diseases start well the main effects of them come from neuronal loss which comes from damage

in the brain due to different pathologies so one of the things i came across when i was doing this is uh a lot of research particularly in alzheimer's disease on melatonin and i was originally quite confused i found a lot of studies talking about using a hundred milligrams of melatonin for alzheimer's disease i found studies combining the shape of the melatonin molecule with acetyl-chlorestrace inhibitors like donopazil which are currently used to improve cognition and alzheimer's disease i found a great deal of these things and i wondered why what i realized quite quickly is that melatonin

is an extremely powerful scavenger of free radicals meaning it deals with reactive oxygen species and reactive nitrogen species very well now it's not the most powerful scavenger free radicals that we can take but what's interesting about it is it is metabolized in the body into various other metabolites which are independently powerful as scavengers of free radicals and they affect different kinds of free radicals in different ways not only that but melatonin is readily it readily passes the blood-brain barrier meaning it's one of the only antioxidants and anti-nitrogen species i forgot the word for acting nitrogen

species there's a word for it too like antioxidant but it's one of the only ones that we know will pass the blood-brain barrier and get into the brain protecting your brain from the damage that comes from oxidative stress and so on which is a hallmark of the aging brain so in that sense melatonin is very interesting that's what attracted me to using it uh consistently despite my uh you know extreme interest in circadian rhythms and my concern over that and in this video what i'm going to try to do is i'm going to introduce you

to melatonin a little bit i have some notes here and i'm going to tell you essentially what it can do for you why it can do what it can do and how i would think about approaching using it as a replacement therapy as on a daily basis in the long term so first of all melatonin was discovered it was isolated from cows in 1958 by a guy called aaron lerner it is a very very very ancient molecule what that means is it's found in all kinds of species of living organisms it's found in fungi it's

found in plants it's found in invertebrates and vertebrates it's everywhere which means it's extremely ancient and our bodies are you know have been producing it since way before we were humans um now melatonin has activities in terms of its pharmacodynamics it has activities at two dedicated receptors one is called the melatonin one receptor mt1 which by well i'll tell you about that in a second one is the mt1 receptor one is the mt2 receptor some species also have an mt3 receptor we don't have one that's working now if you take so the circadian rhythms of

the body are governed by something called the suprachiasmatic nucleus in the brain which is shortened i'll call the scn so the scn is what you can imagine as a master clock it sets the rhythm for the whole all of the body's peripheral clocks you have a peripheral clock in your pancreas you have one in your liver you have clocks everywhere in your body they're all governed by the suprachiasmatic nucleus the suprachiasmatic nucleus responds to melatonin so if you agonize the mt1 receptor what happens is the new the neurons of the scn um basically lower their

firing rate they stop firing as much if you agonize the mt2 receptor they experience a phase shift in their circadian rhythm which means they they um they they uh fire later like the whatever they were about to fire they're gonna fire later if you agonize the empty uh two receptor but melatonin does much more than that which maybe this is the time i should mention it so for people that have severe circadian rhythm disruptions there they have been developing some analogs of melatonin that agonize the mt1 and mt2 receptors may sometimes with more affinity or

efficacy than melatonin but do not have the other effects of melatonin because melatonin doesn't just agonize these receptors so people have been developing these analogues or these uh ligands of the mt1 and mt2 receptors with the purpose of just affecting sleep because melatonin does much more than that it ends up governing a lot of the circadian rhythms of the body and the way it does that is number one it's also a natural it is the natural the endogenous ligand of the retinoic uh a receptor or the is it the retinoic acid receptor and the retinoid

x receptor which are rar and rxr those are the receptors that respond to for example um uh what's what are those medications called basically vitamin a related medications retinol and retin-a those are the same receptors that respond to it we actually have an endogenous molecule that does that that's melatonin we produce it it also agonizes or binds to a lot of other proteins and alters their behavior in the body i'm not going to go into too much detail about this but if you check out the article below you'll see over 60 citations i've hand-picked them

