What mechanism of action underlies the (in)efficacy of OTC melatonin's sporific effects?
Is this just simply transient increases in blood level? One would think binding would need to occur, such as is the case for the melatonin agonist, Rameleton (Rozerem). Can someone explain how this may or may not work?
Thanx, AzR :-). I didn't think OTC melatonin could antagonize M1 and M2 receptors in the SCN like, Rozerem.
Sorry, above, I meant "bind to", not antagonize.
AzR: I guess I'm really curious about what advantages Rozerem has over OTC melatonin. I figured, perhaps the latter can not bind to melatonin receptors. Or, it does not have specific affinity for them. What is the mechanism of action underlying OTC melatonin WRT Rozerem? Is the only advantage of the latter simply an FDA rubber stamp?--I suppose one can assume this carries certain implications...
Thanx for the edit, AzR :-). I was talking to mdGreg C about this and he has suggested that perhaps Rozerem may have greater avidity for M1 and M2 receptors relative to OTC melatonin. This makes sense.
Wicked interesting add regarding the manufacturing practises. Below animal feedstock. Gross, man, and kinda scary, really. Hypnotics are scarier, or, perhaps just equally so, though. LOL. Almost all of these studies are funded by big pharm:
Much of the literature I've read, paint hypnotics with an innocuous brush (I have many example of this): No withdrawal, no tolerance. A short-acting benzo (essentially) with no withdrawal or tolerance? Not bloody likely ;-). I have heard many MD's made similar claims about their "safety". I can see many problems arising, here. Interdose withdrawal, as one instance, being diagnosed as anxiety, perhaps, complicated initial insomnia etc, etc...
Shoot, please excuse the spelling errors, above...
AzR: Thanx, again, man :-).
I ended up looking up DHSEA and just came across some wishy washy "act" from the 90's:
All I could ascertain is that the onus is on the manufacturer to ensure "quality". I was thinking of this repetitive slogan I heard via TV ads to do with nutritional supplements: "Jaimeson, a name you can trust". So, I went to their website and there is zero info on *what* is done to ensure quality. Just some bull about things are "clinically tested". In the face of mola, I wonder how much or what is done by this and other manufacturers towards quality assurance. This is an eye-opener. I never considered this which bugs me. I'm not exactly a trusting lamb when it comes to this kinda thing. As skeptical as people come, generally ;-) :-).
I have NEVER bothered to read or even notice "conflict of interest" aspects of empirical works. If I'm just cruising around, I generally rely on abstracts. If something "smells", I'll typically delve into design and statistics--I have a fair bit of experience to understand, here. I figure, if everything looks sound; methodology is rigourous, stats add up, I tend to believe/rely on what appears to be statistically valid and reliable. How naive, right? One must apparently consider much more.
Given what you've said about insomnia and anxiety, I think my spelling faux pas may have tweaked my intended meaning when I was providing exemplification of how "interdose withdrawal" may be mistaken for something else (??). If so, I want to clarify. I just meant that I can see interdose withdrawal not only mimicking anxiety but perhaps complicating primary insomnia. I suppose, the latter may more likely occur as a result of common side effects associated with hypnotics, like rebound insomnia, though...
I definitely see the likeness between z drugs and benzos, btw. I remember you mentioning this before now, too.
Also, animal feces, viagra analogues, and all other 'nasties' you mention? My gawd! I wonder how much of this is NOT revealed. I could imagine some poor sod seeking help for a problem to do with a contaminant and it either never being identified, so the patient suffers, or at least is never linked to the real culprit. Wow.
Re: Conflicts of Interest: The disclosure statement. First time I've even noted this. Shoot. Just leafing through some papers on my desktop, here....
AzR: I wonder if the same is true of what you say regarding the safety of supplements in Canada. I think you are in the US. I doubt the average consumer is aware of what you know. Scary, really.
I have heard of rTMS, but not the approval hoopla. Is this even effective for depression? I assume this is how it may be most commonly used. It sounds very barbaric.
AzR: So, rTMS, I guess a treatment option for mainly the rich. Hmm. People who have resistant depression, I would imagine, have had their lives screwed up by it. Perhaps it might be fair to say that money may be an issue for them, particularly in countries where one pays for these things out of pocket. In Canada, we don't pay for the services you guys do in the US, but there are other problems. The wait times here are ridiculous. I have many e.g's of consequences, to do with this. But, generally, if you are not going to die within a year, you're the last on the "specialist" or "surgery" list, no matter how you are suffering. I hear the quality of medical care kinda stinks here compared to the US, too. Doctor competency a problemo.
