A Meta Analysis Of RCT's Showing Melatonin as Beneficial For People With PD

[chartist]

This new meta analysis (10/10/2023) of randomized controlled trials (RCT's) utilizing melatonin in people with PD suggests that melatonin is useful for PD at 10 mg/day and even more so at 50 mg/day or more, and usage length of a year or more is additive to the beneficial effects of melatonin in PD. Immediate release melatonin was shown to be superior to prolonged release melatonin in this study. It is also suggested that earlier application of melatonin in the disease may be even more beneficial than application in advanced disease states :

frontiersin.org/articles/10...

Some relevant quotes from the meta analysis of RCTs :

' These findings reinforce the rationale of our study, suggesting that melatonin, when used in specific treatment regimens, may alleviate symptom severity and reduce sleep disturbances in Parkinson’s disease. '

' Analysis of UPDRS total scores indicate that after at least 12 weeks of treatment, melatonin significantly impacts Parkinson’s disease progression when doses of ≥10 mg/day are used. This trend of enhanced melatonin efficacy with higher doses at longer treatment durations has been consistently reported in trails comparing 50 mg/day melatonin with 0.25 mg (61, 62) and 50 mg/day melatonin with 5 mg (63) for various outcomes. Furthermore, trials included in our analysis also reported significant results with 50 mg/day melatonin for 1 year (56) and non-significant results with 10 mg/day or 4 mg/day melatonin for 12 weeks (57, 58). These findings, supported further by melatonin’s ability to exhibit virtually no acute or chronic toxicity (64, 65), strongly advocate its long-term utilization at higher doses as a safe choice. '

' Analysis of UPDRS total scores in groups receiving melatonin ≥10 mg/day revealed significant results with no heterogeneity (I2 = 0%). However, including studies with <10 mg doses increased heterogeneity substantially (I2 = 63%). Potential contributors may include dose-dependent and formulation-dependent pharmacokinetics of melatonin, as low dose studies used prolonged release formulations and high dose studies used immediate release formulations (44). Moreover, variations in treatment duration could also play a role, as longer durations with higher doses consistently demonstrated enhanced efficacy in previous studies (56–58). '

' Apart from dosage and duration, a crucial difference among these trails was the timing of melatonin intervention. In the significant study (56), melatonin was initiated in newly diagnosed patients immediately after observing a satisfactory response to anti-Parkinson’s therapy. In contrast, patients in non-significant studies (57, 58) had mean disease duration of 5.7 ± 1.9 and 5.0 ± 3.9 years respectively, indicating significant pre-existing damage at the time of melatonin introduction. This selection of patients with longer disease duration and introduction of melatonin at a later stage reveal an inherent flaw, as starting melatonin before neuronal loss is crucial for its free radical scavenging and antioxidant properties (18, 19, 31, 33, 42) to effectively prevent degeneration and reduce symptom severity in Parkinson’s disease. In addition, a sub-analysis focusing on only immediate-release formulations, also yielded significant results, however, use of prolonged-release formulation in only one study (58) hinders appropriate comparisons. '

' Hence, melatonin can indirectly lead to an improvement in motor symptoms through sleep improvement. This effect appears to be unrelated to its antioxidant properties, indicating a multifaceted potential for melatonin in Parkinson’s disease treatment. '

' As far as we know, a systematic categorization of melatonin into dose groups for motor symptoms and sleep disturbances in Parkinson’s disease has not been conducted before, and is a defining feature of this meta-analysis. Furthermore, it strongly recommends the use of long-term, high-dose immediate-release melatonin in future investigations and emphasizes the significance of selecting patients with shorter disease duration and initiating melatonin early to fully explore its true therapeutic potential. '

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My favorite quote from this meta analysis :

' These findings, supported further by melatonin’s ability to exhibit virtually no acute or chronic toxicity (64, 65), strongly advocate its long-term utilization at higher doses as a safe choice. '

I'm glad to see studies confirming the potential of melatonin in PwP whereas earlier studies only hinted at such possibilities based on the known healthful methods of action in humans.

Art

[MarionP]

I like it! Could be helpful. Certainly is intriguing. Definitely enough to convince me to look into this further. If you get the nightmares or the thrashing of the sleep deprivation or is it difficulty getting to sleep and staying asleep, well those of us who do certainly would want to take notice.

It's not quite as encouraging if you're someone who's had PD diagnosis for a time though. Clearly the message was it's much better to start while you still have some dopamine producing cells left. And it is very helpful to move us through some of the dosing dilemmas that have kept us conservatives down in the very low dose range and confused by the complication of differing doses and how long the dose last. This helps narrow down some of that confusion quite a bit if we could take it at face value.

For sure the safety factor or the safety question is a very big one and that is really very encouraging, very much agree with you on that, and actually feel reassured enough to start exploring those higher doses and shorter durations, up to now I've been afraid to go past 10 mg no matter what the preparation.