so that if someone's very interested they can find some of the best papers on the subjects you can get a really detailed introduction to the biology of melatonin in the body which is very complex also i've mentioned i've mentioned the antioxidant and anti-nitrogen species effect basically the benefits of melatonin of supplementing melatonin you can think of it as in two ways number one your natural melatonin synthesis in your body declines after the age of 25 as it declines and other things change in your body also over time your circadian rhythms which is means how your

body's biology changes through the day they flatten out meaning your body starts to act like you're a night time during the day and it starts to act like you're in daytime during the night this becomes very pronounced when you get older leading to a reduction in rem sleep that's rapid eye movement or dream sleep which has serious consequences for longevity and for other things also leads to less sleep at night and it leads to a weaker deep sleep which is non-rem sleep stages three and four or stage three if you have a different metric and

it also causes it seems to cause a lot of dysfunction in the body in general so when your circadian rhythms are off for example you become insulin resistant you're more likely to become diabetic you absorb your food worse you partition it worse you start to store visceral fat it may be one of the main reasons that older people store more visceral fat the circadian rhythms so what you do when you supplement melatonin exogenously is you can maximize the amount of melatonin that your mt1 and mt2 receptors can get as well as all of its other

activities so you can get to just like replacing testosterone can get you functioning in some way sexually as if you're in your 20s the same thing can happen with melatonin where if you supplement it you can start to uh have a circadian rhythm at least the knock well both parts because melatonin synthesis at night also affects your insulin sensitivity during the day so basically you can hardwire your circadian rhythm to function a bit better by the way how do you hardwire during the day the way you do that is by exposing yourself to light by

doing exercise and moving or by using uh a drug called sr9009 or sr9011 which will hardwire that heart like it'll force you to basically wake up during the day so when you're older maybe in your 60s you might want to combine both of these so that you you force your circadian rhythm to continue working as well as it can but the point is the first thing you can do by supplementing melatonin is force your body to um function at its peak circadian rhythms if you take at the right time of day of course you can't

be taking melatonin during the daytime otherwise you're going to force flatten out that you know it has to be taken at the right time of day usually melatonin starts being released about two to three hours before you go to bed by the way so most recommendations are to take the supplemental melatonin about two or three hours before you go to bed however that has issues also and i'll get into that probably at the end of this discussion so that's the first thing the second thing and this is why i'm particularly interested in it is my

circadian rhythms are actually really good and really stable because i do a lot of things to to deal with it and i used to for example use light blocking glasses a lot i still use them but to a lesser extent because i take so much melatonin which by the way the reason you take light blocking glasses is mainly because if you get blue light during the night time it sends a signal to your brain to stop synthesizing melatonin so you synthesize less melatonin so say you're synthetizing less melatonin you take a high dose of melatonin

like 10 10 milligrams a night you get a replacement dose of melatonins if you're in your 20s or more now your receptors may down regulate but they're not gonna they're they're only gonna down regulate to a certain uh equilibrium in the body they're not just gonna keep keep going down so if you go to a certain amount you're getting the maximum saturation of melatonin effects in the body is it possible that 10 milligrams or 20 milligrams of melatonin does something other than to the mt1 and mt2 receptors for example at the ro rxr receptors that

uh a 20 year old's melatonin does not do it is possible but i don't think it's that much of a concern myself there's no studies indicating that it is there's no evidence to show that there's something going on that we don't want to go on but taking it during the daytime is obviously wrong the other effect which is what i'm interested in is the free radical scavenging that's very powerful that happens at many levels of melatonin metabolism and that happens in the brain because it goes into the brain very easily so it may it may

go into the brain for example at a higher dose higher level than what your body produces naturally and maybe it saturates the mt1 and mt2 receptors and there's no need for more melatonin but the more melatonin you have the more reactive oxygen species and react nitrogen species and generally free radicals are being scavenged now in the body uh there is a theory that if you scavenge too many free radicals and this is why one of two reasons that i'm for example again against injecting glutathione but it's not the main reason actually the main reason is

my concern that your body may synthesize less glutathione which i think is dangerous because it's such an important free radical scavenger but with melatonin the thought may be that if you're if you're scavenging too many free radicals there will be less apoptosis in the body and if there's less apoptosis then you could have uh cells dividing that shouldn't be dividing so that could be the concern at the same time of course when you have more and more free radicals you get dna damage that causes the cells to get to a state where you don't want

