Back to Melatonin - Dosing?

[Bolt_Upright]

I won't go as deep as Art does on Melatonin, but am picking up on a point Art makes often: Dosing!

I read all these papers and frankly skim over a lot. Today somebody on FB reposted one of my favorites: 2021 - Melatonin as a Chronobiotic and Cytoprotective Agent in Parkinson’s Disease ncbi.nlm.nih.gov/pmc/articl...

So I take 10 mg of melatonin, but this re-post made me read the report closer (every time you read one of these you take in more). I went through all of the tables.

I guess Table 1 is the table that got me thinking of dosing. It's the animal studies:

Melatonin equivalent dose for a 75 kg adult patient: 1991 - 12 and 120 mg - Reduced apomorphine-induced rotational behavior.

Melatonin equivalent dose for a 75 kg adult patient: 1996 - 60 mg - Reduced lipid peroxidation and TH-positive neuronal loss in striatum after MPP+

Melatonin equivalent dose for a 75 kg adult patient: 1998 - 120 mg - Reduced lipid peroxidation and protected against DA neuronal loss induced by MPP+

Melatonin equivalent dose for a 75 kg adult patient: 1998 - 36 and 120 mg - Increased striatal DA synthesis and levels.

Melatonin equivalent dose for a 75 kg adult patient: 1998 - 36 and 120 mg - Reduced motor deficit and improved dopaminergic neurons survival.

Melatonin equivalent dose for a 75 kg adult patient: 2001 - 15 mg - Prevented apomorphine-induced rotational behavior and mitochondrial damage.

Melatonin equivalent dose for a 75 kg adult patient: 2002 - 24–300 mg - Prevented apomorphine-induced rotational behavior and depletion of striatal DA and serotonin levels.

Melatonin equivalent dose for a 75 kg adult patient: 2002 - 120 mg - Decreased MPP+-induced toxicity and recovered GSH levels.

Melatonin equivalent dose for a 75 kg adult patient: 2003 - 30 and 60 mg - Increase in mitochondrial complex I activity in nigrostriatal neurons.

Melatonin equivalent dose for a 75 kg adult patient: 2006 - 6 mg - Normalized motor deficits and augmented TH immunoreactivity.

Melatonin equivalent dose for a 75 kg adult patient: 2006 - 6 mg - Prevented apomorphine-induced rotational behavior.

Melatonin equivalent dose for a 75 kg adult patient: 2007 - 120, 240 and 360 mg - Reduced levels of hydroxyl radicals in mitochondria and increased GSH levels and antioxidant enzymes activities in SNc.

Melatonin equivalent dose for a 75 kg adult patient: 2009 - 120 mg - Reduced DA neurons apoptosis.

Melatonin equivalent dose for a 75 kg adult patient: 2009 - 120 mg - Reduced mitochondrial NO levels, reduced lipid peroxidation and improved complex I activity in striatum and SNc.

Melatonin equivalent dose for a 75 kg adult patient: 2001 - 30 mg - Reduced DA neurons loss and locomotor activity deficits. Improved mitochondrial respiration, ATP production, and antioxidant enzyme levels in SNc.

Melatonin equivalent dose for a 75 kg adult patient: 2011 - 180 mg - Reduced lipid peroxidation, TH-positive neurons death, and apoptosis.

Melatonin equivalent dose for a 75 kg adult patient: 2012 - 120 mg - Improved motor performance without causing dyskinesia. Improved DA neurons survival.

Melatonin equivalent dose for a 75 kg adult patient: 2013 - 120 mg - Improved DA neurons survival.

Melatonin equivalent dose for a 75 kg adult patient: 2013 - 30 and 60 mg - Improved motor performance, striatal DA level, GSH, and antioxidant enzyme activities, and reduced lipid peroxidation. Improved motor response to l-DOPA.

Melatonin equivalent dose for a 75 kg adult patient: 2014 - 120 mg - Improved DA neurons survival and increased DA levels.

Melatonin equivalent dose for a 75 kg adult patient: 2014 - 120 mg - Reduced oxidative damage and apoptosis of DA neurons.

