Have anyone tried sustained release versions and noticed any differences?
There are two suppliers of suppositories that run at 200 and 400mg, but they release quite quickly in my experience. The sustained release versions around are OK to take before going to sleep, but again they release quite quickly. I saw this on a dexcom CGM as it kicked down the blood glucose whilst I was asleep which is a proxy for melatonin levels.
I have experimented with DR capsules in a russian doll style and use this for my wife who has delayed release melatonin inside 5 capsules (000,00,0,1 and 2). That works to a point, but still does not delay as much as I would like.
Ideally I would like to work with some form of pharmaceutical company to design a release pattern that works with the two compartment model as otherwise it involves holding melatonin sublingually in a way which controls release. However, this is not a personal priority as I am quite happy with how everything works. Last night I slept solidly for about 6 hours (probably because I was reasonably drunk - not so drunk that I forgot to measure my biomarkers before going to sleep (weight, bp, hr) - but quite drunk. When I woke up I took a total of 110mg of melatonin partly because I didn’t take DHM and Pantethine whilst drinking (intentionally - I am monitoring the alcohol rebound) and hence had a bit of a hangover which has now subsided. I will go to the pub to have my regular breakfast (without alcohol) at about 9am. For people in the UK the pub is part of the Wetherspoons chain.
Incidentally I am pretty certain that pantethine in accelerating the metabolism of acetaldehyde brings forward the alcohol rebound, but I continue to keep an eye on this.
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I assume you decided that galantamine was not something you want to take on a regular basis? On the other hand, what about melatonin? If you’re taking or are going to be taking higher doses, do you have any type of schedule for what dose to take and when to take it? Thanks
John_Hemming, With your large doses of melatonin, do you have any type of schedule for what dose you take and when you take it? Thanks
Its not really a schedule. It is more that I time things in a way which I find best enables me to extend my sleep. Sleep is very complex and the interplay with the HPA ultradian cycle and melatonin is quite complex. My own protocol increases the energy state of my cells (levels of Acetyl-CoA via ACLY and ACCS2) with a view to increasing gene expression. This has the effect of increasing cytosolic ROS - depending on other factors like NF kappa b. I am running a particularly intense form of the protocol at the moment and a side effect is an increase in visible inflammation. Melatonin helps to keep this under control. Because melatonin has a relatively short half life (about 30 mins) I might take 10mg every 10 minutes or every 5 minutes to maintain a vaguely constant serum level.
Obviously if I don’t wake up in the middle of the night all I can do is to take some melatonin when I wake.
I am not sure one way or another, as most studies see effects at very lose doses, so that’s why I was asking why they use such high doses. In adults, studies have found the benefits from melatonin are for people who have sleeping problems related to delayed sleep-wake phase disorder and jet lag. Evidence in small studies have indicated that melatonin may be useful in children with certain conditions including epilepsy and some neurodevelopmental disorders such as autism spectrum disorder and Angelman’s syndrome. High doses of melatonin increase sleep duration during nighttime and daytime sleep episodes in older adults.
In my understanding, we do see some age related decrease in melatonin synthesis, but the literature is mixed on this. I am fortunate to be able to learn from a great group of circadian rhythm field experts such as , Dr. Gianluca Tosini, who is a pioneer in the melatonin/circadian rhythm field. I talked to him about this issue before as we know the SCN and retina from older mice and humans a show a decrease in responsiveness to melatonin, and he said that as we age, it less so the effect of melatonin synthesis decreasing and more so the effect of melatonin receptor responsiveness decreasing that leads to disruption of sleep as we age. We also talked about melatonin’s antiaging effects, and the one study he knew of claimed to help in anti-aging and in the paper it was shown that if you give exogenous melatonin only at night, you can extend lifespan in mice. But his issue with the paper is that it is hard to distinguish between the effects of melatonin or if it is sleep that is causing this extension of lifespan.
There is a really good review on the aging clock that I will attach:
https://www.jci.org/articles/view/90328
What was interesting was their talk on melatonin:
" However, other evidence suggests that a “young” melatonin rhythm is in fact preserved in very healthy older adults, and a reduction in peak melatonin may occur only in older individuals whose total melatonin levels are at the lower end of the population distribution. For example, a 6-year longitudinal study found no evidence of a decrease in total melatonin secretion in healthy older adults (ages ranging from 55 to 74 years). This discrepancy in findings may suggest that a reduction in the melatonin rhythm is not a feature of a healthy aging process, and in fact may signal underlying pathology. To this end, Waller and colleagues reported a lower nightly melatonin peak in middle-aged men (mean age of 57 years) with cognitive impairment compared with age-matched healthy controls. Furthermore, significant reductions in melatonin synthesis and expression of melatonin receptors in the SCN have been documented in individuals with neurodegenerative diseases such as Alzheimer’s or Parkinson’s, or those with prodromal symptoms. "
I also know of Melatonin disruption leading to health disorders such as obesity, type 2 diabetes, insulin resistance, etc. A variant in MTNR1B is associated with increased risk of type 2 diabetes and impaired early insulin secretion. There have been some studies talking about melatonin over signaling being a risk factor for type 2 diabetes. In insulin secreting cells, melatonin seemed to reduce cAMP levels and MTNR1B overexpression exaggerated the inhibition of insulin released exerted by melatonin.