them dividing so there's one thing but with melatonin what's different is we know that melatonin selectively causes apoptosis which means cell death in cancer cells whether it doesn't do that to other cells so it has a specific element that has to do with its unique metabolism not to do with its reactive oxygen species reactive nitrogen species stuff that causes apoptosis in in cancer cell lines so it's not so much a concern there so basically there's two reasons to take it one is to get the circadian rhythms as close as you can to a 20 year

old or really to like a although the studies show synthesis of melatonin peaks around 18 to 22 something like that but really probably most of you remember it being very high when you were 17 or 18. to try to get it to that level and get your circadian rhythms functioning as well as they can and by the way i'm going to talk about circadian rhythms in this in this video but if you want to get a book on it it's really short book it's a book called circade the circadian code by sachin panda sachin panda

is the leading researcher in circadian rhythms from the salk institute is really wonderful the book is very readable you don't need any scientific background to understand it so i'm gonna but i'm gonna discuss them a bit in this video and but the point is when the circadian rhythms are functioning as well as you can there's so many different biological effects and the other reason you would want to take it is to reduce reactive species across the body and particularly in the brain especially at higher doses this is very interesting so i'm going to take you

through a tour of the notes that you'll see in the blog post um let's begin with the brain first of all melatonin has been tied to neurogenesis in the brain for a couple of reasons i mentioned directly in the blog post i'm going to try to keep this a bit short so you can read the details in the blog post and check out the paper yourself but it's been tied to the differentiation of neurites it's been tied to gdnf and bdnf which are glial cell derived neurotrophic factor and brain derived neurotropic factor it's co-localized and

with them in the brain which often means that it may affect their synthesis um it is uh being researched for the treatment of parkinson's disease uh als which my grandmother died from and i'm quite concerned about and is being researched extensively for alzheimer's disease as i mentioned before um mainly due to this reduction of reactive species in the brain because just to give an example for example in in alzheimer's disease you have what are called uh amyloid plaques which develop in between cells these amyloid plaques cause reactive species to exist in the brain and they

cause damage to neurons melatonin is neuroprotective and deals with these free radicals the same exists for parkinson's disease although it's a slightly different kind of development of proteins in the brain and with als for example it's really tied to having very high levels of reactive species in the body so als seems to be to progress tremendously when people have more reactive species higher c-reactive proteins in their from their liver and so on um interestingly melatonin has been shown to attenuate the damage from methamphetamine toxicity which methamphetamine toxicity kills neurons in the brain specifically well i

won't get into too much detail it's been shown to do that for methamphetamine as well as ethanol and probably other drugs as well and not just in the brain of course with ethanol because ethanol affects the liver and melatonin is very uh potent at reducing uh liver damage which we'll talk about in a second i think in more detail it's also thought to be potentially supplemental melatonin it's thought to be potentially uh likely to increase longevity and it's been shown to do some and do so in some small organisms i don't know if it's been

researched in rodents yet but it there are reasons to for this for example it seems to reduce cell senescence so in the body cells have a certain number of times this is one of the reasons i'm against growth hormone use by the way so cells in the body have only a certain number of times that they can divide when they get to that uh nth division where they can't divide anymore they either commit what's called cell apoptosis which means programmed cell death or they turn into what's called senescent cells which are like zombie cells these

cells don't function fully but they continue to release toxins in the body now it's been shown in studies that when these senescent cells are removed for example from people's knees they no longer get knee pain the old people they no longer get knee pain and when rodents have uh treatments that room and there are by the way a lot of pharmacologic uh treatments for senescence being researched right now it's one of the leading things being studied for uh reducing the effects of aging it's been shown in rodents that when these treatments are given the rodents

don't die too much later but they don't exhibit the old phenotype where they have difficulties walking their fur gets worse all this stuff so a lot of stuff to do with the um health span to do with the way we feel when we're older seems to deal with senescence and melatonin reduces the cell's likelihood to turn senescent it also act increases the activity of sirtuins so sirtuins are what are increased by for example resveratrol and nmn and nicotinamide riboside so there are good reasons to think that it may have a longevity element as well especially