Melatonin equivalent dose for a 75 kg adult patient: 2015 - 60, 120 and 180 mg - Improved DA neurons survival and enhanced the therapeutic effect of l-DOPA.

Melatonin equivalent dose for a 75 kg adult patient: 2015 - 120 mg - Improved DA neurons against antioxidant enzyme activities and reduced lipid peroxidation.

Melatonin equivalent dose for a 75 kg adult patient: 2016 - 6 mg - Reduced motor deficit and DA neurons loss.

Melatonin equivalent dose for a 75 kg adult patient: 2017 - 60 mg - Reduced DA neuronal damage.

Melatonin equivalent dose for a 75 kg adult patient: 2017 - 60 mg - Preserved mitochondrial oxygen consumption, increased NOS activity and reduced locomotor activity.

Melatonin equivalent dose for a 75 kg adult patient: 2018 - 120, 240 and 360 mg - Reduced DA loss and improved mitochondrial complex-I activity in SN.

Melatonin equivalent dose for a 75 kg adult patient: 2018 - 240 mg - Improved motor function by upregulation of tyrosine hydroxylase in striatum. Reduced DA neuron damage.

ON THE FLIP SIDE, IF YOU LOOK AT TABLE 2 - Clinical trials with melatonin in Parkinson’s disease:

You will see the dosages were much lower for humans and the best result looks to be for the trial where they used 10 mg (2020): Melatonin supplementation significantly reduced UPDRS part I score, PSQI, BDI and Bai. It also resulted in an increase in antioxidant capacity, and reduced serum insulin levels, HOMA-IR, total and LDL-cholesterol as well as gene expression of TNF-α, PPAR-γ and LDLR.

The 50 mg (25x2) trial in 2017 also had good results: Melatonin decreased COX-2 activity and improved some antioxidant markers. UPDRS score decreased in the melatonin-treated patients but no in the placebo group.

I'll dig into the individual reports later. It sure seems like I should try to get my melatonin at least up to 40 mg at night.

[MBAnderson]

Great find. Important.

Why did you pick 40 mg?

[Bolt_Upright in reply to MBAnderson]

40 mg is not a firm choice yet. I just know millions of people have been taking between 3 and 12 mg and still progressed (except for that one 72 yo on 2 (or 3), so I probably need to move out of that range. I guess I like splitting the difference between choices. I'm at 10, 100 seems like a lot. I know a gu in my REMSBD group doing 50. 40 sounds interesting. Plus, it is on top of the other things I do. Hopefully complimentary.

I've tried to go over 10 mg at night before. I did not wake up well, but I am also depressed about this situation so it may not be the melatonin.

Thanks!

[MBAnderson in reply to Bolt_Upright]

I've been at 10 mg, too, but am going to study the study more, but it might be a decision like with B1, that is, the safety profile is so good there may not be a good reason not to take 60 + mg

[Bolt_Upright in reply to MBAnderson]

I should add: Art has posted this paper multiple times. I just tried to put those animal dosages out front.

[Bolt_Upright]

Here is a link to Art's last post on Melatonin and PD: Melatonin For Parkinson's Disease healthunlocked.com/cure-par...

[chartist]

Bolt,

In the 50 mg melatonin / PwP study it took the full length of the study to just barely start to see motor symptom improvement during off time.

sciencedirect.com/science/a...

Melatonin is definitely working in the brain to protect DA neurons as well as mitochondria, but at least as important, melatonin is produced in the gut at a rate that is estimated at between 400 and 1000 times the amount produced in the pineal gland and this has great significance that has not yet been fully elucidated in studies. That level of production in the gut microbiota is no accident, it has an important role in conjunction with SCFAs. FMT restores these factors and the FMT studies are important for showing us what we need to know about the importance of the gut microbiota.

To illustrate what the right dose of melatonin does compared to a dose that is too low, look at these two studies :

This first study uses 250 mg/day in diabetic patients and look at the results :

ncbi.nlm.nih.gov/pmc/articl...

