Melatonin For Parkinson's Disease (Pt... - Parkinson's Movement

Parkinson's Movement

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Melatonin For Parkinson's Disease (Pt. 2)

chartist
chartist

In case you missed part 1, here is a link to it :

healthunlocked.com/parkinso...

Melatonin is the only naturally occurring substance in the body that I have found that can help return the body toward homeostasis through multiple pathways.

Definition of homeostasis:

the tendency toward a relatively stable equilibrium between interdependent elements, especially as maintained by physiological processes.

This includes returning elevated inflammatory levels and elevated oxidative stress levels back toward normal/healthy. I have not found any other single molecule produced in the body that can potentially do that and much much more in terms of protecting the body and its organs. Here is a link where they used 100 mg/night in resistance trained athletes for 4 weeks and were able to return them to " redox equilibrium" with that dose. Here is a link to that study which is behind a paywall.

pubmed.ncbi.nlm.nih.gov/281...

Here are some important quotes from the article :

>>>We conclude that melatonin supplementation at doses of 100 mg.day-1 during four weeks, 30-60 min before bedtime, enhances the efficiency of the endogenous antioxidant defence system leading to redox equilibrium, and yields skeletal muscle protection against exercise-induced oxidative damage, without adverse effects (Zhang and Zhang 2014).<<<

>>>Our findings confirm the beneficial effects of melatonin treatment on athletes, without any undesirable side effect that could affect athlete's performance.<<<

The study above showed the health benefits and safety of 100 mg / night in athletes. The following study shows the value of just 10 mg / night of melatonin in PWP :

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

It makes you wonder what that same 100 mg study would have shown in PWP.

Melatonin promotes stabilization of Nrf2 as well as increased gene and protein expression of Nrf2 while suppressing KEAP1. This is highly desirable as more activated Nrf2 will increase the antioxidant status to levels capable of greatly reducing oxidative stress which does much of the damage in PWP. Melatonin via activation of Nrf2, HO-1 and Sirt 1 is able to also reduce neuroinflammation.

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

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

In PWP it is known that the total antioxidant capacity(TAC) is significantly reduced and significantly below healthy controls. The bodies response to this is to produce more melatonin, to increase TAC, but the body does not seem to be able to produce enough melatonin on its own to complete this task. This is why studies of PWP show elevated serum melatonin levels, but not nearly high enough to return to homeostasis as glutathione and TAC are at reduced levels even though melatonin serum level is above normal control levels. Of course this problem is exacerbated with age as native melatonin levels decline fairly quickly from puberty to the 50's at which point they continue to decline at a lesser pace. Even so, just 10 mg of melatonin per night starts to increase glutathione and TAC, but not enough to reach redox equilibrium as was seen in the 10 mg PWP study. Keep in mind that although the exact cause of PD is not known, it is established that excess oxidative stress and excess inflammation are what is doing most if not all of the damage in PWP, so you can see the value of returning the body to redox equilibrium to slow or stop this destructive process.

In the following study, children with Duchenne Muscular dystrophy were given melatonin at 70 mg/day for 9 months and the effects were remarkable! There was a follow up report on these children the following year which was also remarkable and is the second link below!

pubmed.ncbi.nlm.nih.gov/202...

sciencedirect.com/science/a...

Melatonin is the most potent antioxidant in the body for multiple reasons. Melatonin upregulates gene expression of the following natural antioxidants in the body, superoxide dismutase(SOD), catalase(CAT) glutathione(GSH), glutathione peroxidase (GPx) and heme oxygenase 1(HO-1). Each of these antioxidants have potent properties of their own. Take HO-1 as an example. By itself, it has the following qualities of antioxidant, antiinflammatory, anti apoptotic, antiproliferative and immunomodulatory effects, but the positive effects of melatonin go much further!

Melatonin itself is a potent scavenger of the following : reactive oxygen species (ROS)/hydroxyl radicals, reactive nitrogen species (RNS), H2O2 and peroxynitrite (ONOO). All of these are at elevated levels in PWP. Further, melatonin can neutralize up to 10 oxygen radicals compared to the antioxidants vitamin C and vitamin E, which can only neutralize oxygen radicals on a one to one basis. Melatonin works through multiple pathways, one of which is the Nrf2 / KEAP1 pathway which Albert has gone in to detail about. The following study describes how elevated levels of peroxynitrite

(almost 50% elevation) lead to elevated UPDRS score while melatonin is an effective scavenger of peroxynitrite, ROS, RNS and H2O2, either directly or indirectly.

europeanreview.org/article/...

This next link shows how RNS and ROS are also at elevated levels in PWP and the damage they do.

link.springer.com/article/1...

Melatonin is also a protector of the mitochondria and in fact is produced in the mitochondria and melatonin is also absorbed by the mitochondria. This is important because PD is a mitochondrial function disruptor and the malfunctioning mitochondria can lead to dopaminergic neuron death as outlined in the abstract below. Keep in mind that the body is not able to produce enough melatonin on its own to prevent all of the damage to the mitochondria.More melatonin is found in the mitochondria than in the blood by a very significant amount. Melatonin has already proven to restore mitochondria function in Alzheimer's mice.

pubmed.ncbi.nlm.nih.gov/288...

pubmed.ncbi.nlm.nih.gov/294...

onlinelibrary.wiley.com/doi...

The following full study highlights some of the abilities and usefulness of melatonin in PD including melatonin's ability to reduce alpha synuclein aggregation to protect dopaminergic neurons from death, protect mitochondria also to protect dopaminergic neurons from death, antiinflammatory properties to control inflammatory damage in the brain, scavenge multiple radical types to protect the brain as a whole and protect dopaminergic neurons specifically, points out that PD impairs brain melatonin production as well as decreases melatonin receptors in the substantia nigra.

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

You're probably wondering how melatonin can do so much in these studies above, but this is nothing compared to what melatonin is doing in the rest of the body! All of the above concerning melatonin is barely a snippet of what melatonin is capable of in the human body! The following August 2020 full study goes into significant detail concerning the broad spectrum beneficial health effects of melatonin in humans and animals.

mdpi.com/2218-273X/10/9/121...

Keep in mind that the melatonin health benefits highlighted in the above study is not a complete list!