I'd say it's a pretty good find, usually I find meta-analyses pretty much useless!

[chartist in reply to MarionP]

Marion,

Well melatonin is considered a frontline treatment for RBD and that is very common in PD at 33% - 46% as discussed here, so that is helpful.

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

It generally seems that going after it early on is often more beneficial.

As far as dosing, they confirm what other studies have shown through the years that more is usually more effective. Comparing the 10 mg study to the 50 mg studies showed that also. I'm still at 132 mg/day and have been doing high dose melatonin for over a decade. There was an ALS study that used 300 mg suppository dosing for up to two years and the suppository route is much more bioavailable than the oral route where melatonin only offers approximately 3% bioavailability.

Regarding meta analyses, supplement studies often do not fare well in these, partly due to the increased criteria requirements. So this seems to be a very good outcome.

Add in the cardiovascular disease and osteoporosis preventative effects, which PwP are at increased risk for both, imo, melatonin has a lot of appeal for PwP and everyone else!

healthunlocked.com/cure-par...

healthunlocked.com/cure-par...

There are also the anticancer effects afforded by melatonin.

Art

[Esperanto]

Very interesting Art! In particular, the short-term effects seem mainly linked to better sleep quality. Some variables can in that case also have an impact on the results. The timing of melatonin intake, seasonal changes, and exposure to artificial and natural light throughout the day are all important factors that can influence the effectiveness of melatonin.

If these variables are not taken into account in the studies, and it looks like that, it can be challenging to assess their specific impact on the results. The outcomes may vary depending on when melatonin is taken, the amount of light exposure during the day, and potential seasonal variations in light levels.

Given the personal results with greatly improved sleep from a, psychic or non- psychic, consequence of low doses of melatonin supplementation combined with lots of sunlight this summer, could future research that accounts for these factors provide a better understanding of how they affect the effectiveness of melatonin in treating PD.

[chartist in reply to Esperanto]

Esperanto,

Melatonin is generally taken in the evening to coincide with the release of melatonin from the pineal gland and also to help keep the circadian rhythm intact and in time. Exceptions would be acute illness such as Covid-19, cancer, stroke or heart attack etc., where the importance shifts from maintaining the circadian rhythm to rapidly getting involved with the disease process in a very timely manner (less than 3 hours in the cases of stroke or heart attack) to significantly improve the health outcome. This has shown the most meaningful and statistically significant results in heart attack and stroke study patients.

Melatonin has a very good established safety profile at high dosing levels. In the two 50 mg/day melatonin studies in PwP, there were no side effects noted nor any issues with light exposure mentioned.

The following study used 300 mg/day of melatonin given as a suppository, which is more bioavailable than the oral route, for up to 2 years in ALS patients and this returned their oxidative stress levels to healthy control levels.

onlinelibrary.wiley.com/doi...

Art

[Esperanto in reply to chartist]

What I tried to explain that these studies do not provide specific information about the timing of melatonin medication intake, nor do they consider the concept of Zeitgebers and DLMO.

Zeitgebers, such as external signals like light, temperature, food and social activities, play a crucial role in synchronizing our circadian rhythm, including the natural production of melatonin. Also DLMO, the time at which melatonin production begins in response to dim light in the evening, is an important marker for our individual circadian rhythm.

It is understandable that the timing of melatonin medication intake and its interaction with Zeitgebers and DLMO can influence its effectiveness. Taking melatonin at the right time, in accordance with our individual DLMO, also taking into account, activities, seasons and place of residence (amount of sunlight) may have a more positive effect on sleep and reduce PD symptoms.

[MarionP]

So suppositories are handily available to purchase, OTC and etc?

[chartist in reply to MarionP]

Suppositories are available over the counter but they are cost prohibitive for daily use and they are very high dose such as used in the ALS study which were 300 mg each. Here is a link to one type that is 400 mg :

amazon.com/Zetpil-Melatonin...

It makes me wonder who is using this high dose suppository and for what? Even Dr. Shallenberger reports using only 360 mg/day in his stage 4 cancer patients. In the ALS study, apparently suppositories avoided the next day drowsiness that some users report experiencing.

Art

[rhyspeace12]

My husband with Parkinsons was sun downing. He left the house in the middle of the night and I found him face down in the dirt with hypothermia. He went to the emergency room in an ambulance and came home later that day. I started giving him 10 mg of melatonin at around 4pm and another 10 mg dose around 9pm. He never sun downed again except when my son forgot to give him his dose at 4pm and gave it at 6 pm.

He lived to be 80 years old. He already had REM sleep disorder at the age of 20. No one knew then that is an early symptom of Parkinson's.

[Nuthatcher]

Glad I am and have been taking 20mgs every night.

[chartist in reply to Nuthatcher]

I'm glad you have too!

