How Melatonin Works as an Antioxidant Beyond Sleep

All right you guys ready for a really deep dive um I was this was a lot of fun and I really have to admit that there's a big personal interest in me answering this question because I personally do supplement with melatonin. So Michael asked Can you discuss the role of melatonin as an antioxidant and the possible benefits versus risks of it as an oral antioxidant supplement and this is an interesting I thought this was a really interesting question because most people when they ask about melatonin they talk about it in the context of sleep like how melatonin can improve sleep does it improve sleep and um not a lot of people are are aware that melatonin is actually a very it's a it is a very powerful antioxidant. But not in the same way as as Vitamin E or vitamin E is so we'll talk about that in a minute um generally speaking just overall summary uh you know melatonin does have have a pretty strong antioxidant effect and there you know there's studies showing that even can be protective against radiation at least some very small studies with cancer patients undergoing radiochemotherapy. However we did discuss back in Q&A number 44 that this balance between oxidation and reduction is very important and so we're going to talk about this um as we as we go into a little bit deeper of a dive.

But I just kind of want to give you guys an overview and then of course melatonin can affect some aspects of sleep so we'll we'll get into that as well all right. So um in studies where melatonin doses were up to 20 milligrams a day which is definitely on the very high end of the dose range for several months it's been shown to be safe with very rare mild adverse effects and really the biggest adverse effects with people taking 20 milligrams of melatonin a day for several months is grogginess in the morning um sleepiness maybe a headache or feeling like cold. So melatonin also plays a role in regulating body temperature so it does sort of lower core body temperature so that's another sort of weird side effect that could be quote unquote adverse to some people with you know very high doses of melatonin supplementation there's really no evidence that my team and I could find that taking melatonin as a supplement can affect your endogenous production of melatonin. So melatonin is a hormone produced in the pineal gland when I say it's a hormone um you know it's it's affecting it's affecting other tissues and it's regulating you know the activation and and deactivation of a variety of genes and.

So um it's affecting a lot of biological processes not just sleep but um there's really no evidence that taking melatonin at least you know in terms of the longer studies that have been done affects a person's capacity to make their own melatonin. So um that hasn't that that has not been observed yet um there's been a few animal studies with extremely high doses I mean we're talking just supraphysiological well over the 20 milligrams melatonin which is already a high dose um that has shown melatonin receptor desensitization. So in other words The receptors are less sensitive to the melatonin hormone um but again human Studies have not shown that prolonged use of melatonin causes tolerance so people don't when they're taking melatonin it doesn't cause them to need a higher and higher higher dose which would be indicative of receptor desensitization. But that's just not the case um which I find very encouraging of course there's you know there's all sorts of interactions with melatonin um and other drugs that are important to consider um which we'll we'll dive a little bit into.

But I want to talk a little bit about its antioxidant activity um it's interesting because melatonin is is also what's called lipophilic like vitamin E and so um it has antioxidant activity in the cell membranes and um it also is activating glutathione which is lipophilic as well. So it has direct and indirect antioxidant activity um it's it's activating a variety of important stress response antioxidant genes so um these are this is been shown actually in a variety of randomized control trials melatonin increases our endogenous production of glutathione superoxide dismutase a variety of different glutathione enzymes like glutathione peroxidase glutathione reductase like these are really important antioxidant enzymes it activates the NRF2 pathway. So this is the same pathway that sulforaphane activates as well uh it's been shown in human studies to reduce biomarkers of lipid peroxidation so that's like you know that LDL and stuff that gets oxidized. So lipid peroxidation is reduced um protein carbonyls so that's proteins being oxidized um which plays a role in just you know proteins not working as well it also plays a role in protein aggregation.

So there's a lot of evidence that even taking higher doses in fact um have a more pronounced antioxidant effect in human studies that really suggests melatonin definitely has a very strong antioxidant effect in in humans and um it's also got an indirect action. So um you know it's I'm sorry it so this is kind of the indirect where it's activating the genetic pathways but it's also activating the melatonin 1 and melatonin 2 receptors um and that's how it's activating all those pathways. So that's the indirect antioxidant activity the direct action is actually melatonin itself being able to react with um reactive oxygen species so the structure of melatonin itself it's this aromatic indole which just that structure itself sort of helps buffer um some of the reactive oxygen species. So it can in in some ways act a little bit as a direct antioxidant like vitamin C can like vitamin E can um but but I I would say the major way that it's an antioxidant is its indirect action by actually just activating through um these you know the the melatonin 1 and melatonin 2 receptors activating all these different antioxidant genes that we have.