Dr. Neel, Dr. Reiter and Dr. Shallenberger (74 years old) all use melatonin at 100 mg /day or higher for extended periods of time. Dr. Neel uses it in his Covid-19 patients very successfully at 1 mg per kilogram! Dr. Russell J. Reiter is a world renowned melatonin researcher who has been involved in over 600 studies and uses it in his animal studies and himself @ 100 mg+/night for 25 years as a preventative and he is in his 80's. Dr. Shallenberger uses it in all of his patients and himself @ 180 mg / night and up to 360 mg/ day in some of his stage 4 cancer patients. Some researchers are considering over 500 mg/day of melatonin for Covid-19.

In PWP, there is increased potential for heart problems and melatonin is heart protective as well as protective of the major organs, including the brain and vasculature.

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

The following is only a rat study, but it shows that melatonin protects dopaminergic neurons from death. Keeping in mind that melatonin easily crosses the blood brain barrier and enters all tissues of the body including the substantia nigra in the brain to impose its highly potent antioxidant and multiple radical scavenging activities, it is like another piece of the puzzle being put in place. We already know that 10 mg of melatonin per night confers positive and measurable health benefits in PWP in just 12 weeks with a very good safety profile. The melatonin receptors are there in the substantia nigra pars compacta for a reason. Now we just have to find out what higher dosing and longer duration can do for PWP.

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

Another animal study shows that melatonin at high dose, protected against nigral dopamine loss and replenished the striatal dopamine loss that resulted in amelioration of rotational behavioral bias in Hcy denervated animals.Melatonin administration significantly improved mitochondrial complex-I activity and protected the SN neurons from the toxic insults of oxidative stress induced by Hcy. Amelioration of oxidative stress by melatonin in Hcy-infused SN was bought by dose-dependently scavenging of hydroxyl radicals, restoration of glutathione level and elevation in the activity of antioxidant enzymes.

pubmed.ncbi.nlm.nih.gov/291...

The following study is 16 years old, but it was already showing the huge potential of melatonin in human health :

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

There is still more research to be done, but the past and current studies have peeled back many of the layers of melatonin and continues to show what a remarkable and useful molecule it is for human health and PWP. At this point further studies using high dose melatonin in PWPs are warranted and desperately needed to determine the most effective dose.

The following abstract shows that a 100 mg intravenous dose of melatonin in humans was very well tolerated with no adverse effects or sedation :

pubmed.ncbi.nlm.nih.gov/261...

THE SAFETY OF HIGH DOSE MELATONIN

It took a bit of time, but I have gathered the information regarding the safety or lack of safety of high dose melatonin in the 10 links below. As much as possible I tried to use scientific human studies as opposed to animal studies or test tube studies. The last link lists side effects of melatonin and side effects of Sinemet to give some type of comparison to a known quantity such as Sinemet which is considered as a common and often times frontline treatment for PD. Keep in mind that at the doses used in these studies that we are no longer looking at melatonin as an over the counter sleep aid, but rather as an effective treatment for some fairly serious diseases.

1. The following abstract briefly discusses what is currently known about the safety of melatonin in humans and is in line with the above information :

pubmed.ncbi.nlm.nih.gov/266...

2. In the following ALS human and mouse study, the mice and humans were given melatonin at 300 mg/day for up to 2 years to very good effect. They also used suppository melatonin for the humans with no next day sleepiness suggesting that the suppository approach may be a way forward for people who report excess next day drowsiness!

onlinelibrary.wiley.com/doi...

3. Melatonin studies using up to 2,000 mg/day in cancer patients have been done with no side effects.

4. This RCT human study gave a one time dose of 50 mg per kilogram of body weight. To put that into context, if you weigh 150 lbs or 68 kg, your dose would be getting 3,400 mg of melatonin!.If you weigh 80 kg, the dose of melatonin would be 4,000 mg! Yes, nobody has ever died or been seriously injured by melatonin.

pubmed.ncbi.nlm.nih.gov/214...

5. In this study, a 100 mg intravenous bolus of melatonin was given to humans. This study is important because oral dosing only delivers as low as 3% to 15% of the melatonin into the system. So a 100 mg bolus is equivalent to a much much higher oral dose. Other important points to this study are no side effects and no next day sedation effects. Important for people who feel groggy the dater after taking melatonin (melatonin hangover).

pubmed.ncbi.nlm.nih.gov/261...

6. In this human study of cancer patients, a dose of 100 mg night was given for up to 5 years with positive effects.

imedpub.com/articles/five-y...

7. This lengthy new study for treating Covid-19 based on previous studies is suggesting a dose of 8 mg per kilogram or 8 times the dose that Dr. Neel is effectively using for his Covid-19 patients! This a good study and although lengthy, it is interesting reading. Here are a couple of interesting quotes from it :

Nordlund & Lerner (26) treated patients with 1,000 mg melatonin/daily for 3 months and they did not find obvious side effects in these subjects.

Voordouw et al. (27), testing melatonin as a contraceptive medicine, treated 12 women with 300 mg melatonin/daily for 4 months and no significant side effects were reported.

Weishaupt et al. (28) gave to severely ill ALS patients 300 mg melatonin daily for 2 years, without any adverse effects.

For the acute melatonin treatment, the dose can be as high as 50 mg/kg for surgical patients, who tolerated this extremely high melatonin dose well and without serious side effects (29).

All data indicate that large doses of melatonin, whether given chronically or for acute treatment will not cause intolerable or uncontrollable side effects and that the safety margin of melatonin for humans can be up to 3,750 mg/day for a 75kg individual (29).

melatonin-research.net/inde...

8. In the following study, melatonin was given to children at a total of 70 mg day for 9 months :

pubmed.ncbi.nlm.nih.gov/202...

Here is a follow up on the first abstract :

sciencedirect.com/science/a...

9. This is an interesting article that discusses high dosing of melatonin in some major diseases including PD. They are suggesting dosing in the 25 ~ 100 mg range. Here is a quote from the article :

>>>Degeneration of the dopaminergic neurons is caused finally by increased oxidative stress and inflammation. Treatment with melatonin at doses between 25 mg and 100 mg are able to significantly reduce oxidative stress in the substantia nigra thus blocking neuron death. This treatment needs to be started at the initial steps of the disease since it is not able to reverse the already degenerated neurons. The combined treatment with L-dopa and melatonin reduces the doses needed of the dopamine agonist and blocks the evolution of the disease, by preventing the oxidative stress induced neuron death. The disease remains stable and does not continue its evolution.<<<

antiaging-systems.com/artic...