This second study also used melatonin in diabetic patients at 10 mg/day and look at the results :

ncbi.nlm.nih.gov/pmc/articl...

The second study concluded that, the current study did not support the improving effect of melatonin on glucose homeostasis.

Are you starting to get an idea of the importance of dose when it comes to melatonin? I'm still at 106 mg+ per night and considering going higher!

Art

[Bolt_Upright in reply to chartist]

This caught my ear today: "Your blood levels of melatonin are exclusively from the pineal gland" youtu.be/9ThOqgMHKQc(Not working as expected?)

Prof Reiter

I must be misunderstanding or why take supplements?

At 20:17 he explains the only melatonin that gets into the blood comes from the pineal gland. interesting.

[chartist in reply to Bolt_Upright]

Supplemental can go to the gut, blood and brain or just about anywhere in the body. Melatonin produced in the gut does not make you sleepy or go to the blood according to Dr. Reiter. Melatonin increases SCFAs and SCFAs increase melatonin and melatonin receptors in the gut and this is a repetitive positive health cycle that will need to be stimulated appropriately for better health in my opinion.

Art

[Bolt_Upright in reply to chartist]

I will try the move to 15 mg again tonight.

[hanifab23 in reply to Bolt_Upright]

how much is that

[Bolt_Upright in reply to Bolt_Upright]

Gastrointestinal melatonin: localization, function, and clinical relevance

The concentration of melatonin in the gastrointestinal tissues surpasses blood levels by 10-100 times and there is at least 400x more melatonin in the gastrointestinal tract than in the pineal gland.

pubmed.ncbi.nlm.nih.gov/123...

[Bolt_Upright in reply to Bolt_Upright]

You have probably seen this. Lot's of positive info from 2017:

Melatonin: Pharmacology, Functions and Therapeutic Benefits

Sylvie Tordjman,1,2,* Sylvie Chokron,2 Richard Delorme,3 Annaëlle Charrier,1 Eric Bellissant,4,5 Nemat Jaafari,6,7 and Claire Fougerou4,5

ncbi.nlm.nih.gov/pmc/articl...

[chartist in reply to Bolt_Upright]

Keep in mind that that is 2017 and even more is known about melatonin now and the list of benefits is even longer. I definitely would describe melatonin as a "smart molecule" if there is such a thing.

Melatonin seems to me, to be a molecule that tries to maintain homeostasis in almost all areas of the body, but with age comes declining melatonin levels and gut dysbiosis leading to lowered levels of melatonin then there is no longer enough melatonin to maintain homeostasis and as this melatonin decline sets in so do age related diseases such as PD, AD, CVD and Cancer. Possibly coincidence, but an interesting one.

It is very important to note that along with SCFAs, FMT also increases gut melatonin content which increases and repairs the mucosal barrier and protects the endothelial cells while reducing inflammation and oxidative stress in the gut. It seems like there is a theme forming here.

Art

[hanifab23 in reply to Bolt_Upright]

which brand

[PwPKaren in reply to chartist]

This site can’t be reached Check if there is a typo in ncbi.nlm.nih.gov.

[kstavert]

There are bazillions of melatonin supplements...

Any suggestions on what to look for???

What to make sure it does NOT contain?

Thank you

[Bolt_Upright in reply to kstavert]

Some melatonin has B6. I don't like it when they mix other things with the melatonin. Some people use timed release. I don't know anything about that.

[CaseyInsights in reply to kstavert]

This sublingual is a starteramazon.com/gp/product/B07JM...

Try this 20mg product as you up your dose

amazon.com/gp/product/B0016...

[SELFMeder]

Okay. Bottom line, what is the effect of Melatonin on PD’s sleep?

[Bolt_Upright in reply to SELFMeder]

I wish there was a bottom line. Everybody is different. I should add that I have not been diagnosed with PD. I have been diagnosed with REM Sleep Disorder. Some call it prodomal PD

Even if Melatonin does not help you sleep, you may want to take it anyway. New article (2021): Melatonin as a Chronobiotic and Cytoprotective Agent in Parkinson’s Disease

ncbi.nlm.nih.gov/pmc/articl...