So you might think oh wow well it's reducing all this oxidative stress that's great and it is but you know as with anything you always want to balance right and um while a lot of people are familiar with oxidative stress and how it's not good to have a lot of it because you get oxidized lipids and proteins and you can get DNA damage and mitochondrial damage and all that um when you have too much of the other side you know the the the antioxidant effect you can have what's called reductive stress and it's equally important to not go too overboard with that reductive stress unfortunately there's no really easy way to measure this in humans and it's not even really there's a lot of um Technical and I would say Pro protocol problems even just doing it in animal studies as well do you have to measure like the NAD to nadh ratio rather than just measuring like NAD levels right. So a lot of people are interested in these precursors to NAD or NAD boosters like nicotinamide riboside nitin nicotinamide mononucleotide um and and you'll find human studies where you know NAD is directly measured it's a lot easier to just measure NAD. But when you're looking just like for that ratio of NAD to nadh it's it's it's much more finicky and um it's really difficult to measure that sort of balance and. So until we have more sensitive assays I don't know that we're going to have a direct measurement of reductive stress and everything I'm talking about with well how how do you know if you're getting you know too much or you're you know having this type of reductive stress we just it's all sort of speculation at this point there's no evidence that it's occurring in people that are taking let's say 20 milligrams of melatonin a day um because we don't really know how much of this oxidative stress is even going on and there's probably a very um an age dependent lifestyle dependent as well mechanism I mean the more oxidative stress you have the more you need to counter it as well.

So um it's just one of those things where you kind of want to be a little bit cautious where you you don't want to go overboard on the antioxidants either. Now the question also um there was a bit a hint of radio protection so there's been a lot of animal studies that show melatonin um can help protect against ionizing radiation. So that's like causing DNA damage in all sorts of problems um a very there's a there's a few randomized control trials that have found melatonin supplementation can actually mitigate some of the side effects associated with radiochemotherapy in cancer patients. So um it reduced fatigue so there's a meta-analysis that combined a variety of randomized control trials together and it reduced the relative risk of fatigue by about 63% it reduced neurotoxicity by 81%.

Now that's pretty to me that's pretty um intriguing and then it reduced um a variety effects on blood cells as well so thrombocytopenia um and again um it seemed to have a little a little bit of a protective effect on um you know just just blood cells in general. So uh that's super interesting not a lot of people digging up in those those studies um those old studies but you know again there's there there's not a ton of evidence out there this is just looking at what there actually is you know tons of there's not a lot of people studying this that's the problem right there's also been some interest in the effect uh on blood pressure. So there's been several different again meta-analysis of randomized control trials and looking at melatonin supplement supplementation on blood pressure and there does seem to be a general blood pressure reduction. So there's five different randomized control trials that found melatonin supplementation anywhere between 3 to 10 milligrams a day um caused a significant decrease in blood pressure so systolic blood pressure on average was about 3.5 millimeters of mercury lower and then diastolic blood pressure was about 3 or.

So millimeters of mercury lower uh there's also an effect on nocturnal blood pressure so there's been other studies looking at you know during nighttime your blood pressure changes it was found that taking a controlled release of melatonin about two to three milligrams a day lowered the systolic blood pressure by about six millimeters of mercury and diastolic by 3.5. So this was um a little bit even higher than just general blood pressure and then there's other studies that I looked at like people with metabolic syndrome and um it seemed as though there was really substantial redu um blood pressure reductions in people with metabolic syndrome in um in a couple of studies with melatonin supplementation. So um again very interesting that melatonin is affecting blood pressure as well and then there's a variety of other just general health you know aspects that have been looked at with randomized control trial. So things like surgical outcomes interestingly anxiety is reduced um it was lower in people that were taking melatonin versus a placebo um pregnancy so it seems to there's there's like some you know a few studies looking at the effect of melatonin on fertility and it seems that uh it's it improves mature oocytes it seems to improve embryo quality um and you know it's not it's probably linked to its antioxidant activity if I were to guess.