10. Here is a link to side effects of melatonin :

drugs.com/sfx/melatonin-sid...

Here are the side effects for Sinemet from the same source :

drugs.com/sfx/sinemet-side-...

CONCLUSION :

I have tried as much as possible through the use of scientific studies to show the potential of melatonin in PD beyond what the 10 mg study showed in terms of safety and efficacy in PWP in 12 weeks. Beyond what you see above I also drew information and ideas from videos by Dr. Russel J. Reiter Ph.D., MD., D.Sc, who has spent the last 25 years of his life espousing the benefits of melatonin in human health and is a world renowned melatonin expert who believes in his research and work so much that he has taken a minimum of 100 mg of melatonin himself for the past 25 years every night. He participated in over 600 studies according to PubMed.

pubmed.ncbi.nlm.nih.gov/?te...

What is needed at this point is an actual 100 mg+ PWP study to prove or disprove the idea that HDM can positively impact PWP to a much greater extent than the 10 mg study in PWP earlier this year, via returning the redox system to equilibrium while reducing inflammation and protecting dopaminergic neurons from death as already shown in vitro and in animal studies. In the DMD study in children who received 70 mg melatonin / day for 9 months, that study also showed a return of redox status to the control normal level while reducing inflammation markers and muscle damage, but it took the full 9 months of the study in order to achieve those results. Similarly, the ALS study which used 300 mg day for up to 2 years also showed a return to control value in terms of oxidative stress. The longest study I found so far is 5 years at 100 mg /day and this is longer than any drug trials by a very significant amount.

I am not recommending anyone try this idea and definitely not without a doctors support. I have just gathered what I thought were the relevant studies in order to show the potential that melatonin may offer PWP as a potential treatment and how it might do that, given the limited prospects currently available short of DBS or FUS, which are cost prohibitive for the uninsured. Melatonin is inexpensive.

Art

76 Replies
oldestnewest

Just glanced and seems interesting. Will read in detail during the weekend. I gave my mother 10mg of melatonin for more than 3 months and it did not help. Frankly, very nervous to give her a dose as high as 100mg on a daily basis. You know what I mean. It is going to be a hard decision. Will read and then take some time before going ahead (if at all).

But thanks a lot for the article and all the info.

John

Hi John,

I understand what you are saying about dosing and I am not recommending others take such high dosages. I have taken up to 180 mg of melatonin myself and am currently at the 70~80 mg dose range, because like B1 that I have written about, I wanted to know as much as possible about what I am writing and describing to others so I experimented with B1 up to 4,000 mg day for about a month when I had to stop as it gave me a tremor. My hope is that a research group will do a study of 100 mg or more for PD just as they did on those athletes. There are high dose studies in humans and some were for significant duration, but there has not been one in PWP, only the 10 mg study which did show clear and measurable benefit in PWP!

Art

That's actually very sensible of you. Melatonin is a hormone, it's not a harmless supplement to experiment at such a mega dose despite all the positive highlights, especially while not being actively monitored by a physician.

sleepadvisor.org/can-you-ov...

healthline.com/health/melat...

everydayhealth.com/melatoni...

Parkie-
Parkie- in reply to rescuema

I asked my pharmacist how high I could increase my 10mg melatonin for my REM sleep disorder. She said that because it is a hormone, the max dose was 10 mg. I didn’t want to create an hormonal problem on top of all my pd symptoms, so I listened to her. Thanks for the links.

Yes it’s a worry isn’t it. The doctor can prescribe and if it goes wrong it’s tough but if a caregiver does it will all get blamed on us if anything goes wrong.

I have tried melatonin before bedtime to improve sleep but find even a low dose (5 mg) leaves me feeling hung over and groggy in the morning , Does anyone have experience with taking it during the day?

chartist
chartist in reply to ladya2020

ladya2020,

You are correct, some people simply can not tolerate melatonin.

I have felt the melatonin hangover and I have taken it during the day to try and replicate a human study I had read years ago where they used 70 mg/day of melatonin in children for 9 months.

What I have found with melatonin is that the hangover normally lasts for 2 to 3 weeks as my body adjusts to having significantly higher levels of melatonin. After 3 weeks, the hangover has faded away.

One thing that helped me with the hangover was staying as busy as possible during the adjustment period instead of just sitting. If I sat at my computer or just read a book, the hangover was very noticeable and I could easily fall asleep sitting down during that period.

Art

ladya2020
ladya2020 in reply to chartist

Thank you.

Coling
Coling in reply to chartist

Hi Chartist, perhaps I missed this bit but what are the beneficial effects that you have observed in yourself taking the optimal dose of melatonin? Many thanks for the post

chartist
chartist in reply to Coling

Coling,

I do not know the optimal dose of melatonin. I am experimenting and my best guess is it likely depends on what you are trying to treat. Apparently cancer and ALS require ultra dosing, but Covid -19 only requires high dosing. I have bumped my current dose to 80 to 90 mg/night, but have gone up to 180 mg/night for a brief test.

It has helped bring my severe erythrodermic and pustular forms of psoriasis to about 96% of normal. Both of these rarer forms of psoriasis can be deadly and are extremely hard to control. Here is what they look like :

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

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

I looked like some of the worst images in those pictures and had about 95% coverage where it was impossible to see any significant area of clear skin. Oddly some bottles of melatonin say not to use it on an autoimmune disease like psoriasis, but I beg to differ.

I think the dose Dr. Neel is using in his Covid-19 patients is a reasonable general guide based on what I have read. He uses 1 mg per kilogram of body weight and some times higher if he feels it is a tougher case since he has seen two different strains in his practice. Although it varies by the person, when used in a combination as I previously posted, it is quite effective as a sleep aid for me and better than melatonin alone!

healthunlocked.com/parkinso...