Personally, I don’t see much benefit in taking large doses of melatonin until we get much much older, and even then I would weigh the risk/reward in relation to the benefits of melatonin dosing vs how much longer you think you have left. I don’t see the harm in taking a large dose if your 70-80+ and you more than likely are heading toward your marginal decades, but if your younger than that, I would wait to see more research come out.
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It is worth remembering that the concentration in the CSF is much higher (factors) than in serum. Particularly in the third ventricle. Hence studies that look only at serum levels may miss changes that happen in the CSF. I would expect the metabolism in the CSF to be different to the serum.
However, in the end I am concerned primarily as to the impact on myself. I am a lot healthier now than a few years ago and I consider melatonin to be part of that.
I would be interested in studing the profile in serum of large doses. I would think a proportion is absorbed into cells quite quickly and possibly faster than an orthodox half life of 30 mins.
Actually am going to take galantamine hydrobromide, 8mg daily, sublingually for some time to see if I can find any subjective positive effects or deduce any effects it might have on my biomarkers. I think I have already posted references to the positive effects attributed to galantamine, but here are some of the positive effects gleaned from several articles about galantamine:
Improving memory and cognitive function.
Slowing down the progression of Alzheimer’s symptoms.
Enhancing thinking, learning, and problem-solving abilities.
Relieving depression.
Improving sleep quality.
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I’m aware of the diabetes connection and agreed best to wait and see before supplementing or megadosing melatonin outside of say delayed sleep-wake phase since the safety of long-term exogenous melatonin use is not well documented, nor are side effects actually well established. “Melatonin dysfunction” doesn’t necessarily mean taking melatonin would do much if it is an epiphenomenon, as you already know. As an example, an iron chelator for newly diagnosed drug naive PD reduced iron in niagrostriatal pathways and ended up increasing progression of PD despite the characteristic “iron dysfunction”, suggesting an epiphenomenon.
There is only a small benefit for sleep onset and none for sleep maintenance with a statistically significant but small improvement in sleep latency and total sleep time which doesn’t seem to be clinically significant afaik. Would be interested if you’re aware of any increased REM and/or N3 without significantly compromising any other parts of sleep architecture. The only suggestive deal I have seen with better safety profile is low dose gabapentin especially more justified with anxiety disorder and gabapentin responder with only limited use due to “tolerance”.
Not sure about high doses, but generally I want a fairly well defined potential benefit and high enough safety profile (although it might be the case where melatonin megadosing could turn out to be “safe”) to really consider it, let alone megadosing anything.
I’m also interested in whether low dose (ie 300 mcg) sustained-release dosing could “augment” natural circadian alignment over the longer term, as you know - we are not quite on the 24 hr mark, so I’m not quite saying we shouldn’t bother using melatonin in the long term especially if individual variation brings it down, the purported high safety profile just isn’t actually proven or disproven. Just dunno how much it matters in efficacy either.
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https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2800004
I just switched to candesartan based on this article, Brain/Dementia benefits theorized. Go ahead, change my mind 
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Btw I use canagliflozin intermittently instead of continuously partly to indirectly lower serum urate to <5.8 despite adequate hydration and a low fructose diet etc with FHx of gout (bimodal curve).
The main issue I see is the difference in safety and risk profile in my specific situation (it’s a high safety profile in general so far but there are several caveats and rare but important issues, especially in the context of rapa), hence intermittent dosing.
There may be some theoretical vascular and brain SGLT1/2 related effect in case anyone is interested in looking further
I am not aware of any increased REM or N3 without compromising other parts of sleep architecture. Our body, as you are aware, is very good at homeostatic regulation. The reason any stage of sleep gets increased/decreased unequally is due to a disorder or disruption of sleep homeostasis, so your body tries to “regain” that lost sleep. Our bodies spend the time it needs in the stages of sleep, I would say you could potentially increase QUALITY of that sleep stage, by figuring out ways to increase the delta wave power within NREM and theta wave power within REM, but in reality that would only occur if there was a disruption of sleep homeostasis prior. Also, how would one increase that power without disrupting other portions of sleep anyways? I agree a lot with your sentiments about melatonin and definitely agree about the supraphysiologic doses people are taking over long term. I also do not know at one point one would achieve maximum efficacy and receptor binding vs just excreting/wasting the extra melatonin they take. I have too many questions, so it’s not a practice I would partake in personally.