because we know we're synthesizing less melatonin as we age for sure we're synthesizing less than when you when we're younger and the only way to change that really is to replace it um now i'm going to talk to you guys now about some of the effects of hardwiring that circadian rhythm to function better over time as you age and i'm we're going to talk about some people with diseases like type 2 diabetes and stuff like that but in general this all may and people with hypertension but in general this may be the case for all

people that are aging in general because they're producing less melatonin so i'm just going to briefly take you through it you can read the papers in the blog post which is very readable so um first of all let's talk about blood pressure melatonin significantly reduces systolic and diastolic blood pressure not that much but it reduces it significantly showing that it has an effect on improving the circadian rhythm which in turn affects but also melatonin has a direct effect with the renin angiotensin system the renin-angiotensin system affects melatonin and melatonin affects that as well so it

may have a direct effect also melatonin improves lipids in this lipidemia so the most consistent effect is that it lowers serum by the way everything i'm mentioning so far is significant means which means it's statistically significant it's not my i don't anything that was minor and that was not statistically significant i did not include in the notes so it reduces triglycerides but that's the most significant effect but some studies show reductions in hdl cholesterol and uh some studies show it in total cholesterol that are not specific to ldl or hdl i mean sorry increases in

hdl cholesterol some studies also show reductions in ldl cholesterol but most significant is the triglyceride lowering effect melatonin is also immunomodulatory so melatonin is synthesized by the parts of the immune system also it's not just synthesized in the brain i didn't mention it's synthesized in several parts of the body but also it governs the activities of the immune system so one of the things it does is increase the activity of natural killer cells which are cells that are surveillance cells for cancers they're the cells we rely on significantly to detect and kill cancers but it

also improves activity of or reduces activity of pro-inflammatory cytokines like interleukin-6 for example and tnf alpha tumor necrosis factor alpha and it on the whole across so many studies reduces c-reactive protein which c-reactive protein is a protein released by the liver when your body is in a high inflammatory state so it's a it's a proxy by which you can judge a high inflammatory state in the body so seeing improvements in the c-reactive protein basically indicates that a person is in a less inflammatory state which is key because there are so many diseases in life that

gets get worse when you're in a pro-inflammatory state chronically you should have some inflammation in the short term when you're dealing with something like a virus or a bacteria or when you go into the sauna but it shouldn't be a chronic inflammatory state that's the concern so also to talk about cancer there is evidence that melatonin reduces the incidence of cancer in some way there's not very controlled studies but there's reasons to think it does and there's a lot of reason to think melatonin reduces the ability of cancers to metastasize which means for to prevent

for example liver cancer so for example liver cancer hepatocellular carcinoma is very deadly actually but the reason it's deadly is because it spreads so quickly in the body so the spreading is called metastasizing so breast cancers that don't metastasize are quite treatable but when they metastasize it becomes a bigger issue so melatonin seems to be particularly good at preventing that from happening it causes apoptosis selectively in cancer cell lines it also inhibits angiogenesis in cancers which is angiogenesis is the creation of new blood vessels which many cancers rely on to grow which usually happens through

something called vegf which is a vascular endothelial growth factor so it inhibits this in cancer cell lines um you know also it's thought that the reason that night shift workers develop breast cancers more often is because they have less melatonin so night shift workers of course develop less melatonin because they sleep during the daytime so they get melatonin while they get you know they get melatonin at night while they're at work probably a little bit and then they get way less during the daytime so it's thought that that may be the actual reason um now

melatonin is very researched in terms of the metabolic syndrome so metabolic syndrome something that happens very frequently in america it's marked by five uh you know things uh five noticeable things like low hdl cholesterol high uh high visceral fat hypertension stuff like that so it's been shown number one it's very well understood uh in terms of the pharmacodynamics of it that melatonin causes insulin resistance when you take melatonin so when you for for example this is the reason why you partition food worse at night once your melatonin gets synthesized in your body you start to