Art

Art,

Excellent post. A lot of information that you don't learn from medical doctors. :(

Husband is on 3mg nightly and feels very groggy the next morning. I asked him several times to up his dose to 5mg but flatly refuses.

chartist
chartist in reply to Despe

Thank you, Despe,

In this post is a link to a study where they used a 100 mg melatonin intravenous injection and it produced no side effects or sedation in humans. So this may turn out to be one way to avoid the next day "melatonin hangover". This study is somewhat more important than the 100 mg a day study in athletes which I referenced in the post, because oral melatonin is poorly absorbed with some estimates as low as 3% absorption, whereas the 100 mg injection all goes directly to the blood and could potentially be over 6x stronger than the same oral dose, but more studies would be required to determine accurate serum levels.

I see a parallel or two between melatonin and B-1. One, is the difference in dosing required to achieve an effective dose from an injection as opposed to an effective dose from oral dosing. The other is that some people chose B1 based primarily on its established very good safety profile rather than the incomplete scientific evidence and if studies for HDM in PWP never materialize, there may be a future patient or two who may try HDM based on its established very good safety profile as opposed to incomplete scientific evidence. Obviously, melatonin has many more human and animal studies suggesting applicability to PWP than B1 does and we already know that 10 mg orally has shown benefit in PWP. Now to wait for an HDM study for PD.

Art

Despe
Despe in reply to chartist

Art,

Husband stopped B1 injections and that was a huge mistake. We had problems getting the prescription filled in my state although our internist was always willing to prescribe it and he did for a while, but then we had problems with finding someone to inject it. He had to go for an office visit just for the injection which was $50.00 copay weekly. He got tired of driving the distance and pay on top $25 copay. That is why he decided to go oral, but I sure can tell the difference between IM vs oral B1! He is thinking about starting IM again.

Waiting for an HDM study for PD will be long, IMO. If doctors can prescribe HDM, then I would encourage my husband to try it.

By the way, regarding Wriga's latest post, I found this supplement and ordered it--received it today.

BrocElite brocelite.com/

Any suggestions for Reverse Osmosis Water Filtration System under the sink? I have found a lot, just don't know what to order.

chartist
chartist in reply to Despe

Hi Despe,

Why did your husband stop his B1 injections in the first place? I thought he was at or very close to his optimal dose? If the difference is significant between oral and injections for him, it definitely seems like he should go back to the IM.

I am going to be adding safety information to the original post above. I have been working on that post for awhile and have not had a chance to delve into much else and gathering the safety data is taking time. I will say the information I have found so far is interesting!

Despe
Despe in reply to chartist

Art,

It became complicated with unavailability of IM B1. It's not available in my state for starters. Once we found it out of state (originally California and then Missouri), he had to drive about 20 min to have the injection at our Internist's office. On top, he had to pay $50 for an office visit. If he decides to go back to IM, we have to start looking for a state where it's available and they accept out of state prescriptions, don't know anymore!

Please let us know any new information you find about HDM.

chartist
chartist in reply to Despe

I will Despe!

Art

Going to experiment on myself - just a caretaker - with this sublingual - 10 mg Melatoin

amazon.com/gp/product/B07JM...

Going to try to beat the hang over feel of which my spouse complains.

That is a very tiny pill! It looks like a sublingual homeopathic pill. I have found that when I first start at a higher dose of melatonin than I have previously been using, it is helpful to try and avoid the melatonin hangover by staying very busy during the day. Let us know how it goes for you.

Art

Will do 🌺

I very much wish my spouse begin this therapy.

I was totally surprised when I first encountered its anti-oxidant benefits: previously only thought of it as a sleep aid.

Your constant reminder and documentation of its benefits has been a spur to action ✨🙏🏾✨

I look at how close science is to possibly testing melatonin at high dose for PD and I am happy about that, but waiting for the actual study is like watching paint dry, so I hope it comes soon because such a test offers hope for other neurodegenerative diseases also. The high dose has been used in other studies and melatonin has proven safe in other studies for longer time frames. Hopefully that study will happen soon!

Art

Shall start taking 100 mg Melatonin as from tonight.

Wow, did you read the whole post? That was not what I recommended. I suggested waiting for a high dose study similar to the 10 mg study to be safe about it. Melatonin has a good safety profile, but there aren't any high dose melatonin studies specifically for PD yet to prove the safety and efficacy of a high dose in PWP. The 10 mg study took 12 weeks to see benefit.

Art

rescuema
rescuema in reply to chartist

grrrr that's what I was afraid of. Art, I know you mean well and thanks for posting all the research tirelessly on the topic but this can backfire and you can't blame people for wanting to jump in after seeing all the potential positives while you promote the supplement as your favorite - that's been the big concern I have.

I'll be on the lookout for your safety disclosures that you've been working on to go with these posts.

chartist
chartist in reply to rescuema

I'm working on it, but searching takes time.

Art

Melatonine is potent but it may interfere with L/C meds. This is my experience with it

healthunlocked.com/parkinso...

Last but not least, in italy there is an anti-cancer therapy created by Dr. Luigi Di Bella many years ago that is rising from the oblio and becoming more and more popular and proven, that uses large amounts of melatonine, in a specific formula with adenosine & glicine to be highly bioavailable and active. The site lists an impressive number of studies on melatonine divided by: in vitro, in vivo (only animals), reviewed, Comments of the author, preclinical studies, in vivo (only on humans)

metododibella.org/it/Melato...

Is melatonin same as mannitol

rescuema
rescuema in reply to Masterka

No, it's completely different.

chartist
chartist in reply to Masterka

Melatonin is best known as an over the counter sleep aid at low and ultra low dosing.

Art

9087239779

Heart@bellatlantic.net

chartist
chartist in reply to anthonyiu

anthonyiu,

I would reply to your 2 posts, but I don't know what your posts mean?

Art

In the original post at the top of this thread, I linked to an abstract that used melatonin in children with Duchenne Muscular Dystrophy (DMD) at a rate of 70 mg per day for 9 months continuously to very good effect. I had never seen the whole study, but now that I have, their study showed a return of the redox status to that of normal controls as well as a reduction in markers of inflammation and reduced muscle damage from the disease process. Think about that. DMD is a genetic disease and they were still able to reverse the two main damaging effects of it, excess oxidative stress and inflammation and thus reduce the muscle damage more than any other study for DMD has done before or since!