Good luck.

[SELFMeder in reply to Bolt_Upright]

Good “can’t hurt” advice! Thx.

[chartist in reply to SELFMeder]

SELFMeder,

I think sleep is the least of melatonin's true values and that particular effect seems to be hit and miss and the only way to find out how it will affect your sleep is to try it at several different doses starting at 1/3 or 1/2 mg and working up toward 10 mg. Everybody seems to react differently to melatonin for sleep and it does not help with sleep in everybody.

My main interest in sharing information about melatonin has nothing to do with sleep, but rather the multitude of other health benefits that melatonin has shown in studies, the ability to provide. Benefit in PD starts at 10 mg/day according to a 2020 study.

Art

[MarionP in reply to chartist]

What is a rough time period to expect observable benefits at these enhanced (10mg +)?

[chartist in reply to MarionP]

This study was done at 10 mg/day for 12 weeks and showed improvement in non-motor symptoms :

pubmed.ncbi.nlm.nih.gov/324...

This study was done at 50 mg day and just started to show motor symptom improvement during off time.

sciencedirect.com/science/a...

Art

[Hidden in reply to chartist]

I wonder if taking melatonin with other supplements will be okay? NAC, zinc, magnesium, and liposomal glutathione and a delayed release probiotic are part of my night routine and I’m not sure if that is compatible with melatonin. I am now up to 20 mg. I do have concerns about my body not producing as much bc its being supplemented. I guess dependency on melatonin is the least of my concerns though since I have PD amongst other things.

[Bolt_Upright in reply to Hidden]

Watch the video I posted above. According to Prof Reiter, taking melatonin does not affect your own production of melatonin.

[Hidden in reply to Bolt_Upright]

Thank you. And thank you Bolt for all of this research you do.

[Bolt_Upright in reply to Hidden]

So now I have a question: liposomal glutathione? I'm having trouble finding any information supporting this for PD. Any sources of info please? I know it will boost your glutathione level, but for how long? Thanks!

[Resano in reply to chartist]

Fine, Art, Bolt_upright, Selfmeder, Melatonin is neuroprotective vis-à-vis ROS etc but it is above all the secretion marker of two other key pineal hormones one must not forget: 6-Methoxy-harmalan (daytime consciousness) and Valentonine (important for PwPs because it is that of muscle relaxation and deep sleep). A bit of stress or anxiety, channeled, let us say, through the Gut-Brain axis, disrupts these functions because the corresponding state of wariness is immediately registered.

[Bolt_Upright in reply to Resano]

Please elaborate more. This is interesting. Thanks!

[Resano in reply to Bolt_Upright]

see response to Chartist.

[chartist in reply to Resano]

Resano,

Do you have study links that I can read for these two and where do you get them and how do you use them? This is what I get when I google Valentomine :

google.com/search?q=valento...

PubMed gives "0" results for Valentomine and 6 methoxy harmalan .

Not very helpful at all. This is what I get when I search for 6-Methoxy-harmalan :

google.com/search?q=6-Metho...

Again, not helpful.

You have to keep in mind that my interest in melatonin at this point is not so much supplementing or pineal gland production and release, but rather naturally increased production of melatonin and its receptors in the gut via up regulated short chain fatty acid producing bacteria to stimulate the melatonin /SCFA cycle.

Art

[Resano in reply to chartist]

Art’s, Bolt_Upright’s and colleagues > Thanks to your useful reviews of the literature and these new findings, we are getting closer to a definitive cure for that disease.

The key might be a pineal gland working properly with the corrected balance, not only of Melatonin but also of the two other hormones (6-Methoxy-harmalan and Valentonin).

A first condition is that the 20,000 members or so of the forum be in bed every day at 10pm sharp and wake up at 06am.

Requested references:

6-METHOXY-HARMALAN: Mc Isaac, W.M., Khairallah, P.A. & Page, I.H. 10-Methoxyharmalan, a potent serotonin antagonist which affects conditioned behavior. Science, 134, 674-675 (1961).