immediately for a variety of reasons it has effects for example on glute4 expression on lipolysis on lipogenesis on fatty acid uptake on pancreatic isolate uh function um it modulates igf-1 activity so there's a lot of reasons but it directly causes insulin resistance and it also causes insulin sensitivity during the day time so so what's been studied is this so far i'll give you some examples for example in diabetics melatonin has been shown to improve uh hba1c levels minorly by the way my supplemental melatonin i'm talking about minorly but it does significantly it improves fasting blood

glucose it improves insulin sensitivity as tested by the oral glucose tolerance test it's also been shown to improve in these studies you know blood pressure and lipids and c-reactive protein and measures of oxidative stress including glutathione metrics and things like that it's also been shown to improve weight loss among the obese and in the obese it's been shown to reduce the synthesis of adipoclines which are cytokines inflammatory cytokines or other non-inflammatory cytokines that come out of fat cells they're called adipocytes leptin is one of them for example so it reduces the synthesis of those in

the body the expression of them and it reduces c-reactive protein levels in the obese and we're talking about specifically supplemental melatonin there are different milligrams in each of the studies i've mentioned most of them in the notes that you can find on the website melatonin also has been shown to improve the liver grade quality in non-alcoholic fatty liver disease which is a very common disease in the u.s it also improves c-reactive protein levels which means lowers them in people that have nafld non-alcoholic fatty liver disease so that's basically an overview of things that melatonin does

via its modulation of the circadian rhythms now let's talk about dosing so i want to mention this briefly because it's quite interesting and important first of all uh let me mention that there are studies with higher doses of melatonin so the highest dose i found is 300 milligrams of melatonin taken um i don't know what they call it basically oh rectally it's taken rectally basically they put like some rectal uh you know suppository in their rectum of people with 300 milligrams of melatonin so this is absorbed way more strongly than taking it orally it was

given to patients with als who have of course you know very pro very inflammatory states because of reactive oxygen species and it completely normalized uh the inflammatory environment in the als people that's how powerful it was at a high dose and it didn't have adverse consequences okay that dose um now it's pretty interesting by the way because rectal uh that's actually the only only study i saw reviewing rectal suppositories and generally it's known that rectal administration enters the bloodstream quite uh easily so one would imagine that it would have an almost the serum levels of

melatonin would have an almost linear decrease over time which is what is seen by the way an intravenous melatonin supplementation which has been done by the way because melatonin is very poorly orally absorbed about 15 of it is absorbed most of it's removed in the first pass from the liver which is not so bad you know by the way just getting it in the liver probably causes it to remove reactive reactive species in the liver even the first past ones that is actually removed probably have an effect in the body they go throughout the body

anyway and they still have an effect um because it's not a pro drug it's already melatonin and it's already active but so let me take you through this so 50 milligrams of oral melatonin has been used in parkinson's patients also with no adverse effects whatsoever and these these two studies as well as the studies which i haven't actually cited here but the studies on alzheimer's patients are what made me brave enough to start using more than 10 milligrams myself i'm currently at around 60 milligrams and i'm planning to continue raising the dose slowly as i

figure out how much i should be using exactly of which kind so this is where it gets interesting basically the problem with oral melatonin is that the half-life is of not the timed release of the normal one the half-life is about an hour a little bit less than an hour and peak concentrations are at about 40 minutes so you get a really strong peak concentration now i don't know if i'll include the graphs but you can check out the citations there to see the graphs basically what happens is you take the melatonin so normally in

your body melatonin is like released slowly i mean it's going to be hard to show you but imagine or this way imagine the grafts like this usually melatonin is released uh two hours before you go to bed and it slowly declines for the next six hours or so when you take oral melatonin it goes up very fast and then it declines very suddenly for the next hour or so and then it slowly declines and stays above baseline above the natural level if it's like six milligrams or ten milligrams even three milligrams stays above the natural

level for the next few hours but what i've noticed and what other people have noticed is that i think it's because of the peak even though you have more melatonin than you have naturally you have a likelihood of waking up and in terms of reactive species you huge i mean you can get what needs to be done within an hour anyway so think of it this way if you take an acute dose of the quickly digested not timed release melatonin every night whatever built up reactive species you have if you take enough you're gonna deal