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Appears to be retrospective cohort, seen the same deal with PDE5i then later on null results prospectively. I don’t take a whole lot of stock, but not particularly against careful ARB use (ie might have to drop intermittent canaglifozin) perhaps later on I might consider a 1/2 of lowest dose when my BP increases beyond ~115/75 with a firm over 120/80 range.
Can you explain to me your views on how you would choose candesartan cilexetil vs telmisartan?
I was getting incomplete BP control with telmisartan, now with Candesartan, I have good control at 16 mg with room to move up if needed
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Seems to make sense in your case for BP control specifically, especially with candesartan cilexetil being tested in ITP with some minor positive results, I’m only slightly leaning on the side of low dose telmisartan with improved cognition/CBF as well as reduction in amyloid and seemingly slightly better PPAR gamma activation as opposed to candesartan - but of course these are based on preclinical mice studies that probably don’t apply to humans, so it’s still a toss up IMO. Depends on how you view the gamble.
Possible to reduce BP with other adjunctive agents ie 1.5g taurine (not proven, but should be long-term safe if high quality since from close to the upper limit dietary of well-studied populations) and 75% NaCl 25% KCl salt substitute?
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I’m on a low dose of Telmisartan (20 mg) in addition to a low dose of beta blocker. My BP control is not excellent but ok. Were you taking telmisartan alone without other BP meds?
I was not getting the best BP control with telmisartan, I also read this article, and subsequently asked my PA to put me on candesartan instead, because it is a stimulator of type 2 and 4 angiotensin II receptors and I want to do my best to avoid dementia, as I was adopted I have no knowledge of my own genetic family history and btw who wants dementia anyway. But my BP control is very good now.
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You may want to consider a CLIA-certified whole genome sequencing (some clinical trial options are free as opposed to a validated one will be ~$1000 with academic center discounts, the DTC tests are generally inferior in terms of validation or quality - ie lack of CLIA certification etc) as it might be worthwhile for you as a pretest probability of ~1 in 4 chance of APOE4 carrier is probably sort of worthwhile at least risk stratification wise. As an example for APOE4, there are potentially some micronutrient changes that have suggestive evidence (ie type of omega-3 essential fatty acids that get transported past the BBB) for actionable changes and probably won’t cause harm even if it is only at a theoretical or preclinical stage.
There is also some pharmacogenetics you may be interested in, particularly SNPs that predict CYP (and quite a few with sufficient predictive power on HLA, etc). There is modest strength evidence in grade 1 & 2 options, some that are starting to be validated in fairly large prospective trials with slightly better outcomes (as opposed to FHx only) and have proven not to be harmful overtesting (in those trial situations) already. Many variants are suggestive evidence at best when it comes to grade 3.
Since you have no FHx information, I suspect you may find potentially greater than marginal benefits, assuming one is psychologically ready and willing to receive potentially negative genetic information.
PharmGKB pharmacogenetic recommendations:
https://www.pharmgkb.org/
ACMG 2022 v3.1:
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Yes, I agree with you, though I have been reticent, fearing I might find something I don’t like, and I don’t want to develop a cardiac cripple response to such news. I’m getting closer, emotionally, to taking the plunge. I don’t like the idea of someone out there having my gene sequence; who knows what could be done with that?
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I hear you on privacy. I happen to have an excellent trusted asset protection attorney that has educated me on a wide range of options to preserve privacy through various means on quite a few occasions. I can’t say that it will necessarily apply to you but perhaps some food for thought.
First off, you don’t necessarily have to order it in the US. There are other countries out there. The likelihood it links back to you diminishes drastically.
Second, in some cases, you might be able to legally pull off a different name on a second passport or order a test with pseudonymous or anonymous information.
It’s incredibly unlikely anyone can do anything with a gene sequence with faulty identity data attached to the gene sequence unless you willingly offer too many publicly available clues for someone to eventually tie it to you after the fact.
Third, look into some anonymous form of payment or at the very least prepaid cards. Easiest way to tie your information is payment.
As for the potential for negative information, it’s more of a personal question that I can’t really help you with beyond what you already are aware of - genetic counseling.
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