What they did in that study using melatonin along side of standard care is achieve more than all of the science applied to DMD research has ever done. The 70 mg dose that the children received may be comparable to a 100mg dose in adults, but they have never attempted a similar study in any of the different forms of muscular dystrophy for children or adults.

Unfortunately, beyond their follow up abstract, there has been zero further testing of melatonin in any of the muscular dystrophies other than animal studies and that 70 mg study was done in 2010! Sad, but true. Normally when a study has success like that, it is assumed that further studies along that line will be done, but clearly that is a wrong assumption!

Art

I added human studies at the bottom of the original post that illustrate the safety of high dose melatonin for years of use and some I would describe as ultra high dose. This part is above the conclusion paragraph and is numbered as 1 ~ 10.

Art

If you do not have time to read this very lengthy post, I have added this short summary to quickly and easily understand what I am trying to say :

CONCLUSION :

I have tried as much as possible through the use of scientific studies to show the potential of melatonin in PD beyond what the 10 mg study showed in terms of safety and efficacy in PWP in 12 weeks. Beyond what you see above I also drew information and ideas from videos by Dr. Russell Reiter Ph.D., MD., D.Sc, who has spent the last 25 years of his life espousing the benefits of melatonin in human health and is a world renowned melatonin expert who believes in his research and work so much that he has taken a minimum of 100 mg of melatonin himself for the past 25 years every night. He participated in over 600 studies according to PubMed.

pubmed.ncbi.nlm.nih.gov/?te...

What is needed at this point is an actual 100 mg PWP study to prove or disprove the idea that HDM can positively impact PWP to a much greater extent than the 10 mg study in PWP earlier this year, via returning the redox system to equilibrium while reducing inflammation and protecting dopaminergic neurons from death as already shown in vitro and in animal studies.

In the DMD study in children who received 70 mg melatonin / day for 9 months, that study also showed a return of redox status to the control normal level while reducing inflammation markers and muscle damage, but it took the full 9 months of the study in order to achieve those results. Similarly, the ALS study which used 300 mg day for up to 2 years also showed a return to control value in terms of oxidative stress. The longest study I found so far is 5 years at 100 mg /day and this is longer than any drug trials by a very significant amount.

I am not recommending anyone try this idea and definitely not without a doctors support. I have just gathered what I thought were the relevant studies in order to show the potential that melatonin may offer PWP as a potential treatment and how it might do that, given the limited prospects currently available short of DBS or FUS.

Art

Thanks Art, will look forward to study.

You're welcome, Ernie!

I'm dying for that study to happen. One downside for some people who take melatonin is that they report feeling sleepy the next day. In that post in two studies it was reported that intravenous melatonin and melatonin in the available suppository form avoided the sleepy feeling completely, so apparently there is a work around for that sleepy issue!

Art

I’d be willing to volunteer for such a study if it became available.

I don't even know how they recruit for supplement studies, probably similar to drug studies, but much less elaborate, but that is considerate of you to offer. One good thing about melatonin is that they have never been able to establish an LD50 for melatonin. Dr. Reiter has never had an animal die from melatonin at any dose and I am not aware of any reports of people dying or being severely injured in any of the hundreds of studies I have read about melatonin. Some of the studies I link to for safety of HDM used doses way beyond 100 mg for years with no major side effects!

Art

Thank you for all the effort that has gone into this, Art. Many blessings

Thank you very much for saying so, M1tz1!

I would just like the members to know about this potential option as the science is so close now!

Art

Art,

Thanks a lot for this post. I am really been struggling with insomnia lately. I took fairly high dose, (35mg) I slept great( as good as Parkinson’s patients can sleep) I’ve had a much better day today.

rescuema
rescuema in reply to 38yroldmale

Are you taking any C/L?

chartist
chartist in reply to 38yroldmale

38yroldmale,

You're welcome!

I know you are a fan of upregulation of >>> BDNF and GDNF<<< as others on this forum are also. You will be happy to know that the most potent antioxidant and radical scavenger in the body, melatonin, does that too, at least in animals and possibly in humans, but I haven't looked for that yet, but I will!

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

pubmed.ncbi.nlm.nih.gov/291...

I like the word "normalized " in the second study!

Art

38yroldmale
38yroldmale in reply to chartist

Thanks!! This is what HU is all about!!!

I’m astounded at these intake levels (I thought 20 mg was high)! @bassofspades @marcanderson @rebtar

chartist
chartist in reply to AmyLindy

It seems like it, doesn't it? I think the reason why is we have become accustomed to thinking of melatonin as just a very low dose sleep aid.

The U.S. Institute of Medicine of the National Academy of Sciences has established Adequate Intake (AI) levels for vitamin D. The daily levels in International Units (IU) for everyone are as follows according to age: Under the age of 50: 200 IU. From 50 to 70 years-old: 400 IU., but how often do you now hear people say they are taking 5,000 iu or 10,000 iu or even more? I have even seen studies where they are using 35,000 iu of vitamin d per day in humans to good effect over 6 months!

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

I think as studies reveal more information about these bodily made molecules, the health benefits are better understood and new studies continue to push the envelope until unhealthy results are obtained and a more realistic dosing limit is established.

Art

I started taking Melatonin a couple months ago. started at 1 and then 5 mg, which is infinitesimal when you recognize that your blood stream only get 3% of that. I am currently using Natures Bounty 10 mg. from COSTCO (Canada) . I between I had problems getting the NB brand , a long 3hr drive one way , and the Co-Vid etc forced me to try a different brand at Shoppers Drug , Webber Naturals, they had a large variety of formulations, one with a slow release 5 mg and 5mg of fast release, so fast it was like a Sublingual tablet, and the other was a 10mg. of Melatonin and 150 mg Magnesium containing "Natural Chocolate" - No SUGAR .... with a strange taste.

I thought that I might b e able to not take one of my 200mg of Magnesium Bisglycinate, the PM dose. After the 60 tablets, 1 bottle, were gone I went back to the Natures Bounty and re-added the dropped Magnesium Bisglycinate , 1 Capsule AM and one PM, the absorbtion much better and the cramping much reduced over 24 hrs.

