In case you missed part 1, here is a link to it :
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.
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 :
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.
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!
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.
This next link shows how RNS and ROS are also at elevated levels in PWP and the damage they do.
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.
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.
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.
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.
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.
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.
The following study is 16 years old, but it was already showing the huge potential of melatonin in human health :
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 :
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 :
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!
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.
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).
6. In this human study of cancer patients, a dose of 100 mg night was given for up to 5 years with positive effects.
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).
8. In the following study, melatonin was given to children at a total of 70 mg day for 9 months :
Here is a follow up on the first abstract :
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.<<<
10. Here is a link to side effects of melatonin :
Here are the side effects for Sinemet from the same source :
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.
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.