with them in your brain and your body everywhere within about an hour an hour and a half or so and then it's done basically um so you get like a reset every night in terms of reactive species so other people go to bed they still have reactive species their antioxidants in their body are not dealing with it you don't you do if you take enough you deal with all of it and you wake up fresh but there's also another way to think of it is that you want a longer first of all you want to

stay asleep that's one thing and second what number one you want to stay asleep maybe number two you want enhanced circadian rhythm because it's still going to be enhanced if you take a high enough dose hours later i guess but maybe you want more even of the circadian rhythm uh effect or you want a longer period with antioxidant i mean antioxidants and anti-nitrogen species in your body dealing with those species for a longer time period so you don't accrue any over the night now you're very unlikely to accrue any during the night to be honest

with you but for this reason i've looked into extended release melatonin i was using extended release melatonin myself for a while what i found is when when i first started taking 10 milligrams of extended release by itself before sleeping i i started taking it two hours or so before sleeping i found that i was a little groggy that the next day so what this told me is there was still a higher amount of melatonin the next day that would be there naturally so what i've started doing is eating even earlier than i used to and

taking the extended release melatonin a little bit earlier so like four hours before i sleep or three hours and a half before something like that at the same time i think that my receptors have down regulated a little bit so i no longer get the groggy effect in the morning even though i'm taking much more than 10 milligrams now but let me tell you about the pharmacokinetics of the timed release melatonin first thing is it's it's uh apparently almost equally bioavailable about 15 percent the half-life is now not less than an hour but about three

and a half to four hours which as you can see if you're only sleeping seven hours then it's still quite you know quite significant in your body when you wake up but if you take it earlier and if you sleep later which you will probably tend to sleep uh for a longer time period when you take the extended release it probably ends up quite okay especially if your receptors downregulate but here's another reason to take the sr9009 when you wake up the problem is for people like me my circadian rhythm is still despite this it's

still very solid when i wake up so i don't really need to take it most of the time but i'm interested in taking it uh i will definitely start taking it daily once i'm past maybe the age of 40 or 45 because then the diurnal which means during the daytime rhythm is really off even though melatonin could probably improve the diurnal rhythm also anyway you could if you still feel sleepy during the daytime you could do that also but the point is a half-life is much longer it's about four hours um the maximum serum concentrations

happen between depending on the person between an hour afterwards to three hours afterwards so it's in the very fast metabolizer it's almost the same time as the average of the uh non-extended release but for other people it's about three hours so it depends on your the function of your sip of your p of your sip enzymes which are the p450 enzymes which specifically by the way it's metabolized by the sip 1a1 and the sip 1a2 as well as potentially by the sip c19 though this is not completely clear by the way sixty percent of the

extended release melatonin was shown to bind to proteins including hdl uh particles and you know i i mentioned this already but there are analogs of melatonin that agonize the mt1 and mt2 receptors more than melatonin i've included here at the end of the blog the actual affinity of melatonin for each of the receptors though i'm not sure it's useful for the audience um finally i wanted to mention yeah so an intravenous high-dose intravenous melatonin has been studied so unlike the other melatonin doesn't just rise and then decline and then sort of slowly decline and stay

above baseline but the intravenous one declines sort of linearly through the night so both are very unnatural but anyway i don't think anyone's going to use the intravenous one but there's certainly reason to to want to use that because it'll stay elevated for a longer amount of time but i mean it's not worth it i don't think there's any reason to inject yourself like that but just so you know uh low-dose intranasal melatonin has been studied several studies exist on that transdermal melatonin has been studied uh oral transmucosal melatonin which means sort of keeping it

for example some sublingually or even snorting it or something like that it's much better uh more bioavailable than taken orally i'm not too concerned about that the reason is as i said before even if it gets most of it gets removed from the first pass from from the liver the melatonin is still going to other places like for example the bladder where it still acts against reactive nitrogen species and reactive oxygen species so it's still preserving the functions of the body wherever it's going so i don't mind it going through that especially because i have