Another point , (I was not getting a consistent sleep on-set not in total time,) I re-read one of the TIMING of Medications posts here about a mention of interference of Synamet, proteins and other drugs and SUPPLEMENTS, it recommended a good period between... so for the sake of seeing if there is any interaction , I took # 1 starter Melatonin pill 60 min before lights out and #2, scant minutes before with the rest of my supplements..... After 3 nights I have slept from ~ 10:30 PM - 11PM to 5 AM , a consistent wake up time for a relief break, a Synamet dosage and 2 hrs. more light sleep.

Comparing the stiffness, when first rising , between the 2 varieties, Magnesium BisGlysinate is the winner for me.

Will go a full week now before adding another 10 mg. of Melatonin

chartist
chartist in reply to Sapeye2020

Sapeye,

Wow, thank you for the thorough feedback!

The magnesium glycinate /magnesium bisglycinate is fairly well absorbed, helps to gently relax muscles and is very good as a sleep aid in conjunction with melatonin and if you add in zinc, the three are synergistic together for sleep. I posted about it here :

healthunlocked.com/parkinso...

For the purpose of sleep, you will find that some melatonin has vitamin B6 in it which helps increase melatonin absorption a bit, up from the 3% absorption. So it is good at low dose for sleep in combination with the zinc, magnesium and melatonin combo, but not a good source for high dose melatonin as that will give you way too much B6 and that can definitely be a problem!

Are you having any problem with next day sleepiness? I sometimes have that problem when increasing my dose, but it has always been temporary as my body adjusts to the higher dose and I did not even notice that issue on my last increase, so I suspect my body is adjusting. Staying very busy has helped me work around that issue in the past and going out in direct sunlight for a short period of time is also helpful until I adjust to the new dose. I'm currently at 80~90 mg/night, but tonight I am going to bump it up to 100 and just try hanging there for a minute. I've been higher, but since I have written about 100 mg, I am going to try it out again for a minute.

Art

I have been checking on some of the different types of melatonin that are available and have made the following list of the different types which I thought might appeal to different users:

1. Capsules or pills of varying dosages up to 60 mg per capsule.

2. Intravenous injection and multiple dosing, but this form very likely delivers more melatonin per mg than oral route due to better absorption as melatonin orally is very poorly absorbed at just 3% according to one study, but this varies person to person.

One positive to this form is that it was shown in at least one study to avoid the next day sleepiness or "melatonin hangover".

3. Sublingual melatonin to be absorbed under the tongue. Purported to enter your system more quickly, but oral melatonin enters the system quickly also.

4. Timed release. Has been reported to be more effective to help some people sleep than instant release melatonin and is thought to mimic natural melatonin release by the pineal gland.

5. Delayed release.

6. Chewables for people who have swallowing issues or children.

7. Combination product with instant release and delayed release in one pill or capsule.

8. Suppository form which according to one study did not cause any next day drowsiness or tiredness. It comes in very high dose of 200 mg or 400 mg. I imagine the high doses are for rapidly advancing diseases like ALS or cancer. Potential for gastro upset is mentioned as a possible side effect of regular melatonin. I wonder if this form would avoid that issue?

9. Liquid form from a bottle that you apply under the tongue with an in bottle dropper.

Again, useful for people with swallowing issues.

10. A vape form that you inhale just like a pen vape and delivers melatonin in the vapor. I wonder if this form would be useful with Covid-19 since it goes directly to the lungs. I also wonder if it might target the brain more than other forms? It only delivers low dose, but if it is really well absorbed this way, perhaps it is okay and I also wonder if this method can avoid any gastro issues? If higher doses are eventually made, this may be a way to target the brain a little quicker than the oral route? On the other hand oral dosing still covers the whole body including the brain, less expensively.

11. Topical melatonin cream, probably not as helpful for sleep as there is a bit of delay with absorption as the melatonin traverses the dermal layers. It will take trial and error to determine the correct timing for each individual. On the other hand if you are using it for skin issues, it seems perfect.

I will check further and add any other types of melatonin I find to this list for easy lookup. If anyone else is aware of other types, please post them and I will add them to the list. Thank you!

Art

The following study linked to below, explains how excess oxidative stress is a main cause for the damage in the brain of PWP. Even the normal function of dopaminergic neurons causes significant oxidative stress as does the dysfunctional mitochondria seen in PWP.

Neuro inflammation also comes into play because it too can add to the total oxidative stress burden seen in PWP and this increased oxidative stress from inflammation, results in further neuroinflammation. Together this continues the vicious cycle of oxidative stress and neuroinflammation which just continues to cause damage and death to the dopaminergic neurons and mitochondria, resulting in continuous disease progression and continuous worsening of symptoms.

This article also discusses standard antioxidant supplements such as vitamin C, vitamin E and Coenzyme Q10 or Coq10 and how their actions are not sufficient enough to have much if any positive effect against the high oxidative stress levels seen in PWP. They do however show how Doxycycline(Doxy) can have some effect and I believe it has been reported on this forum by one or two people that doxycycline had a positive impact on their symptoms when they were taking a course of it for other health reasons and this tends to confirm the reason why, as doxycycline crosses the blood brain barrier and reduces some neuroinflammatory mediators which can reduce some of the oxidative stress.

This is what Doxy did in this study :

1. Suppressed MMP3 gene expression

2. Suppressed Nitric Oxide

3. Suppressed Inflammatory Cytokines

4. Provides protection of the nigral dopaminergic neurons

As expected, melatonin crosses the blood brain barrier and has these same effects and many more which also target different aspects of PD such as increased gene expression of many of the body's own natural antioxidants while also activating Nrf2 and suppressing KEAP1 and acting as a scavenger of multiple radicals, while protecting the mitochondria.

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

Art

Melatonin is a myeloperoxidase inhibitor. Currently there is a clinical trial running on Verdiperstat, a myeloperoxidase inhibitor, for multiple system atrophy.

pubmed.ncbi.nlm.nih.gov/182...

multiplesystematrophy.org/b...

chartist
chartist in reply to Rhyothemis

Thank you for that, Rhyothermis. Melatonin has so many positive benefits for human health and the drug companies have tried to create their versions of it, but all of them have fallen short of melatonin, by a huge margin. I hope they find something soon for MSA because that one can move really fast. It seems like many diseases that have excess oxidative stress and excess inflammation at their core, may benefit from melatonin. I remember that Dr. Costantini had said that HDT/B1 could help MSA if given early enough, but at a higher dose. At least that was his experience.