MELATONIN: Fourtillan, J.B., Brisson, A. M., Gobin, P., Fourtillan, M., Ingrand, I., Decourt, J.Ph. & Girault, J. Melatonin secretion occurs at a constant rate in both young and older men and women. Am. J. Physiol. Endocrinol. Metab., 280, E11-E22 (2001).

VALENTONIN: 3 PATENTS

1– Fourtillan, J.B., Fourtillan, M., Jacquesy, J.Cl., Jouannetaud, M.P., Violeau, B. & Karam, 0. Brevet déposé le 14.09.1995; numéro de dépôt : 95931243.0; numéro de dépôt international : PCT/FR/01179; numéro de publication international : WO 96/08490 (21.03.1996, Gazette 1996/13). Brevet Européen EP 0781 281 B1, publié et délivré par l’Office Européen des Brevets le 19.12.2001, Bulletin 2001/51. Brevet EP 1064 284 B1. Brevet Français FR 2724384 A1. Brevet US 6048868 A. Brevets Européens WO 9608490 A1 et WO 9947521 A1.

2– Fourtillan, J.B., Fourtillan, M., Jacquesy, J.Cl., Jouannetaud, M.P., Violeau, B. & Karam, 0. Brevet déposé le 17.09.1996 ; numéro de dépôt : 96931862.5; numéro de dépôt international : PCT/FR96/01444; numéro de publication international : WO 97/11056 (27.03.1997, Gazette 1997/14). Brevet Européen EP 0851 856 B1, publié et délivré par l’Office Européen des Brevets le 05.12.2001, Bulletin 2001/49. Brevet Français FR 273 8818 A1. Brevet US 606 666 3 A. Brevet Européen WO 9711056 A1.

3-Valenonine Patch.N° de dépôt : EP 15305161.0Déposants et inventeurs : Fourtillan Jean-Bernard et Fourtillan Marianne Date de dépôt : 4 février 2015N° de demande PCT : PCT/EP 2016/052376 Déposants et inventeurs : Fourtillan Jean-Bernard et Fourtillan Marianne. Date de réception à l’Office Européen des Brevets : 4 février 2016

[Resano in reply to Resano]

Please note that this knowledgeable researcher is highly critical NOT ONLY of Levodopa. The latter, as a precursor of dopamine in dopaminergic neurons and of noradrenalin in noradrenergic neurons, would actually release as much noradrenalin inside the synaptic clefts of noradrenergic neurons as dopamine in those of dopaminergic neurons…

BUT ALSO of decarboxylase inhibitors (carbidopa, benserazide…). This is harmful and irrational, he adds. This exemplifies its designers’ ignorance of the Wake state/Sleep system, he also says. The total uselessness of L-Dopa-decarboxylase inhibitors would be justified by one existing patent for each Dopa-decarboxylase inhibitor…

Scope and details of the discovery (in English)

valentonine.fr/en/discovery...

including a video already mentioned in our first post:

healthunlocked.com/cure-par...

The story (and you will understand why it jeopardizes 3 big markets dominated by Big Pharma): that of anti-depressants, anti-ALZ and anti-PD drugs

valentonine.fr/en/pr-jbf-en...

[chartist in reply to Resano]

Resano,

I read both of your replies and understand what you are saying about the other two pineal gland secreted molecules and while they have a purpose, that is outside of my current focus. Yes, melatonin in the brain is beneficial and it is depleted with age and further depleted in PD. To me, the importance of the other two secretions of the pineal gland have not been studied nearly enough to fully understand about them.

Since the FMT studies, my focus has shifted to Short Chain Fatty Acids (SCFAs) and melatonin in the gut instead of melatonin in the brain. The reason for this is because the FMT studies were able to improve the motor and non motor symptoms in actual PwP by 50% or more and from what I have seen, there is no other adjunctive treatment for PD that can come close to these results. FMT is not currently available for PD in the US. So I am looking at SCFAs and melatonin as a means to potentially replicate the effects of FMT without actually using FMT.