other supplements or other drugs that may be harming the body in other places and the melatonins going in the same places and reducing some of those reactive species so i'm not too worried about it myself i think that covers almost everything uh oh yeah one thing to mention though melatonin reduces the the uh sex hormone um basically it reduces gonadotropin releasing hormone uh being released from the hypothalamus being sent to the pituitary in turn there's less luteinizing hormone and follicle stimulating hormone from the pituitary being sent to the gonad so basically this means that in

your circadian rhythm naturally you're supposed to synthesize less testosterone or other hormones like progesterone from your gonads during the night time if you go and take melatonin twice a day then you're going to synthesize less gonadotropins or less testosterone and progesterone and everything during the day time also so of course don't do that but nobody would you know that's obviously not something you should do um also there's a theory that people who take melatonin and it quickly becomes ineffective for them are actually slow metabolizers there's about 12 to 14 percent of people that have polymorphisms

at the sip 1e2 enzyme people like that that are slow metabolizers and then what what they're thinking happens is that those people have higher amounts of melatonin throughout the night so the receptors down regulate because they're not metabolizing it as quickly so basically those are my notes on melatonin um i know this may be a little bit a little bit dry i was trying to make these videos more interesting i think the other supplement videos will be more interesting but basically melatonin is probably my um people often ask me like what are the antioxidants or

anti-nitrogen species that you're most fond of and there are many that i'm fond of i usually mention my hormetic shake which is basically sulforaphane from broccoli sprouts combined with moringa powder and moringa powder and sulforaphane are very powerful but the way they work it seems to be as as hormetic stressors things that have a biphasic effect so when you take a little bit of it it causes your body your body is used to sensing these kind of plant phytochemicals and noticing that it has this phytochemical it does this what your body does is for example

with turmeric also or with coca also it reacts in a way that is net positive for the body so it does certain things like synthesize glutathione or do other things to deal with that signal from the plant which is great but this is a technical traditional antioxidant it it's not about your body it does of course affect it's a hormone it changes your body's function improves the circadian rhythm and all that and has therefore effects on dyslipidemia on blood pressure on um on insulin resistance on diabetes on cancer really a lot of effects on cancer

but it also is a traditional free radical scavenger a very powerful one and one that's scavenge free radicals throughout all of its metabolism so it turns into many metabolites most of them also scavenge free radicals in different kinds of ways and more important than that it goes it travels into the brain very readily so it can really help to preserve brain function i mean that's what i think obviously there's no longitudinal studies on this but i'm very suspicious i really think so myself and usually i tend not to do things that are very risky but

i've been taking now for a while about 50 milligrams of melatonin i take a combination actually of extended release and short release mostly extended release that i start a bit earlier but i also take short release to actually make me fall asleep because it seems that the the sudden rise in melatonin helps me fall asleep and if i ever wake up during the nights anyway guys i was just finishing the video and i added like i guess 20 seconds left but the battery finished so i had to change the battery anyway the point is i

take a combination of short release and long release melatonin i think it's great sometimes i wake up during the night that's what i was saying sometimes i wake up during the night and i take an extra short release one it's been working great for me i actually feel really different taking the very high doses of melatonin which shows me how powerful the free radical scavenging is because i take a lot of free radical scavengers or hormetic stressors and i still feel a significant impact so i really think it's great i think it's the main hormone

that most people should be replacing and that aren't and i disagree with the sleep researchers who i think i think most of them are not very familiar with i mean they do research the brain obviously but they're not very familiar with the uh really strong potential of melatonin to scavenge free radicals particularly in the brain so they don't realize that even if your body is reacting to the melatonin synthesizing less or whatever first of all we're not going to run out of melatonin it's pretty cheap it's easy to get you can have it um it's

not like i mean testosterone potentially could be harder to get your hands on than melatonin and if you take testosterone for long enough you know you you really affect your natural ability to synthesize it but melatonin is easy to get and melatonin has way more positives going forward than testosterone so i'm very fond of melatonin i highly recommend you try it i'm not a doctor of course so this is not you know medical advice but non-medically as a friend i think you should try it but anyway thank you guys for watching i'll see you next

time next week we'll have another supplement i haven't thought of which one i should review yet yet i'm thinking of garlic because garlic's one of my favorite supplements but if you have a request post it down below and i'll check it out thank you for watching i'll see you next [Music] time [Music] you