I actually take OTC melatonin. Given all you've said, man, I think I may need to do some research. I (as well as many others) could be ingested who in the hay knows what. Sheesh. Pretty effective for insomnia; this only *my* anecdote, though.
- Az RLv 61 decade agoFavorite Answer
It's my understanding that the sleep promoting effects of melatonin (and Rozerem vicariously) are not due to their systemic circulation in the body, but due to their stimulation of the suprachiasmatic nucleus in the brain and alteration of that region's control of wakefulness. Basically, it doesn't matter how much is in your blood, it matters how much is activating receptors in a specific, very tiny area of the brain. The quantity of stimulation correlates to a particular part of the circadian rythym, and just as you can 'push' it to what would be be a 'sleep' position, you can push it elsewhere.
I guess a way to put it is when you play with this system, you're not turning something on or off. It's not a sedative/hypnotic.You're setting a dial - one that you don't know what it's set to, where you want it to be set, or how far you're turning it.
Sorry I can't give better info. I have only a vague understanding of this area. It involves an intersection of the endocrine system and the CNS both of which vary significantly from person to person - the aforementioned dial analogy.
EDIT: In terms of efficacy, I don't really think there is one. I don't have the literature in front of me, but from memory, they both show the same response rate above placebo in separate studies - not totally comperable of course. Anecdotally I've heard pretty much the same. And that's not a very good success rate compared to say, Ambien.
Since I don't see a demonstrated difference in efficacy, the basic advantage to Rozerem would be that it's manufactured by a drug and has actual regulation and quality assurance. Melatonin is manufactured as a food -a supplement actually under the DHSEA. The manufacturing practices maintained by that law are somewhere below animal feedstock - so there's not only issues of contamination there's issues of manufacturing quality (how much and bioavail). Assuming those are resolved, there wouldn't really be a difference.
EDIT Again: Yes. Actual management of insomnia is extremely poor. I don't like to see benzos used for sedation (admittedly, a frequent presentation of anxiety disorders is insomnia due to.. well anxiety, this is a different issue). But arousal and sedation are systems that the brain does not tolerate much monkeying with before it thoroughly adjusts to the new chemistry - hence why you can't use amphetamines or benzos indefinitely. I've said it before, but the Z-drugs are basically novel benzos as much as that sounds like an oxymoron.
God I would love to see more NIH sponsorship of trials.
Rozerem may indeed have greater binding affinity for MT receptors. However, I don't have the kD values on hand. It may also have lower affinity - which could be equally useful since you're trying to get in a certain 'window' of stimulation.
And yeah. It's pretty revolting. Some of the things that have been found either intentionally or unintentionally introduced to some supplement products are revolting. Animal feces, viagra analogues, in 07 a company got caught with human placenta in their product, a few years ago there was a nipple cream for nursing mothers that contained a potent skeletal muscle relaxant. The only thing that keeps a lot of this stuff from being really bad messes is that most of these companies are rather small - though not always. The tryptophan incident comes to mind.
And when you're reading an article, - ALWAYS- go through the conflict of interest section: if it's longer than the results, take them with a grain of salt.
EDIT3: Part of the issue was the the snarl over manufacturing guidelines, which have finally been layed down and are going into enforcement - but to be honest they're still weak, unenforcable and riddled with loopholes.
One of my favorite conflicts of interest has to be the one that was part of approval study for that rTMS device a while back. It was longer than the references. I mean, everything has some conflicts: people don't do these projects for free. But especially in medical device land - come on people.
rTMS is probably useful - there's a bunch of European originated devices and studies that either haven't been translated, or I haven't seen them. It appears to be fairly effective, but it's also incredibly expensive - very small extremely powerful magnets. The course of treatment with the US device costs more than the most expensive (1 year of) antidepressant treatment I'm aware of.
And yes, I'm in the US. I have no idea what things are like in Canada. The thing is, these things happen, and no one really knows how much because there's no system for managing any of it. They don't seem to be common, but again no one's -looking-. There's no VAERS or MedWatch for supplements - though they do pop up in MedWatch sometimes when they get caught doing something particularly nasty.