In FMT, the transplant increases both SCFAs and melatonin and there is an apparent synergy between melatonin and SCFAs in the gut the that can potentially repair the dysbiosis that exists in PD.

Melatonin in the gut is produced at a minimum of 400 times the rate of production in the pineal gland and that to me is of very significant importance because it highlights the significance of melatonin in the gut.

SCFAs and melatonin in the gut are both depleted with age and further depleted in PD. SCFAs and melatonin work together to repair gut dysbiosis in a pro-health cycle. SCFAs promote health promoting gut bacteria and they also increase melatonin and melatonin receptors in the gut. In turn, melatonin produces bacteria in the gut that when combined with fermentable fiber and or prebiotics can create more SCFAs which in turn produce more melatonin and more melatonin receptors in the gut. Melatonin and the SCFA, butyrate, work together to repair the damaged gut mucosal barrier seen in PD. Melatonin goes further to repair the epithelial cells beyond the mucosal barrier so together butyrate (SCFA) and melatonin work to stop leaky gut and gut permeability. Melatonin goes even further still to potently reduce the total inflammatory and oxidative stress burden of the dysbiotic gut .

Melatonin also activates PPAR-y (PP-y), which Dr. Mailing described as the master switch to reverse gut dysbiosis.

Resano, this is why my interest has intensified in the area of melatonin, SCFAs and the gut microbiota because of those FMT results in PwP. Results I feel that melatonin and SCFAs show the potential to replicate sans FMT.

Art

[PwPKaren in reply to SELFMeder]

SELFMeder, I was up to 160 mg per night and was sleeping really well.

have to know if Melatonin can cause edema so i stopped

Since the edema has cleared up, I'm assuming that melatoninwas the culprit.

i'll go back to beginning and start with a 20 mg tab and go up very

slowly so i can determine best dose.

I was also experiencing some depression - which is not characteristic of

me so, will monitor that, too

[PwPKaren]

there are a number of books on Amazon about the wonders of melatonin.

just starting to read Wake Up. Melatonin if for more than just sleep

[chartist in reply to PwPKaren]

Yes, melatonin is an impressive molecule that although produced in the body, we still do not know all about it. Here are some potential uses not related to sleep :

healthunlocked.com/cure-par...

healthunlocked.com/cure-par...

healthunlocked.com/cure-par...

healthunlocked.com/cure-par...

healthunlocked.com/cure-par...

healthunlocked.com/cure-par...

Art

[hermanuuu in reply to chartist]

Hi Art, does the melatonin help your Parkinson's ?

[chartist in reply to hermanuuu]

Hi hermanuuu,

I don't have PD so I can not personally comment on that aspect of melatonin, but in the 10 mg /day study in PwP it did in terms of non-motor symptoms. In the 50 mg study it improved motor symptoms during off time.

Here are links to those studies :

pubmed.ncbi.nlm.nih.gov/324...

sciencedirect.com/science/a...

My current interest would be to see if they do a 250 mg study as they have done twice already for T2DM. Here are links to those studies :

ncbi.nlm.nih.gov/pmc/articl...

ncbi.nlm.nih.gov/pmc/articl...

Art

[rriddle]

Interesting article on the TIMING of melatonin as well as the DOSE:

uhhospitals.org/Healthy-at-...

[Bolt_Upright]

Interesting. for sleep take them 5 hours before bed time. For therapeutic use you might still want to take them at night. Actually, I don't know when the best time is for therapeutic. Guessing night as your body does the cleanup at night (I think).

[Bolt_Upright]

Hmmm. I took my melatonin from 10 to 15 mg 3 days ago and just found out I had another REMSBD episode 2 days ago. I had gone at least a month without an episode on 10 mg (but I was also taking 600 mg of NAC and 1000 mg of Glycine at night and stopped it a week ago).

Wondering if I should drop back to 10 mg of Melatonin, add the NAC and Glycine back to the mix and stick to 15 mg of melatonin, or... I hate this.

[PwPKaren]

Can high dose melatonin cause edema?