Art

[nednedned]

Just to report something related to this topic. I tried taking 10mg of melatonin and felt really hungover. This has been going on for a year where I would start and stop bcs of the side effects.

Yesterday I switched from immediate release to prolonged release and the hungover side effect was gone.

[Rufous2]

Art, how do you feel about sublingual melatonin? Do you think it improves bioavailability?

[chartist in reply to Rufous2]

I don't use a specifically designed sublingual tablet, but I do use melt in your mouth tablets. I chew them up and swish them around in my mouth for about 5 minutes and then swallow it at bedtime to try and take advantage of the benefits that melatonin has shown in studies to offer to the oral cavity, gums and possibly teeth as well as to bathe my esophagus with it right at bedtime as an esophageal cancer preventative. I am not positive that it is absorbed sublingually this way, but I think it is, based on reports from friends who use high dose melatonin in a similar way. Given that the absorption of oral melatonin is estimated to be only 3%, I think that any extra absorption by using the method I described is an extra benefit.

Currently I am testing topically applied melatonin as a spinal protectant and skin anti inflammatory agent which melatonin has shown those abilities in studies.

Art

[Esperanto in reply to chartist]

“Currently I am testing topically applied melatonin as a spinal protectant and skin anti inflammatory agent which melatonin has shown those abilities in studies” Can you tell a little more about that Art?

[chartist in reply to Esperanto]

A friend of mine told me that he has constant neck tension, stiffness, pain and decreased range of motion in his neck and he was wondering if I had any suggestions for him to try. Another friend has nagging lower back pain that bothers him pretty consistently with somedays being worse than others and he also wanted to know if I could suggest anything for him. A third friend told me that she has a degenerative muscle disease and has both neck and back pain and was wondering if I could offer any suggestions of things to try. All three friends say that the pain is also having a negative impact on their posture, sometimes making it very difficult and painful to stand up straight or it may take them awhile to stand up straight after getting up from a seated position.

They have only just started testing it and if it helps them enough, I might write about it on this forum since those type of pains seem fairly common in PD. I don't want to write about or suggest it until they have at least a month of testing each. Initially it has shown some benefit for all three, but more time is needed to see if further improvement is possible and whether it continues to help or not.

Interestingly, all three take higher dose melatonin orally and in all three, the oral melatonin offered no benefit for their spine related issues and I suspect that is because topical application allows for significantly higher local tissue concentration levels at the areas where they apply it. I don't think taking even 500 mg orally could offer such high local tissue levels. I have used it topically myself and that is why I suggested it as a possibility for my friends. I have written about some of the beneficial effects of melatonin for the spine, but I have not posted it on this forum because it isn't directly related to PD and previously I had a post pulled about Covid-19 on this forum because it wasn't about PD, so I try to stay as PD specific as possible.

Art

[Esperanto in reply to chartist]

There are few themes that are not directly or indirectly related to PD. So don't limit yourself too much!

With similar complaints, who doesn't have them, I often successfully use ibuprofen gel instead of pills. Perhaps this will work locally with a high dose of melatonin with your friends as well. Keep us posted.

[Ob6842]

An 80 year old pickelball friend swears by a spray called EASE for his knee arthritis. It’s a topical Magnesium spray that eases pain, It might be worth a try in many areas of the body. I think it’s about $20 from Amazon,

[chartist in reply to Ob6842]

Thank you for the suggestion for Ease. All three of my friends were already using magnesium chloride spray (mag oil), which is what is in Ease Spray. They were also using Stopain roll on, but it required frequent applications of both in order to maintain the pain relief. With continued use, the melatonin topical is allowing less frequent application and a lower pain level at reapplication time. They have just started testing, so it is too early to know if this effect will last or improve further.

Art

[Stillstandingstill]

I'm going to talk to my GP about this. NHS guidance for melatonin use is far more cautious and it's not available over the counter. Worth a try though as sleep has a huge effect on my symptoms. Presumably if it improves deep sleep there is potential for 'brain washing' for want of a better phrase to describe the glymphatic circulation.

[chartist in reply to Stillstandingstill]

If your GP won't prescribe it, there is always earlier morning and later afternoon sun exposure and red light therapy to consider as alternate ways to increase your melatonin level.

Art

[chartist]

Another study suggesting the beneficial effects of melatonin in neurodegenerative diseases such as PD and AD via reduction of endoplasmic reticulum stress :

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

Here is a relevant quote from the link :

' Although there are many papers on the prevention or suppression of diseases by melatonin, there are very few papers about the effects of melatonin on ER stress in neurons and neurodegenerative diseases. This paper aims to summarize and present the effects of melatonin reported so far, focusing on its effects on neurons and neurodegenerative diseases related to ER stress. Studies have shown that the primary target molecule of ER stress for melatonin is CHOP, and PERK and GRP78/BiP are the secondary target molecules. Therefore, melatonin is crucial in protecting neurons and treating neurodegeneration against ER stress. '

Art