Ryothermis, you bring up another good reason to consider melatonin for PD as myeloperoxidase does damage in PD and of course melatonin works against it according to this study.

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

I'm beginning to wonder what melatonin doesn't work against in PD!

Art

Millbrook
Millbrook in reply to chartist

Hi Art. Thank you for all your hard work and for sharing. My husband finds the time release melatonin most beneficial compared to the immediate release. It enables him to get back to sleep after his many pee trips at night. He is now on 9 mg melatonin and 2 capsules of magtech. I have just ordered the coffee fruit that Getz recommended. After his recent maintenance BCG treatment for bladder cancer he has been waking up 7-10 times a night. It has set us back from the 2-3 times a night. I will slowly work his melatonin dose to 20 mg

chartist
chartist in reply to Millbrook

Miibrook,

You're the one who brought up Dr. Shallenberger, have you considered doing a phone consult with him about your husbands case? It will have to be round the clock dosing at much higher dosing though. Here is a phone listing : (775) 884-3990

Here is a study that may interest you :

pubmed.ncbi.nlm.nih.gov/303...

This one is even better!

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

Zinc and melatonin have synergy just as melatonin and curcumin do and curcumin and zinc have shown synergy together, so giving consideration to zinc seems reasonable. Zinc also helps with sleep.

pubmed.ncbi.nlm.nih.gov/236...

And of course keep your doctor and oncologist in the loop and Dr. Shallenberger if you and your husband are able to.

Art

Millbrook
Millbrook in reply to chartist

Thank you very much Art for the reference articles and contact. Do you happen to have his email contact? You are right about the round the clock dosing- just apprehensive about dose. It is overwhelming to have to deal with PD and bladder CA as well. I will try and email Dr Shallenburger with details and see what he suggest .

Thank you Art

chartist
chartist in reply to Millbrook

Here is their home page:

antiagingmedicine.com/staff...

Here is a simple contact form that you fill out to reach him:

antiagingmedicine.com/contact/

Good luck and keep us posted!

Art

chartist
chartist in reply to Millbrook

Hi Millbrook,

If you do decide to incorporate curcumin, it may be worth considering curcumin with piperine in it because although piperine is proven to very significantly enhance bioavailability of curcumin, which is poorly absorbed on its own, piperine itself has anticarcinogenic qualities!

Art

Millbrook
Millbrook in reply to chartist

Thank you Art. Yes he is on curcumin. I will look out for piperine in the formula

Rhyothemis
Rhyothemis in reply to chartist

Studies of animal models of MSA indicate that myeloperoxidase inhibition works well if given early but not much if given later. Unfortunately MSA is diagnosed late. Experts say they want early diagnosis, but doctors seem reluctant to make the diagnosis since it is so devastating - which seems counter-productive to me. Neurofilament light chain testing could be helpful - at least it might help those patients who are told their symptoms are 'all in their head' (if doctors are willing to order the test). Japanese researchers are developing a blood test based on phosphorylated alpha-syn in red blood cells.

~

OT - Avenanthramide-C prevents amyloid formation of bovine serum albumin

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

If it is a non-specific inhibitor of protein aggregation like anle138b, then it could be broadly effective. Avenanthramides are from oats. I eat a ton of oatmeal.

chartist
chartist in reply to Rhyothemis

MSA, yes, Dr. Costantini also said that early treatment saw better results in his MSA patients. The rate of progression being what it is in MSA, it is easy to see why early treatment is critical.

Again, this is definitely an area where melatonin has shown inhibitory activity of a/b and fibril formation.

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

Art

This meta analysis adds further confirmation to the idea that melatonin is definitely anti-oxidative stress :

pubmed.ncbi.nlm.nih.gov/330...

Art

In PD, Sirtuin1 (SIRT1) is known to have neuroprotective and antiinflammatory effects . The following study discusses this at length as it relates to diseases of neuroinflammation such as PD and AD :

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

This study above also suggests that SIRT1 can ameliorate depression and anxiety associated with neuroinflammation.

In the study link below, it is shown that melatonin promotes SIRT1 as well as Nrf2 and this combination ameliorates much of the damaging effects of neuroinflammation. So this shows another piece or two of the puzzle that is PD. Albert has discussed the Nrf2/KEAP1/ARE pathway at length and this study tends to mirror all that he has described of this pathway which promotes the antioxidant system in the body leading to increased total antioxidant capacity (TAC).

frontiersin.org/articles/10...

This study further illustrates some of the protective actions of melatonin as regards neuroinflammation. Promoting SIRT1 in the brain, as melatonin does, is also shown to be beneficial in controlling neuroinflammation as well as the subsequent depression and anxiety. Melatonin also protects microglial cells against "pyroptotic cell death" and this is another important aspect of the neural protection that melatonin affords!

Art

The following article discusses peripheral neuropathy and its increased incidence in PWP.

parkinsonsdisease.net/answe...

The following study discusses how chronic sleep issues may exacerbate the nerve pain(NP) and goes on to discuss how melatonin may help ameliorate NP :

sciencedirect.com/science/a...

This final study abstract goes into further discussion on how melatonin may regenerate peripheral nerve injury. The full study is behind a paywall.

pubmed.ncbi.nlm.nih.gov/220...

Altogether, this data shows us another piece of the PD puzzle and another potential benefit of melatonin as it relates to PWP.

Art

Here is another human study in children who were given 70 mg/day of melatonin for 6 months to try and treat Charcot-Marie-Tooth neuropathy (CMT). The results showed that melatonin returned hyper elevated oxidative stress levels and inflammatory levels to normal control values. These results are very similar to an older study using the same melatonin dosage in children with Duchenne muscular dystrophy (DMD) with the same outcome of achieving redox equilibrium and return of elevated inflammation markers to that of healthy controls. In that study it took 9 months for the children to reach healthy control levels, but DMD is a serious disease that attacks the muscles and results in death between the age of 20 and 30 years of age on average.