But it's not really known exactly why melatonin's you know improving some fertility aspects there's been some mixed um I would say results with metabolic disease I talked about blood pressure um. But you know melatonin does affect insulin release and so it's one of the reasons why eating late at night is not such a great idea so you know you don't like taking taking a lot of melatonin then um eating a meal probably is not a good idea again we mentioned that we talked a little bit about cancer and it seems as though it seems to help with particularly with um radiochemotherapy there's been um a meta-analysis looking at that remission of cancer has been shown to be improved and then um survival at one year is also improved and again you know this is we need more studies to really make a pretty I would say a conclusive statement. But it's interesting nonetheless and then again with the adverse effects the most frequent is just you know grogginess sleep daytime sleepiness sometimes headaches uh and then hypothermia is another one there's a few that serious you know side effects that can happen in some people. But it's really kind of not not very common looking at high dose so anywhere between 20 to 25 milligrams of melatonin in a day a meta-analysis of several different randomized control trials found that um in adults over the age of 30 years old that took that high dose for six months really there wasn't any you know detectable adverse effects or withdrawals or you know anything like that.

So children and adolescents are a little different I mean it it's unclear you know if melatonin is going to affect puberty or hormonal like you know systems and stuff and. So obviously like that would be a different you know a much more cautious situation you know adults at the age of 40 is when they they start to make less melatonin just endogenously that's kind of when it starts to really sort of starts to go down precipitously and then as you get older 50s and 60s it really goes down um. So you know most most children and adolescents if they don't have some sort of um weird genetic problem shouldn't really have much of a need to take melatonin and then I mentioned drug interactions I would say that's the the concern would be to obviously speak with your physician if if you're considering supplementing because it can interact with a variety of different prescription drugs like for example blood thinners and others. So that's obviously something um to keep in mind as well um but other than that you know I mentioned the endogenous production it doesn't seem to really supplementation with melatonin doesn't really seem to affect people's endogenous production of it at least in the clinical studies that have been done um you know couple of months later you're still like people are still making the same normal amount of melatonin after taking melatonin for several months and then stopping.

So um you know the receptor desensitization while I think a lot of the fear of the melatonin has come from a couple of in vitro studies where you dump melatonin on cells in a Petri dish and that affects it. But that's really not relevant and and then also like a couple of again animal studies that are like just not even the the dose is not even translatable to humans um that have shown a little bit of desensitization. But like there hasn't been any human studies that have shown evidence of that again like I said most people they're they don't show a need to actually have to increase their melatonin dose as they continue taking it which is what you would expect to happen if there was desensitization occurring. So that's kind of the Roundup of melatonin um I continue to be really interested in it and I like I said I do I do actually supplement with melatonin as well um.

But my my biggest concern again would be the reductive stress I you I I take it at night like most people would so I mean you're less likely to have that blunting effect of exercise which is always a concern as well. But you know it I so far I'm I'm not buying into the fear that melatonin supplementation is really bad Matt Miller is asking in the chat how much melatonin I supplement with and if I'm concerned about claims that melatonin supplements contain up to 400% more than advertised I mean that's always a a concern. So my my go-to always is ConsumerLab because um they do a lot of that third- party testing and they do measure the amounts the concentrations of the active you know ingredient that's supposed to be in there you know. So there's always a concern if you're just randomly buying a melatonin supplement off Amazon for example that you may be getting a melatonin dose dramatically higher or dramatically lower than what you think you're getting or you may also be getting something else mixed with it.

So that I mean generally speaking yes I think that's a concern with most supplements and so um it's important to to verify I I take Pure Encapsulations um I was taking quite a high dose of 20 milligrams and then um. Now I'm dropping down to 10 which is still high um but I go I I I've been going back and forth between that mostly because I think I just had a lot of the 20 and I was specifically taking it because it seemed to resolve any night terrors that I can get sometimes um and that seems to be the case with like a higher dose. But I do think I like the 10 milligram dose better than the 20 with respect to like not being groggy when I wake up so I think there's a little bit of you know personal preference in there as well um. But so that's that's kind of my my my dose James is asking in the in the chat yes my night terrors like the melatonin really seems to like my night terrors mostly happen when I'm really stressed and um.

But but even if I'm stressed melatonin seems to help with that and so it's interesting and I wonder if there is a neuroprotective effect going on in my brain where the stress is causing like this oxidative stress um and that's like linked to somehow linked to my my my night terrors that I'm that I sometimes get and melatonin kind of helps because it's not like dramatically affecting my sleep I mean it does affect my sleep latency. So I do fall sleep a little bit earlier than I otherwise would without it um but not much so it it it I you know it's it's doing something with with my um brain during sleep and um again I think that I think that it is a neuroprotective supplement and um you know I I don't know that there's. So far I I'm not convinced there's a lot of evidence that it's like really bad for you.