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

So once again it is confirmed in human studies that melatonin can return elevated oxidative stress levels and elevated inflammatory levels to healthy control levels.

Art

I have been reading about piperine and it turns out it has many potential benefits in PD and it has some similarities with melatonin in that it significantly reduces oxidative stress, neuroinflammation, dopaminergic neuron death and apoptosis as well as also being an activator of the Nrf2/KEAP1 pathway. Piperine is typically used to increase bioavailability of some supplements such as curcumin and resveratrol, but it also has many other effects of its own such as having anticarcinogenic effects as does melatonin.

For now though, melatonin appears to affect many very important aspects of PD in a very positive manner and on that note, I am continuing my melatonin test of 104/mg night.

With a little more reading, it appears that piperine has no synergy with melatonin, so I won't use the two together, but will likely take both, just not at the sametime.

Art

I've been using black pepper essential oil for the piperine benefits, having added it to cedarwood for the sesquiterpenes, glad to hear it may work well with melatonin, which I've been taking low dose for awhile now for sleep and immune system. I have been able to get my CRP levels down quite a bit lately thanks to scrutinizing my diet. I am going to try slowly upping the melatonin to see if that helps as well for the inflammation. I would really like to get it down to an acceptable level, sooner the better, since I know it's not good for the brain. I see that as a long term benefit, although I know it can be instrumental in reducing body pain as well, in the here and now. Thanks for all your info on this.

chartist
chartist in reply to Rosenmu

Hi Rosenmu,

Yes, even a low dose of just 5mg of melatonin will lower CRP levels, IL-6 and MDA as illustrated here :

blog.designsforhealth.com/n...

In the 10 mg study in PWP earlier this year, melatonin @ 10 mg also lowered TNF-alpha, NF Kappa b and IL-1b plus improved certain aspects of PD.

healthunlocked.com/parkinso...

Now it would be nice to see a 100 mg study in PWP! I am currently testing 104 mg in myself.

In multiple high dose studies, melatonin was able to return the redox status and the elevated inflammatory levels to healthy control levels and that would be highly desirable in PWP, but a 100 mg PWP study has not occured yet !

Art

Wow that is an awesome amount of data you have gathered on melatonin. Thanks for warning me about the other stuff. Probably just need to get the suppositories. It really looks like it is beyond beneficial!

Millbrook
Millbrook in reply to pmmargo

Art is awesome👍🏻

The article linked to below discusses many of the protective effects of melatonin in ameliorating the effects of free radicals in PD and gives limited comparisons to other molecules that are well established as being useful in PD such as curcumin, EGCG, Trolox, alpha lipoic acid, acetyl l carnitine, nicotine, resveratrol, creatine, nicotinamide, etc.

This is probably one of the most detailed articles I have read on how melatonin protects dopaminergic neurons and cellular mitochondria from death, oxidative stress and how it works toward mitochondrial homeostasis through its multiple antioxidant effects as well as direct and indirect radical scavenging.

The article further describes how excess oxidative stress is a major component of the disease process and how melatonin effectively works against this damaging process. This has been confirmed in other human studies for other diseases where melatonin was shown to return the redox status to redox equilibrium over a period of months.

The article is long, so if you don't have time to read the full article, the conclusion/summary near the bottom of the article is definitely a worthwhile and quick read.

intechopen.com/books/a-syno...

Overall, this study, although being done in 2013, further highlights the need for a high dose melatonin(HDM) study specifically in PwP. The 10 mg study showed significant benefit in PwP, but an HDM study is more likely to expose the maximum benefit that melatonin has to offer PwP.

On that note, I am still at 104 mg melatonin per night.

Art

alexask
alexask in reply to chartist

Thanks for this. Melatonin appears to be so beneficial for many things. Reflux, ameliorates low iron levels, slows macular degeneration...

chartist
chartist in reply to alexask

I've never seen a molecule that can do everything that melatonin can do. It is protective of the organs of the body, the most potent antioxidant in the body, very good safety profile, can be useful against multiple diseases including Covid-19, PD and AD. Being a sirt1 activator, it is thought to have life extending effects as well as being anticarcinogenic. It activates Nrf2 and can improve hair growth. It significantly reduces inflammation. It can help to quell the cytokine storm caused from multiple health issues. It reduces ldl cholesterol. It can help restore circadian rhythms. It protects mitochondria and dopaminergic neurons. It can help with RBD. It helps some people sleep and the list just goes on and on!

Art

I just got done reading this study that shows that melatonin levels are associated with hypothalamic gray matter volume loss and disease severity in PwP.

cyberleninka.org/article/n/...

There is an inverse correlation between melatonin level and disease severity. Correlation does not prove causation, but the 10 mg melatonin RCT in PwP this year tends to prove cause and effect.

I'm still at 104 mg night of melatonin.

Art

In the study abstract below, the neural protective effects of melatonin are discussed. Here is a quote from the brief abstract :

>>> ' melatonin administration showed a total neuroprotective effect in both regions of the substantia nigra. In conclusion, the data here show that melatonin is neuroprotective against mutant alpha-synuclein-induced injury in the substantia nigra. ' <<<

It seems like when I look at problems occurring in PD, melatonin almost always has an ameliorating effect against those problems. Here is a link to the study abstract:

pubmed.ncbi.nlm.nih.gov/234...

And a related study abstract :

pubmed.ncbi.nlm.nih.gov/221...

Art

Pleased to report that five days has passed on Melatonin therapy. Dosage is set at 10mg, sublingual administration.

So far all is well: better sleep and no hangover. This for the PWP and the support.

Product: Frunutta Melatonin 10 mg -Sublingual

amazon.com/gp/product/B07JM...

Based on available studies, some studies suggest that PwP men are at elevated risk of prostate cancer (PC) while other studies say that PwP men are at the same risk as the general population while other studies suggest a decreased incidence of PC in PwP men. I guess this means that the science is not yet positively conclusive.

In any case, if it turns out there is increased risk of PC in PwP or not, this new study abstract suggests that melatonin can increase survival when used alongside of standard of care and since the chance of getting PC increases with age without a doubt, the following abstract is relevant:

pubmed.ncbi.nlm.nih.gov/331...

Yes, just another potential benefit of melatonin!

Art

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